i
COMPLEMENTARY AND ALTERNATIVE MEDICINE (CAM)
IN CANCER
An Evidence-Based Systematic Review of the Efficacy and Safety of CAMs, and the Perceived vs Real Benefits of CAM Use for the Quality of Life and Psychological Adjustment of Cancer Patients
Undergoing Cytotoxic Treatment
by
Carlo Pirri, B.Sc B.Psych M.Psych (Clin) Equivalent
This thesis is presented for the degree of
Doctor of Philosophy
of
Murdoch University
2014
ii
I declare that this thesis is my own account of my research and contains as its
main content work which has not previously been submitted for a degree at any
tertiary institution.
……………………………………..
Carlo Pirri
iii
COMPLEMENTARY AND ALTERNATIVE MEDICINE (CAM) IN CANCER An Evidence-Based Systematic Review of the Efficacy and Safety of CAMs, and the Perceived vs Real Benefits of CAM Use for the Quality of Life and Psychological Adjustment of Cancer Patients Undergoing Cytotoxic Treatment
Carlo Pirri
School of Psychology and Exercise Science, Murdoch University
PERTH, WESTERN AUSTRALIA
ABSTRACT Complementary and alternative medicine (CAM) continues to evoke fierce debate and
divergent views within the medical community. Nevertheless, it remains an attractive and
commonly used treatment option for many cancer patients regardless of whether their
doctors like it or believe in it. Complementary medicine is used by 14-65% of Australian
adult cancer patients (up to 73% in Europe and 91% in the US), and alternative medicine by
8-14%. It is therefore important that clinicians have an awareness of the type of patients
that are likely to use CAM, as well as a good understanding of the levels of evidence
available for the efficacy and safety of specific complementary and alternative therapies.
Two large studies were performed to this end.
Study 1 examined the incidence and type of complementary therapy (CT) use,
perceived benefits of use, and the relationship between demographic, clinical or quality of
life/psychological factors and use in 200 Australian cancer patients across conventional
chemotherapy-based treatment. Overall, 30% of patients reported CT use. CT users were
predominantly younger, tertiary educated, possessed comorbid conditions and underwent
iv
lengthy treatment (.004 ≥ p ≤ .023). Patients who underwent lengthy treatment (> 6
months) were 3 times more likely to use complementary therapies. Of all CT users, 64%
perceived benefit and primarily cited enhanced physical and emotional well-being. CT
users, however, did not score significantly better than non-users on any measure of quality
of life, physical health or psychological adjustment. CT users generally reported greater
psychological distress than non-users across treatment, particularly at pretreatment
(baseline). However, with ongoing/new CT use these patients significantly reduced their
distress levels to that of non-users by 8 weeks on-treatment (p = .042).
Study 2 entailed a systematic review of the benefits and health risks of popular
CAMs used by cancer patients. Specifically, the efficacy and safety of over 50 individual
CAMs were examined across 363 publications, including over 300 meta-
analytic/systematic reviews. Evidence indicated that some CTs are beneficial in reducing
disease/treatment symptoms and improving quality of life and psychological adjustment
(e.g. relaxation), and in years to come may be integrated into everyday clinical practice.
Evidence of potential harm, however, also exists. Nutritional supplements, herbal
preparations and other natural therapies may pose direct safety risks because of their
potential adverse effects or interactions with conventional anticancer treatments and other
medications. Some should not be used by cancer patients under any circumstances
irrespective of benefit (e.g. St. John’s wort), while others are beneficial and safe under
medical supervision (e.g. valerian). Alternative therapies promoted as “cures” in place of
conventional treatments (e.g. laetrile/amygdalin) potentially cause patients the most harm.
Collectively, the studies demonstrated that CTs, at the very least, may enhance the
psychological well-being of cancer patients during the early stages of conventional medical
treatment. Indeed, CT use by cancer patients may be a clinical marker for psychological
v
distress, and should trigger clinicians to enquire about physical symptoms and concomitant
anxiety and depression. Research, however, indicates that 20-77% of patients do not
disclose CAM use to their physicians. Moreover, discussions about CAM are uncommon
and are most likely to be initiated by patients rather than physicians, many of whom believe
that they cannot effectively communicate with patients about CAM use partly due to having
insufficient knowledge about the efficacy and safety of specific CAMs. Patients’
perceptions that CAMs are more “natural” and safer than conventional treatments are
problematic. Indeed, they may pose direct safety risks. It is therefore imperative that those
involved in the medical care of cancer patients are equipped with the skills and knowledge
to help patients appropriately evaluate CAMs, in order to receive benefit while avoiding
harm. Additionally, clinicians are strongly encouraged to routinely ask patients about CAM
use. Offering evidence-based complementary therapies (or at least safe forms of them)
alongside conventional treatments in cancer services can influence patients’ decisions to
continue with mainstream care, and help avoid any potential harm that may occur with
autonomous CAM use.
Keywords: cancer, complementary and alternative medicine / therapies, quality of
life, psychological distress, anxiety, depression, psycho-oncology, cancer treatment,
cytotoxic, chemotherapy, radiotherapy, surgery, efficacy, safety, adverse events / effects,
drug interactions, systematic review
vi
ACKNOWLEDGEMENTS
There have been many people who have been significant in my long PhD journey – far too
many to list individually – but know this, I am grateful for your involvement in my journey
and I thank each and every one of you.
First and foremost, I would like to acknowledge with the deepest respect the five gentlemen
that served as my research supervisors. They remained firm in their belief and faith in my
professional and personal attributes as both a researcher and an individual of substance to
“bring it all home” – when many others did not – and see this long PhD journey of mine to
fruition. I simply cannot thank you enough, but I will try now nevertheless. To Dr James
Trotter and Dr Evan Bayliss, the consultant medical oncologists at Royal Perth Hospital, I
thank you for your wisdom and bedside manner, for trusting me with your cancer patients
and for taking a chance at the outset on a young, inexperienced health professional,
unknown to you and from outside the medical fraternity. To Paul Katris at WACOG, I
thank you for your consistent encouragement and support, not only in helping me initially
cold-canvas the RPH medical oncologists to undertake such an ambitious research project,
but also for the professional, moral and financial support throughout that have
immeasurably enhanced my professional and educational learning in the cancer area. To
my academic supervisors Dr Bob Bennett and Prof. Peter Drummond, I thank you for
believing and trusting that I knew what I was doing whilst at the helm in all of this, as well
as your humour and collegiality and for being the yin and yang that I needed when
providing feedback on the various manuscripts that I prepared for publication.
I would like to express my deepest gratitude to the cancer patients and staff at Medical
Oncology, Royal Perth Hospital, who made my research possible. Thank you to all the
patients who selflessly took the time to complete questionnaires and share the most intimate
details of their lives, in the full knowledge that it would not directly benefit them, and
during what had to be one of the most difficult and uncertain periods of their existence.
You have touched my life immeasurably and I will never forget how much I learned from
you all.
vii
I would also like to acknowledge my colleagues and friends at Murdoch University, Royal
Perth Hospital, WA Clinical Oncology Group, Cancer Council WA, the Clinical Oncology
Society of Australia and Roche Australia, for assisting with the research and providing
research/conference funding. I would especially like to thank Lorna Rogers (ex-Roche),
Paul Katris (WACOG), Terry Slevin (CCWA), Lawrie Wright (ex-COSA) and Marie
Malica (COSA) for their ongoing financial support of the research itself and related
conference travel over the years. To Prof. Ian Olver (Cancer Council Australia) and Dr
Monica Robotin (Cancer Council NSW), thank you dearly for your invitation to contribute
to the CAM in cancer publications in 2011/12 and for your great patience, editorial
assistance and mentoring in that time. To the anonymous and third-party reviewers of the
publications included in this thesis, thank you for your thoughtful, invaluable critiques and
insights. To Prof. Phyllis Butow, Prof. Madeleine King, Dr Angela Ebert, Francis Lee, Man
Trac, Jenny Edmonds, Karen Olkowski, Prof. Laurence Hartley and A/Prof. David Leach,
thank you for your collegiality and kindness.
To my Murdoch office mates, old and new (Doug, Gaynor, Renee, Steve, Susanne, Gerald,
Don, Mei’en, Cath, Eva, Rachael, Lisa, Marie, Anita, Melanie, Alice; Sarah, Corey, Stuart,
Rob, Jacquie, Cathy, Olga, Matthew, Nick, Aries), thank you for the camaraderie,
friendship and fun memories. Special mentions also go to Khristin Highet (yes, we finally
made it!), Caroline Wallis, Beth Gouldthorp, Marco Sturniolo, Lorenz Mattaboni, Bernie
O’Hara, George Rebelos, Tony Loretto (RIP) and all my old UWA friends (Dan, Elysia,
Jason, Debs, Pete, Michelle, Geoff, Carrie, Jez, Evelina) for their unique brand of moral
support, humour and friendship that kept me sane in the final, gruelling stages of my PhD.
Finally, I would like to thank my family, particularly my Mum, Dad (RIP) and godmother
Maria for always supporting and believing in my educational and career pursuits
irrespective of how ambitious they have been. To my nephews (Anthony, Andre, Stefan)
and ex-stepson Brendan, thank you for being largely oblivious to the fact that I was
working on a PhD thesis, and for allowing me to share your wide-eyed innocent
perceptions of life, devoid of the scripts that adults all too frequently become accustomed
to, while growing up.
viii
On a parting note, I would like to share with you a collection of quotations that inspired,
motivated and otherwise cajoled me towards the finishing line of my long PhD journey:
‘Do not judge me by my successes, judge me by how many times I fell down and got back
up again.’
‘The greatest glory in living lies not in never falling, but in rising every time we fall.’
‘I learnt that courage was not the absence of fear, but the triumph over it. The brave man is
not he who does not feel afraid, but he who conquers that fear.’
‘It always seems impossible until it’s done.’
— Nelson Mandela, from “Nelson Mandela by Himself” (published 2010) and his
autobiography “Long Walk to Freedom” (published 1994)
‘A certain degree of neurosis is of inestimable value as a drive, especially to a
psychologist.’
— Sigmund Freud, from “Fragments of an Analysis with Freud” (published 1935)
‘The world ain't all sunshine and rainbows. It is a very mean and nasty place and I don't
care how tough you are, it will beat you to your knees and keep you there permanently if
you let it. You, me or nobody is going to hit as hard as life. But it ain't about how hard you
hit, it is about how hard you can get hit and keep moving forward. How much you can take
and keep moving forward. That’s how winning is done!’
— Rocky Balboa, from “Rocky Balboa” (film, 2006), written by Sylvester Stallone
‘No. Try not. Do....or do not. There is no try.’
— Yoda, from “Star Wars-The Empire Strikes Back” (film, 1980), written by George Lucas
‘If you can’t explain it simply, you don’t understand it well enough.’
— Albert Einstein / Anonymous, source unknown
‘As to diseases, make a habit of two things — to help, or at least to do no harm.’
— Hippocrates, from “Epidemics” (Book I, Section XI, written circa 400 B.C.)
ix
LIST OF ORIGINAL PUBLICATIONS The present thesis comprises the following peer-reviewed publications:
1. Pirri, C., Katris P., Trotter J., Bayliss E., Bennett, R., & Drummond, P (2008). Use of complementary and alternative therapies by Western Australian cancer patients. Asia-Pacific Journal of Clinical Oncology, 4(3), 161-169.
2. Pirri, C. (2011). Integrating complementary and conventional medicine. Cancer Forum,
35(1), 31-39. Retrieved from http://www.cancerforum.org.au/file/2011/March/Mar_2011_Forum8.pdf
3. Pirri, C. (2012). Complementary and alternative medicine use by adult cancer patients: An
overview. In: I. N. Olver & M. C. Robotin (Eds.), Perspectives on complementary and alternative medicines (pp. 439-459). London: Imperial College Press.
4. Pirri, C. (2012). Complementary and alternative medicine used by patients with cancer:
Evidence for efficacy and safety. In: I. N. Olver & M. C. Robotin (Eds.), Perspectives on complementary and alternative medicines (pp. 31-87). London: Imperial College Press.
5. Pirri, C. (2013). Embracing complementary and alternative medicine. Medical Journal of
Australia (MJA) InSight, 5. Retrieved from https://www.mja.com.au/insight/2013/5/carlo-pirri-embracing-cam
Note on Original Publications Citations 2-5 above were invited publications that stemmed from conference presentations and related media releases (see page overleaf). Notes on Formatting and Style This PhD thesis comprises a number of research publications. The original formatted manuscripts of these publications are reproduced in the thesis chapters that follow in the form in which they were accepted following peer review, and are incorporated into this thesis along with additional text that has been provided to introduce and link together the published works. Consequently, there may be a small degree of repetition and some minor inconsistencies in Anglo/American orthography across the thesis. Nevertheless, it is hoped that the final collated body of work that forms the present PhD thesis represents a cohesive body of research, one which can be readily followed by audiences of various expertise on the subject matter globally. Notes on Terminology The terms “doctor” and “physician” are used interchangeably throughout this PhD thesis, often referring to (cancer) specialists and general practitioners alike. In contrast, (cancer) specialists per se are usually referred to as “clinicians”, “cancer physicians” or “oncologists”. Nonetheless, readers should be mindful of the context in which all these terms are used to avoid any uncertainty.
x
LIST OF ORAL PRESENTATIONS / SEMINARS
1. Pirri, C. (2014, September 23). Complementary and alternative medicine among cancer patients (CAM): Reasons for using CAMs and their impact on psychological adjustment and quality of life during cancer treatment and survivorship. Western Australian Clinical Oncology Group (WACOG) Inaugural Psycho-Oncology Research Symposium, Mt. Claremont, Australia.
2. Pirri, C. (2013, October 4). The good, the bad & the ugly: Integrating complementary and
conventional medicine. Murdoch University School of Psychology Research Seminar Series, Murdoch, Australia. Retrieved from http://www.murdoch.edu.au/School-of-Psychology-and-Exercise-Science/_document/Research-Seminar-Series/seminars-semester-2-2013.pdf
3. Pirri, C. (2012, November 13). An evidence-based systematic review of complementary and
alternative medicine (CAM): Recommendations concerning the efficacy and safety of popular CAMs used by cancer patients. Part II. The best of the best in integrative cancer care. IPOS 14th World Congress of Psycho-Oncology & Clinical Oncology Society of Australia (COSA) 39th Annual Scientific Meeting, Brisbane, Australia. Abstract retrieved from http://onlinelibrary.wiley.com/doi/10.1111/ajco.12029/abstract
4. Pirri, C. (2012, September 17). Evidence-based complementary therapies. Cancer Council
Western Australia ‘Live Well: Life During Treatment’ Patient Education Program, Shenton Park, Australia. Retrieved from http://tinyurl.com/m4m4us4
5. Pirri, C. (2011, November 15). An evidence-based systematic review of complementary and
alternative medicine (CAM): Recommendations concerning the efficacy and safety of popular CAMs used by cancer patients. COSA 38th Annual Scientific Meeting, Perth, Australia. Abstract retrieved from http://onlinelibrary.wiley.com/doi/10.1111/j.1743-7563.2011.01477.x/abstract
6. Pirri, C. (2011, June 9). Top 5 CAMs cancer patients should bend over backwards to avoid:
Evidence for efficacy & safety. WACOG Education Meeting, Subiaco, Australia. Retrieved from http://tinyurl.com/pnjws6d
7. Pirri, C., Katris P., Trotter J., Bayliss E., Bennett, R., & Drummond, P. (2008, October 18).
Use of complementary and alternative therapies by Western Australian cancer patients. Cancer Council Western Australia 5th State Conference, Perth, Australia. Abstract retrieved from http://tinyurl.com/p3utn9r
8. Pirri, C., Katris P., Trotter J., Bayliss E., Bennett, R., & Drummond, P. (2008, August 8).
Use of complementary and alternative therapies by Western Australian cancer patients. Australia and New Zealand (ANZ) Joint Scientific Meeting, Christchurch, New Zealand. Abstract retrieved from http://onlinelibrary.wiley.com/doi/10.1111/j.1743-7563.2008.00172.x/abstract
Note on Oral Presentations / Seminars Citations 1, 4 and 6 above relate to an invited conference presentation and two educational seminars that were delivered to oncology health professionals and/or cancer patients.
xi
LIST OF MEDIA ARTICLES / INTERVIEWS
1. Clinical Oncology Society of Australia. (2012, November 13). Patients missing out on benefits of complementary therapies due to doctors’ lack of knowledge [Press release]. Retrieved from https://www.cosa.org.au/media/158616/13nov12-cosaasm-mediarelease-patients-missing-out-on-benefits-of-complimentary-therapies.pdf
2. Tahmane, M. (Interviewer) & Pirri, C. (Interviewee). (2012, November 13). Cancer
conference told patients suffering unneeded pain because of distrust of complementary therapies [Audio file]. Retrieved from ABC News Radio web site archive: http://tinyurl.com/ngtbzyg
3. Mullen, N. (2012, November 13). Complementary therapies safe and effective for
cancer patients. Medical Observer. Retrieved from http://www.medicalobserver.com.au/news/complementary-therapies-safe-and-effective-for-cancer-patients
4. Aubusson, K. (2012, November 13). Doctors should consider alternative therapies:
expert. 6minutes.com.au. Retrieved from http://www.6minutes.com.au/news/latest-news/doctors-should-consider-alternative-therapies-expe
5. Burton, K. (2012, November 13). Patients miss out on complementary medicines.
Pharmacy News. Retrieved from http://www.pharmacynews.com.au/news/latest-news/patients-miss-out-on-complementary-medicines
xii
TABLE OF CONTENTS
Abstract.………………………………………………………….................................... iii Acknowledgements.………………………………………………………….................. vi List of Original Publications.……………………………………………….................... ix List of Oral Presentations / Seminars.……………………………………….............. x List of Media Articles / Interviews.……………..………………………....................... xi List of Tables and Figures.………………………………………………........................ xvii List of Abbreviations.……………..………………………............................................ xx
CHAPTER ONE.…………..………………………………………………...................... 01 Complementary and Alternative Medicine Use by Adult Cancer Patients: An Overview
1.1 Introductory Overview and Research Aims…………………………………........ 01 1.2 Summary Overview and Literature Review…………………………................... 02
References………………………………………………..………………............. 04 Abstract…………………………………….....…….............................................. 07 Introduction…………………………………….....……........................................ 08 Background…………………………………….....……........................................ 08 Definitions…………………………….....……......................................... 08 Prevalence and Cost of Complementary & Alternative Medicine (CAM) Use…. 08 CAM Use by Cancer Patients……………………...….......................................... 09 Profile of CAM Users……………………...….......................................... 09 Attraction of Cancer Patients to CAMs and the Motivation to Use
Them……………………...….................................................................... 09 Patient-Clinician Communication and Decision-Making…………………........... 10 Concerns and Attitudes of Cancer Physicians Relating to CAM Use........ 10 Disclosure of CAM Use by Patients & Barriers to Open Communication
Between Cancer Physicians and their Patients about CAM……………… 11 Making the Decision to Use CAM Alongside Conventional Anticancer Treatment and the Information Sources and Types of Evidence Used by Cancer Patients to Make Such Decisions…………………........................ 12 Making the Decision to Forego Conventional Anticancer Treatment in Favour of Alternative Therapies and Physician Responses to Patients Making Such Decisions…………………................................................... 14
Efficacy and Safety of CAM………………………………………....................... 16 Acknowledgements………………………………………………………............. 18 References………………………………………………..………………............. 18
CHAPTER TWO……………………………….………………………………..……..... 30 Use of Complementary and Alternative Therapies by Western Australian Cancer
2.1 Preface to Study 1………..…………………........................…............................. 30 Study 1……………………………….....……....................................................... 31 Abstract………..………………….....……................................................ 32 Introduction……………………………………......................................... 33 Method……………………………….....……........................................... 34 Patients………………………………………................................ 34 Eligibility Criteria……………....……........................................... 35 Data Collection………….……....……........................................... 35
Questionnaires……………....……..…........................................... 35 Statistical Analysis…………....…….............................................. 37
xiii
Results………………………………………......……........................................... 37 Patient Characteristics………....……............................................. 37 Reliability……………....……........................................................ 37 Association between Complementary and Alternative Therapy
Use and Demographic/Clinical Factors…...................................... 37 Complementary and Alternative Therapy Practices……............... 38 Association between Complementary and Alternative Therapy
Use and Health-Related Quality of Life / Psychological Functioning…................................................................................. 42
Discussion………………………………………...…..…...................................... 42 Acknowledgements………………………………………………………............. 45 References………………………………………………..………………............. 46
Footnotes………………………………………………..………………............... 49 CHAPTER THREE …………………………….………………………………..…….... 50 Complementary and Alternative Medicine Use by Patients with Cancer: Evidence for Efficacy and Safety
3.1 Preface to Study 2………………………........................…................................... 50 Study 2……………………….....……................................................................... 51 Abstract………..………………….....……................................................ 51 Popular CAM Approaches and Evidence for Use……………............... 53 Whole Medical Systems…………................................................ 53 Homeopathy…………........................................................ 53 Naturopathy…………......................................................... 53 Traditional Chinese Medicine…………............................. 54 Mind-Body Techiques…………..................................................... 54 Relaxation…………............................................................ 54 Meditation…………............................................................ 55 Hypnotherapy…………....................................................... 56
Yoga…………..................................................................... 57 Tai Chi………….................................................................. 58 Music Therapy…………..................................................... 58 Support Groups………….................................................... 58 Spirituality, Religion and Prayer………….......................... 59 Biologically-Based Practices…………....................................................... 60 Nutritional Supplements (Dietary/Food Supplements)……............ 60 Antioxidants…………......................................................... 61 Omega-3 Fatty Acids (n-3 Polyunsaturated Fatty Acids)… 63 Shark Cartilage and AE-941 (Neovastat)............................. 65 Laetrile and Amygdalin (Vitamin B17)............................... 66 Chinese Herbal Medicine …………................................................ 67 Astragalus (Astragalus Membranaceus/Mongolicus/ Propinquus, Radix Astragali)............................................... 68 Ginseng (Panax Ginseng/Quinquefolium, Eleutherococcus Senticosus, Angelica Sinensis)............................................. 69 Ginger (Zingiber Officinale)................................................ 70 Lingzhi / Reishi Mushroom (Ganoderma Lucidum/ Tsugae………….………..................................................... 70 Green Tea (Camellia/Thea Sinensis)................................... 71 Ginkgo (Ginkgo Biloba, EGb 761)…………...................... 71
xiv
Western Herbal Medicine……................................................... 72 St. John’s Wort (Hypericum Perforatum..................... 72 Garlic (Allium Sativum)…………................................. 73 Kava (Piper Methysticum)………................................. 73 Valerian (Valeriana Officinalis)………......................... 74 Evening Primrose Oil (Oenothera Biennis)…............. 75 Black Cohosh (Actaea/Cimicifuga Racemosa)…….... 76 Echinacea (Echinacea Purpurea/Angustifola/Pallida)..... 76 Milk Thistle (Silybum/Carduus Marianum)....................... 77
European Mistletoe (Viscum Album L.)............................ 78 Manipulative and Body-Based Practices............................................... 79
Massage Therapy........................................................................... 80 Acupuncture.................................................................................... 80 Exercise Interventions.................................................................... 81 Energy Therapies....................................................................................... 83 Biofield Therapies.......................................................................... 83 Qigong................................................................................. 84 Bioelectromagnetic-Based Therapies…….................................... 85 Microwave (UHF Radiowave)/Tronado Therapy........... 85 Summary Conclusions............................................................................... 86 Acknowledgements..................................................................................... 87 References................................................................................................... 87 Post-Publication Update to the Systematic Review in Study 2................................ 108 Whole Medical Systems…………........................................................................ 108 Homeopathy………….............................................................................. 108 Naturopathy…………............................................................................... 108 Traditional Chinese Medicine…………................................................... 108 Mind-Body Techiques…………........................................................................... 109 Relaxation………….................................................................................. 109 Meditation………….................................................................................. 109 Hypnotherapy…………............................................................................. 111 Yoga…………........................................................................................... 111 Tai Chi…………...................................................................................... 112 Music-Related Therapies………….......................................................... 113 Support Groups…………......................................................................... 115 Spirituality, Religion and Prayer…………............................................. 116 Biologically-Based Practices…………................................................................. 117 Nutritional Supplements (Dietary/Food Supplements)............................ 117 Antioxidants…………................................................................... 117 Omega-3 Fatty Acids (n-3 Polyunsaturated Fatty Acids)…….. 122 Shark Cartilage and AE-941 (Neovastat®).…………................... 123 Laetrile and Amygdalin (Vitamin B17).………….…................... 123
xv
Chinese Herbal Medicine…………........................................................... 124 Astragalus [Astragalus Membranaceus/Propinquus, Radix
Astragali, Huang Qi, Astragalus Mong(h)olicus, Milk Vetch]...... 124 Ginseng (Panax/Radix/Asian/Red Ginseng, Ren Shen, Panax
Quinquefolium, American/White Ginseng Eleutherococcus Senticosus, Siberian Ginseng, Angelica Sinensis, Female Ginseng, Dong Quai)…………..................................................... 125 Ginger (Zingiber Officinale). …………........................................ 127 Lingzhi / Reishi Mushroom (Ganoderma Lucidum/Tsugae)....... 128 Green Tea (Camellia/Thea Sinensis)………….…........................ 129 Ginkgo (Ginkgo Biloba, EGb 761)………………........................ 131 Western Herbal Medicine………….......................................................... 132 St. John’s Wort (Hypericum Perforatum, LI 160, Kira®,
WS 5570/5572/5573, Perika®, Hyperiplant®, Ze 117, Remotiv®)……….......................................................................... 132
Garlic (Allium Sativum)................................................................ 134 Kava (Piper Methysticum, Kava Kava, Kavain, WS1490)............ 135 Valerian (Valeriana Officinalis)..................................................... 137 Evening Primrose Oil (Oenothera Biennis)................................... 137 Black Cohosh (Actaea Cimicifuga Racemosa, iCR,
Isopropanolic Black Cohosh Extract, Remifemin®, Ethanolic Black Cohosh Extract, CR BNO 1055, Ze 450, Cr 99)................. 137
Echinacea (Echinacea Purpurea, Echinacin®, Echinacea Angustifolia/Pallida, Radix Echinaceae, Esberitox N®, Samital®)....................................................................................... 139
Milk Thistle (Silybum/Carduus Marianum)................................... 140 European Mistletoe (Viscum Album L., Viscum Fraxini-2, Iscador®, Eurixor®, Helixor®, abnobaVISCUM, Isorel, Cephalektin, Lektin, PS76A, Lectin ML-1, INN: Aviscumine, PS76A2, Lektinol™)...................................................................... 140
Manipulative and Body-Based Practices................................................... 142 Massage Therapy........................................................................... 142 Acupuncture................................................................................... 145 Exercise Interventions.................................................................... 149 Energy Therapies....................................................................................... 154 Biofield Therapies.......................................................................... 154 Qigong................................................................................ 154 Bioelectromagnetic-Based Therapies……..................................... 155 Microwave (UHF Radiowave)/Tronado Therapy.............. 155 References.................................................................................................. 156
3.8 Preface to Commentary Article Based on Study 2 − “Embracing Complementary and Alternative Medicine (CAM) for All the Right Reasons”.......... 187 Commentary Article Based on Study 2.................................................................. 188
xvi
CHAPTER FOUR…………………………….………………………………..……….. 191 Integrating Complementary and Conventional Medicine
4.1 Preface to General Discussion and Summary Conclusions................................... 191 Summary Conclusions........................................................................................... 192 Abstract...................................................................................................... 192 Introduction................................................................................................ 194 Background................................................................................................ 194 Definitions...................................................................................... 194 Prevalence and Cost of Complementary and Alternative
Medicine (CAM) Use..................................................................... 194 Profile of CAM Users, Reasons Cancer Patients Use CAM, and
Disclosure of CAM Use by Patients.............................................. 195 Cancer Physicians’ Concerns and Attitudes Regarding CAM................ 195 Efficacy and Safety of CAM...................................................................... 197 Future Research in CAM and Establishing Research Priorities................. 202 Integrative Cancer Care in Australia Today……....................................... 204 Integrating Complementary Medicine into Mainstream Cancer Care: Bridging the Gap Between Patients and Doctors and Making the Move from CAM Toward Integrative Oncology……......................................... 205 Conclusion.................................................................................................. 206 Acknowledgements.................................................................................... 207 References.................................................................................................. 208
APPENDICES…………………………….………………………………..…………... 217 Appendix A............................................................................................................ 217 Methodology (Study 1) Appendix B............................................................................................................ 249 Study 1 Questionnaires Appendix C............................................................................................................ 259 Complementary and Alternative Medicine Used by Patients with Cancer – Evidence for Efficacy and Safety (Draft Manuscript) Appendix D............................................................................................................ 374 Complementary and Alternative Medicine Used by Patients with Cancer – Evidence for Efficacy and Safety (Methodology, Study 2) Appendix E............................................................................................................ 384 Embracing Complementary and Alternative Medicine (CAM) for All the Right Reasons (Commentary Article Based on Study 2 – MJA InSight Online Publication) Appendix F............................................................................................................ 388 Cancer Patients’ Complementary/Alternative Therapy Use in Relation to Demographics & Clinical Factors (An Alternative Analysis Correcting for Multiple Comparisons using the Benjamini-Hochberg Procedure – Table A2, Study 1)
xvii
LIST OF TABLES AND FIGURES TABLES…………………………….…………………………………...……………..... Chapter 2
Use of Complementary and Alternative Therapies by Western Australian Cancer Patients Study 1
Table 1........................................................................................................ 39 Cancer patients’ complementary/alternative therapy use in relation to demographics & clinical factors Table 2........................................................................................................ 40 Complementary/alternative therapies used by cancer patients (n=59) Table 3........................................................................................................ 40 Perceived benefits of complementary/alternative therapy use by cancer patients (n=59) Table 4........................................................................................................ 41 Cancer patients’ quality of life and psychological functioning in relation to CAT use
Chapter 4 Integrating Complementary and Conventional Medicine
Table 1........................................................................................................ 196 Reasons why cancer patients use complementary and alternative medicine (CAM) Table 2........................................................................................................ 196 Concerns held by physicians for cancer patients using complementary and alternative medicine (CAM) Table 3........................................................................................................ 198 Safety of complementary and alternative medicine: direct harm resulting from CAM use by cancer patients Table 4........................................................................................................ 202 Safety of complementary and alternative medicine (CAM): indirect harm resulting from CAM use by cancer patients
Appendix A Methodology (Study 1)
Table A1..................................................................................................... 224 Assessment instruments used in the present study
Appendix C Complementary and Alternative Medicine Used by Patients with Cancer – Evidence for Efficacy and Safety (Study 2 – Draft Manuscript)
Table 1........................................................................................................ 313 Classification of complementary and alternative therapies Table 2........................................................................................................ 314 Evidence supporting benefit in using whole medical system approaches to prevent/ameliorate cancer symptoms and treatment side-effects Table 3........................................................................................................ 315 Potential adverse effects and contraindications of whole medical system approaches in cancer patients
xviii
Table 4....................................................................................................... 316 Evidence supporting benefit in using mind-body interventions to prevent/ ameliorate cancer symptoms and treatment side-effects Table 5....................................................................................................... 318 Potential adverse effects and contraindications of mind-body interventions in cancer patients Table 6....................................................................................................... 321 Evidence supporting benefit in using nutritional supplements to prevent/ameliorate cancer symptoms and treatment side-effects Table 7....................................................................................................... 323 Potential adverse effects, drug interactions and contraindications of nutritional supplements in cancer patients Table 8....................................................................................................... 325 Evidence supporting benefit in using Chinese and Western herbal medicines to prevent/ameliorate cancer symptoms and treatment side-effects Table 9....................................................................................................... 328 Potential adverse effects, herb-drug interactions and contraindications of Chinese and Western herbal medicines in cancer patients Table 10..................................................................................................... 336 Evidence supporting benefit in using manipulative and body-based interventions to prevent/ameliorate cancer symptoms and treatment side-effects Table 11..................................................................................................... 337 Potential adverse effects and contraindications of manipulative and body-based interventions in cancer patients Table 12..................................................................................................... 339 Evidence supporting benefit in using energy therapies to prevent/ ameliorate cancer symptoms and treatment side-effects Table 13..................................................................................................... 340 Potential adverse effects and contraindications of energy therapies in cancer patients
Appendix D Complementary and Alternative Medicine Used by Patients with Cancer – Evidence for Efficacy and Safety (Methodology, Study 2)
Table D1..................................................................................................... 377 Classification of complementary and alternative therapies evaluated for efficacy and safety
Appendix F Cancer Patients’ Complementary/Alternative Therapy Use in Relation to Demographics & Clinical Factors (An Alternative Analysis Correcting for Multiple Comparisons using the Benjamini-Hochberg Procedure – Table 2, Study 1)
Table A2..................................................................................................... 390 Cancer patients’ complementary/alternative therapy use in relation to demographics & clinical factors (study 1)§
xix
FIGURES…………………………….…………………….……………...…………..... Chapter 1
Complementary and Alternative Medicine Use by Adult Cancer Patients – An Overview
Figure 1...................................................................................................... 13 Factors involved in the decision-making process utilised by cancer patients to use CAM. Used with publisher’s permission from ‘‘Patient decision-making about complementary and alternative medicine in cancer management: context and process’’ by Lynda G. Balneaves, RN PhD, Laura Weeks, PhD, and Dugald Seely, BSc ND MSc, in Current Oncology, 15 (Suppl 2): S94-S100 (2008).
Appendix A Methodology (Study 1)
Figure A1................................................................................................... 222 Study overview
xx
LIST OF ABBREVIATIONS μg microgram admin. administration AE-941 Neovastat® AIDS acquired immune deficiency syndrome ALA alpha-linolenic acid AO antioxidant BDI-SF Beck Depression Inventory Short Form BP blood pressure CAM complementary and alternative medicine CAT complementary and alternative therapy chemo chemotherapy CHM Chinese herbal medicine CINV chemotherapy-induced nausea and vomiting COPD chronic obstructive pulmonary disease COSA Clinical Oncology Society of Australia CNS central nervous system CRC colorectal cancer CRF cancer-related fatigue CT complementary therapy CV cardiovascular CYP cytochrome P-450 CYP450 cytochrome P-450 enzyme DHA docosahexaenoic acid EF Emotional Functioning (EORTC QLQ-C30 subscale) EGCG epigallocatechin gallate EGFR-TL epidermal growth factor receptor tyrosine-kinase EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire– Core 30 EPA eicosapentaenoic acid EPO evening primrose oil EPQ-R Eysenck Personality Questionnaire − Revised esp. especially FDA Food and Drug Administration (US) g gram G6PD glucose-6-phosphate GABA gamma-aminobutyric acid GH global health GI gastrointestinal GLA gamma-linolenic acid HIV human immunodeficiency virus HIV/AIDS human immunodeficiency virus / acquired immune deficiency
syndrome ICSG internet cancer support group IES-IS Impact of Event Scale– Intrusion Subscale incl. including ISG internet support group iv intravenous
xxi
kg kilogram mg milligram MJA Medical Journal of Australia MAOI monoamine oxidase inhibitor MASCC Multinational Association of Supportive Care in Cancer MBSR mindfulness-based stress reduction NCCAM National Center for Complementary and Alternative Medicine (US) NICM National Institute of Complementary Medicine (Australia) no. number NSAID non-steroidal anti-inflammatory drug NSCLC non-small lung cell cancer NHMRC National Health and Medical Research Council (Australia) PH Physical Health Uniscale PMR progressive muscle relaxation PTSD post-traumatic stress disorder QLQ-C30 European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire– Core 30 QoL quality of life r Pearson’s correlation RCT randomised controlled trial SCGH Sir Charles Gairdner Hospital (Western Australia) SD standard deviation SF short form SJW St. John’s wort SPANOVA split-plot analysis of variance SNRI serotonin and noradrenaline reuptake inhibitor SSRI selective serotonin reuptake inhibitor TCM traditional Chinese medicine TGA Therapeutic Goods Association (Australia) TM transcendental meditation tx treatment UHF ultra high frequency US United States of America Vit. vitamin WACOG Western Australian Clinical Oncology Group WHM Western herbal medicine
1
Chapter 1: Complementary and Alternative Medicine Use by Adult Cancer Patients –
An Overview
1.1 Introductory Overview and Literature Review
A summary overview detailing the aims and hypotheses of the present thesis and
how they are related in the chapters that ensue is presented first (see section 1.2). It is
followed by a general overview and literature review for the area of complementary and
alternative medicine in cancer underwent peer review, which was published as an invited
book chapter in the edited publication, Perspectives on Complementary and Alternative
Medicine. The manuscript in the form in which it was published is presented (see p6).
Original Publication
Pirri, C. (2012). Complementary and alternative medicine use by adult cancer patients: An
overview. In: I. N. Olver & M. C. Robotin (Eds.), Perspectives on complementary
and alternative medicines (pp. 439-459). London: Imperial College Press.
2
1.2 Summary Overview and Research Aims
Like it or not? Believe in it or not? The simple fact is that the majority of cancer
patients will use at least one CAM following diagnosis. In a recent Australian study, two in
three people (67%) with cancer used at least one type of complementary therapy (CT)
during or after their cancer treatment (Oh et al., 2010). Results from other Australian
studies have ranged widely from 14-89% (Wilkinson & Stevens, 2014; Kremser et al.,
2008; Sibbritt, Adams, Easthope, & Young, 2003; Correa-Velez, Clavarino, Barnett, &
Eastwood, 2003; Begbie, Kerestes, & Bell, 1996). Differences may be due to the
methodology (e.g. small sample sizes; most studies are cross-sectional rather than
longitudinal and report lower prevalence of use; Horneber et al., 2012; Ernst & Cassileth,
1998), types of CTs included in studies (e.g. those that included prayer and exercise in their
definitions of CAM reported higher use, while those that restricted CAM use to certain
categories reported lower use; Horneber et al., 2012; Ernst & Cassileth, 1998), or the type
of cancer population focused upon (e.g. breast cancer; palliative, elderly or regional
populations; Ernst & Cassileth, 1998). Consequently, the purpose of study 1 in the present
thesis was to reconcile some of the differences found in previous Australian studies (and
those elsewhere) by examining CAM use across cancer treatment and during cancer
survival via a prospective, longitudinal, observational study spanning the length of
conventional anticancer treatment and acute survival (6 months). Specifically, the aim was
to assess the “real world” incidence (or period prevalence) of CT use among cancer patients
receiving chemotherapy-related treatment (i.e. chemotherapy ± surgery and/or
radiotherapy) in a routine clinical setting. Additionally, the type of CTs used, perceived
benefits of use, and the relationship between demographic, clinical or quality of
life/psychological factors and CT use were examined (see chapter 2).
No CAM has reliably cured or suppressed any form of cancer thus far (e.g. Deng et
al., 2009). Unsurprisingly, this is why doctors generally do not believe in CAM. Doctors
believe in scientific evidence, which is the foundation of modern medicine. Patients,
however, believe in CAM because they want to believe, they need to believe, in order to
maintain hope and feel a sense of empowerment over their own health at a time where they
have such little control over the surgery, radiotherapy, chemotherapy and other
conventional medical treatments they are being subjected to. Despite generally
understanding the meaning of scientific evidence and making use of it in some instances,
the basis for cancer patients’ beliefs is more commonly non-scientific (e.g. patient
3
testimonials, anecdotes from family or friends, expert opinion from general practitioners
and pharmacists, the internet and other popular media, gut feelings; Verhoef, Trojan,
Armitage, Carlson, & Hilsden, 2009; White, Verhoef, Davidson, Gunn, & Cooke, 2008;
Verhoef, Mulkins, Carlson, Hilsden, & Kania, 2007; Pihlak et al., 2014), and is often
considered by patients to be as valuable as scientific proof (Verhoef et al., 2007).
When the patient does not receive positive news or encouragement from his or her
doctor, he or she is likely to resort to other sources such as CAM to maintain hope and may
withhold this information from their physicians. Indeed, 20-77% of patients do not disclose
CAM use to their oncologists (Davis, Oh, Butow, Mullan, & Clarke, 2012). Moreover,
discussions about CAM are uncommon and are most likely to be initiated by patients rather
than oncologists, many of whom believe that they cannot effectively communicate with
patients using CAM partly due to having insufficient knowledge about the efficacy and
safety of specific CAMs (Roberts et al., 2005; Hann, Baker, & Denniston, 2003; Schofield,
Juraskova, & Butow, 2003; Newell & Sanson-Fisher, 2000; Trimborn et al., 2013).
Patients’ beliefs that CAMs are more “natural” and safer than conventional treatments are
problematic also. Undeniably, they may pose direct safety risks because of their potential
adverse effects or interactions with conventional oncology treatments (e.g. Deng et al.,
2009). Alternative therapies promoted as “cures” in place of conventional treatments have
the potential to cause patients the most harm, however, when they forego evidence-based
cancer treatments that are likely to be more effective. It is therefore imperative that those
involved in the medical care of cancer patients are equipped with the skills and knowledge
to help patients appropriately evaluate complementary and alternative therapies, and be
aware of interactions with conventional anticancer therapies, in order to increase the
likelihood that patients avoid harm and, where possible, receive benefit should they choose
to use CAM. To this end, the purpose of study 2 in the present thesis was to perform a
systematic review evaluating the efficacy and safety of several popular CAMs, with a view
to increasing the knowledge base of oncologists and associated health professionals and
therefore improve the overall care of cancer patients (see chapter 3).
4
References
Begbie, S. D., Kerestes, Z. L., & Bell, D. R. (1996). Patterns of alternative medicine use by
cancer patients. Medical Journal of Australia, 165(10), 545-548.
Correa-Velez, I., Clavarino, A., Barnett, A. G., & Eastwood, H. (2003). Use of
complementary and alternative medicine and quality of life: Changes at the end of
life. Palliative Medicine, 17(8), 695-703.
Davis, E. L., Oh, B., Butow, P. N., Mullan, B. A., & Clarke S. (2012). Cancer patient
disclosure and patient-doctor communication of complementary and alternative
medicine use: a systematic review. Oncologist, 17(11), 1475-1481.
Deng, G. E., Frenkel, M., Cohen, L., Cassileth, B. R., Abrams, D.I., Capodice, J.L., . . .
Sagar, S. (2009). Evidence-based clinical practice guidelines for integrative
oncology: complementary therapies and botanicals. Journal of the Society for
Integrative Oncology, 7(3), 85-120. Retrieved from
http://www.integrativeonc.org/index.php/docguide
Ernst, E., & Cassileth, B. R. (1998). The prevalence of complementary/alternative medicine
in cancer. Cancer, 83, 777-782.
Hann, D., Baker, F., Denniston, M., & Entrekin, N. (2005). Long-term breast cancer
survivors' use of complementary therapies: perceived impact on recovery and
prevention of recurrence. Integrative Cancer Therapies, 4(1), 14-20.
Horneber, M., Bueschel, G., Dennert, G., Less, D., Ritter, E., Zwahlen, M. (2012). How
many cancer patients use complementary and alternative medicine: a systematic
review and metaanalysis. Integrative Cancer Therapies, 11(3), 187-203.
Kremser, T., Evans, A., Moore, A., Luxford, K., Begbie, S., Bensoussan, A., . . . Zorbas, H.
(2008). Use of complementary therapies by Australian women with breast cancer.
Breast, 17(4), 387-394.
Newell, S., & Sanson-Fisher, R.W. (2000). Australian oncologists' self-reported knowledge
and attitudes about non-traditional therapies used by cancer patients. Medical
Journal of Australia, 172(3),110-113.
Oh, B., Butow, P., Mullan, B., Beale, P., Pavlakis, N., Rosenthal, D., & Clarke, S. (2010).
The use and perceived benefits resulting from the use of complementary and
alternative medicine by cancer patients in Australia. Asia-Pacific Journal of
Clinical Oncology, 6(4), 342-349.
5
Pihlak, R., Liivand, R., Trelin, O., Neissar, H., Peterson, I., Kivistik, S., . . . Jaal, J. (2014).
Complementary medicine use among cancer patients receiving radiotherapy and
chemotherapy: Methods, sources of information and the need for counselling.
European Journal of Cancer Care (English), 23(2), 249-254.
Pirri, C. (2012). Complementary and alternative medicine use by adult cancer patients: An
overview. In: I. N. Olver & M. C. Robotin (Eds.), Perspectives on complementary
and alternative medicines (pp. 439-459). London: Imperial College Press.
Roberts, C. S., Baker, F., Hann, D., Runfola, J., Witt, C., McDonald, J., . . . Blanchard, C.
(2005). Patient–physician communication regarding use of complementary therapies
during cancer treatment. Psychosocial Oncology, 23(4), 35-60.
Schofield, P.E., Juraskova, I., & Butow, P. N. (2003). How oncologists discuss
complementary therapy use with their patients: an audio-tape audit. Supportive Care
in Cancer, 11(6), 348-355.
Sibbritt, D., Adams, J., Easthope, G., & Young, A. (2003). Complementary and alternative
medicine (CAM) use among elderly Australian women who have cancer.
Supportive Care in Cancer, 11(8), 548-550.
Trimborn, A., Senf, B., Muenstedt, K., Buentzel, J., Micke, O., Muecke, R., . . . Huebner, J;
Working Group Prevention and Integrative Oncology of the German Cancer Society
(2013). Attitude of employees of a university clinic to complementary and
alternative medicine in oncology. Annals of Oncology, 24(10), 2641-2645.
Verhoef, M. J., Mulkins, A., Carlson, L. E., Hilsden, R. J., & Kania, A. (2007). Assessing
the role of evidence in patients' evaluation of complementary therapies: a quality
study. Integrative Cancer Therapies, 6(4), 345-353.
Verhoef, M. J., Trojan, L., Armitage, G. D., Carlson, L., & Hilsden, R. J. (2009).
Complementary therapies for cancer patients: assessing information use and needs.
Chronic Diseases in Canada, 29(2), 80-88.
White, M.A., Verhoef, M. J., Davidson, B. J., Gunn, H., & Cooke, K. (2008). Seeking
mind, body and spirit healing: why some men with prostate cancer choose CAM
(complementary and alternative medicine) over conventional cancer treatments.
Integrative Medicine Insights, 3, 1-11.
Wilkinson, J. M., & Stevens, M. J. (2014). Use of complementary and alternative medical
therapies (CAM) by patients attending a regional comprehensive cancer care centre.
Journal of Complementary and Integrative Medicine, 11(2), 139-145.
6
Chapter 22
Complementary and Alternative Medicine Use by Adult Cancer Patients: An Overview
Carlo Pirri
Faculty of Health Sciences (Psychology), Murdoch University, Murdoch, Australia
Running Head: CAM Use by Cancer Patients
Correspondence: Carlo Pirri (Research Associate/PhD Candidate), Faculty of Health
Sciences (Psychology), Murdoch University, South Street, Murdoch WA 6150, Australia.
Email: [email protected]
Tel.: 61 (0) 8 9360 7382
Fax: 61 (0) 8 9360 6492
7
Abstract
Complementary and alternative medicine (CAM) continues to evoke fierce debate and
divergent views within the medical community, yet complementary medicine is used by
14% to 65% of Australian adults diagnosed with cancer (with estimates as high as 80% to
91% in the US and Europe) and alternative medicine by 8% to 14%. Cancer patients who
use CAM are typically female, younger, better educated, and of higher socioeconomic
status. While surgery, chemotherapy and radiotherapy have proven increasingly successful
but still have limited curative potential, these conventional approaches are generally more
invasive, aggressive, and associated with toxicities than CAMs, and tend to take a slower,
gentler approach by attempting to bolster constructive forces (e.g. the immune system)
rather than battling the destructive forces of growing cancer cells. They focus on symptom
control and patients are generally encouraged to be active participants in the management
of their illness. This patient-centred approach, which is more easily accessible, contributes
to the appeal of CAM. Many CAMs, however, have drawn steadfast opposition from cancer
physicians, primarily because they remain unproven in clinical trials and pose potential
safety risks and financial or psychological harm of CAM use to their patients. Research
indicates that 33% to 77% of patients do not disclose CAM use to their physicians, often
because of a perceived negative response. The perception that CAMs are more “natural”
and, by association, safer than conventional treatments is problematic. Indeed, they may
pose direct safety risks because of their potential adverse effects or interactions with
conventional oncology treatments. Alternative therapies promoted as “cures” in place of
conventional treatments have the potential to cause patients the most harm. It is therefore
imperative that those involved in the medical care of cancer patients are equipped with the
skills and knowledge to help patients appropriately evaluate complementary and alternative
therapies, and be aware of interactions with conventional anticancer therapies, in order to
increase the likelihood that patients avoid harm and, where possible, receive benefit should
they choose to use CAM.
Key Words: complementary and alternative medicines, interactions, natural
8
1. Introduction
Complementary and alternative medicine (CAM) continues to evoke fierce debate and
divergent views within the medical community. It remains an attractive and commonly
used treatment option for many cancer patients, regardless of whether their clinicians like it
or believe in it. Consequently, it divides health professionals providing conventional cancer
care and CAM practitioners offering unconventional care.
2. Background
2.1 Definitions
The US National Institutes of Health’s National Center for Complementary and Alternative
Medicine (NCCAM) defines CAM as ‘a group of diverse medical and health care systems,
practices and products that are not presently considered part of conventional medicine’.1
Complementary and alternative therapies must be distinguished, however. “Complementary
therapies” are adjuncts to conventional medical treatment increasingly perceived as an
important part of supportive care;2,3 they are often used for symptom management and to
enhance quality of life (QoL) and overall patient care.4 “Alternative therapies”, in contrast,
are clinically unproven and are used instead of conventional treatments.2 This is
particularly damaging for cancer patients, as delay or outright refusal of conventional
treatment often compromises their likelihood of cure or remission.5 More recently, the term
“integrative oncology” has emerged and involves a standard of care for cancer patients that
utilises safe, evidence-based complementary therapies in conjunction with conventional
anticancer treatments via a multidisciplinary approach designed to evaluate and treat the
whole person rather than the disease per se.6
2.2 Prevalence and cost of complementary and alternative medicine (CAM) use
In 2004, an estimated 52.2% of the Australian population used CAM, which was at least
equivalent to prescription drug use7,8 and cost AUD$1.8 billion (approximately four times
the public contribution to the Pharmaceutical Benefits Scheme).7 More recent surveys in
2005/06, however, revealed a significant increase in prevalence to an estimated 67%9 and
out-of-pocket spending of AUD$4.13 billion, with as many visits being made to CAM
practitioners as medical practitioners (approximately 68 million each).10
9
CAM use is quite prominent in oncology, with prevalence often being higher in cancer
patients than in the general and other chronic disease populations.11-15 In adult cancer
patients, a systematic review of 21 studies worldwide reported an average prevalence of
CAM use of 31.4% (range: 7-64%),16 while a more recent European survey of 13 countries
found an average prevalence of 35.9% (range: 14.8-73.1%).17 Other studies report even
higher prevalence, depending on CAM definitions used and cancer populations studied. For
instance, the 2002 Datamonitor Survey encompassing the US and Europe revealed 80%
prevalence amongst adult cancer patients,18 while 91% of US patients reported CAM use
(including prayer and exercise) during treatment in another study.19 In Australia, CAM use
by cancer patients has varied widely from 14.5%20 to 65%.21 More specifically, 22-52% of
medical oncology,21-24 40% of palliative,25 and 46% of paediatric oncology patients26 report
CAM use.
3. CAM Use by Cancer Patients
3.1 Profile of CAM users
Studies have consistently shown that cancer patients who use CAM are typically female,
younger, better educated, and of higher socioeconomic status than those who do
not.2,17,24,27-29 This mimics the basic trend observed in the general population.30 CAM use is
also associated with being married,31 medical comorbidity,24 advanced cancer,31-33 longer
disease/treatment,24,28 greater symptoms,31,87 psychosocial distress and poor QoL,24,27,33 and
engaging in self-help groups and other active coping strategies.32-35
3.2 Attraction of cancer patients to CAMs and the motivation to use them
The underlying philosophy of most CAMs primarily focuses on health and improving well-
being, (e.g. [Cohen et al]) rather than on the disease itself.36 Conventional treatments are
generally invasive and aggressive, while CAMs tend to take a slower, gentler approach, by
attempting to bolster constructive forces (e.g. the immune system), rather than battling the
destructive forces of growing cancer cells. Patients are generally encouraged to be active
participants in the management of their illness, as opposed to being passive spectators in
the case of taking prescribed medical treatment. These ingredients culminate in a highly
empowering holistic treatment approach that is tailored to patients and preserves a sense of
hope, which makes CAM, like the patient-centred approach per se, very attractive.
10
There are many reasons why cancer patients use CAM. Common reasons include cancer
cure or prolongation of life;22,23,25,26,37-42 relief from cancer symptoms and conventional
treatment side-effects;29,40,43,44 to assist conventional treatments;23,38 boosting
immunological function or energy;24,29,40,43 enhancing physical, emotional and spiritual
well-being;17,24,45,46 and maintaining a sense of control or hope.22-25,29,32,37,38,45 Other
motivations for patients to use CAM include perceptions that CAMs are natural/non-toxic,
beneficial and, at worst, will do no harm; strong encouragement from family, friends, other
cancer patients/survivors and the media;29,34,41,47-50 congruence with cultural values and
beliefs;46 poor prognosis resulting in limited conventional treatment options;51
strengthening the body to cope with conventional treatments in surgery, chemotherapy and
radiotherapy; improving QoL; to prevent recurrence following conventional treatment;52,53
high accessibility of CAMs (e.g. due to non-prescription or self-referral);54 greater
individual attention from CAM practitioners; dissatisfaction with some aspects of
conventional medical care;54 and a poor doctor-patient relationship.54
4. Patient-Clinician Communication and Decision-Making
4.1 Concerns and attitudes of cancer physicians relating to CAM use
Conventional treatments do not always relieve cancer symptoms adequately, nor do
prescribed medications provide total coverage against their side-effects. Some CAMs (e.g.
acupuncture, relaxation, massage) have received medical endorsement for use as
complementary therapies alongside conventional treatments, due to their proven efficacy in
relieving disease symptoms/treatment side-effects or enhancing QoL/psychosocial
functioning, as well as the minimal health risks they pose to patients.6,55,56 Other CAMs
(e.g. herbs, nutritional supplements, antioxidants), however, have drawn steadfast
opposition from oncologists, primarily because they remain unproven in clinical trials
(particularly as curative alternative therapies replacing conventional treatments); possessing
greater health risks due to adverse interactions with prescribed cancer treatments or
medications (e.g. CAM-drug interactions, surgical complications such as bleeding); and as
they may delay or reduce the efficacy of conventional treatments such as chemotherapy and
radiotherapy and, subsequently, compromise the likelihood of cure/remission and shorten
survival time.57 Additionally, concerns are held that CAMs may inflict financial or
psychological harm (e.g. by creating false hope in medically hopeless situations);
11
precipitate the abandonment of conventional treatment; lead patients to confuse a
physician’s willingness to discuss and support their decision to use CAMs with actual
medical support for them; and result in litigation against physicians in instances of failure if
they (appear to) advocate CAM use.58
4.2 Disclosure of CAM use by patients and barriers to open communication between
cancer physicians and their patients about CAM
Despite the empirical benefits of some CAMs and greater endorsement of their use as
complementary therapies, support is far from universal17 with many oncologists exhibiting
dismissive attitudes and negative views towards them.59 Indeed, while one study revealed
that cancer patients expected their physicians to be supportive, caring, accepting and non-
judgmental about CAM use and to inspire a sense of hope in them,60 several studies have
demonstrated that the reality is frequently different.
Oncologists consistently underestimate their patients’ use of CAM.61,62 Discussions about
CAM are also uncommon and most likely to be initiated by patients, rather than
physicians.63-65 Research has shown that 33-77% of patients do not disclose CAM use to
their physicians,66 with one Australian study reporting that 40% of cancer patients did not
inform their oncologist.22 Another study has revealed that only 54% of cancer patients
disclosed CAM use to their doctor, while medical treatments were discussed with their
CAM practitioner in 94% of instances.67 Patients do not tell their doctors for several
reasons, including anticipation of a negative response to their CAM use (e.g. fears that
physicians will discontinue their health care, will not support their CAM use, or try to
dissuade them from using CAM);66-69 the belief that it is unimportant for physicians to
know due to perceptions that CAM is entirely natural and safe and irrelevant to the course
of conventional treatment;67 perceived inability or unwillingness of physicians to provide
useful information about CAM due to inadequate training or bias against CAM use;67
physicians simply not asking about CAM use or appearing disinterested (35% of patient
attempts to initiate CAM discussions were ignored by oncologists in one Australian
study);66-69 physicians’ emphasis on scientific evidence;69 and patients’ uncertainty about
the benefits of CAM.68
Although cancer patients typically do not inform their physicians about their CAM use,
patients and their doctors report that it usually enhances their relationship when it is being
12
discussed and patients exhibit greater satisfaction and treatment compliance.63,70
Nevertheless, few oncologists feel comfortable discussing CAM with their patients, with
one survey of 291 oncology health professionals revealing that only 34% thought they
could effectively communicate with patients using CAM and 42% believing that they
lacked the skills to help patients maintain hope.70 In another survey, cancer physicians and
nurses were significantly less likely to instigate CAM discussions with patients than social
workers.64
Many CAM studies have examined patient perspectives, but few have investigated the
barriers to effective communication from oncologists’ viewpoints. Major obstacles to
physicians initiating such discussions with patients include the lack of proven efficacy for
many individual CAMs in clinical trials,71-74 limited time for patient consultations,68,70 and
a lack of knowledge of specific CAMs (including benefits and adverse effects) preventing
them from sufficiently addressing patient questions or concerns.68,71 Indeed, an Australian
study of 161 oncologists reported self-identified gaps in their knowledge of CAMs used by
some patients, and highlighted the need for including education about them in medical
training in order to provide adequate advice to patients.75 Other barriers to effective
physician-patient communication about CAM also include limited physician resources for
patient referral (e.g. information about qualified CAM practitioners, knowledge of CAM
practitioner specialties),76 and distrust of CAM practitioners to educate them about non-
biomedical therapies.71
4.3 Making the decision to use CAM alongside conventional anticancer treatment
and the information sources and types of evidence used by patients to make such
decisions
Cancer patients may make the decision to use CAM upon diagnosis, during conventional
treatment, in response to disease progression or recurrence, or during
remission/survivorship. In contrast to information needs and decision-making for
conventional treatments, relatively little is understood about how information is utilised and
evaluated by cancer patients in their decisions about whether to use CAM and which
therapies to undertake. The decision to use CAM is a highly personal and individual one (as
patients differ in their perceptions of the benefits and risks of available treatment options),
and is complex and dynamic in nature.
13
CAM decisions are influenced throughout the cancer experience by a number of
demographic, disease-related psychological and social factors, many of which have been
discussed above. Several decision-making models describing the complex interaction
between these factors and the cognitive processes underpinning decision-making have
evolved from CAM research that has predominantly involved breast and prostate cancer
patients. A recent qualitative review of such studies has identified four main stages within
the CAM decision-making process of cancer patients: (1) taking stock of treatment options,
(2) gathering and evaluating CAM information, (3) making a decision, and (4) revisiting
the decision (Figure 1).104
Figure 1. Factors involved in the decision-making process utilised by cancer patients
to use CAM. Used with publisher’s permission from ‘‘Patient decision-making about
complementary and alternative medicine in cancer management: context and process’’ by
Lynda G. Balneaves, RN PhD, Laura Weeks, PhD, and Dugald Seely, BSc ND MSc, in
Current Oncology, 15 (Suppl 2): S94-S100 (2008).104
14
4.4 Making the decision to forego conventional anticancer treatment in favour of
alternative therapies and physician responses to patients making such decisions
A study of CAM use amongst breast cancer patients41 revealed that few patients distinguish
explicitly between conventional treatments and CAMs, and perceive their treatment options
as a menu from which to choose a unique treatment protocol or package. Although most
cancer patients utilising CAM employ them alongside conventional treatments as
complementary therapies (CTs),20,23,77 others decline all conventional treatments and
substitute them with alternative therapies. Clinicians often view such choices made by
patients as irrational and non-compliant in nature, especially when the proposed
conventional treatment is curative.78,79 They find such decisions difficult to accept and
particularly troubling, given the reduced likelihood of cure and shorter survival time that
delay/complete refusal of conventional treatment often confers to patients and the
potentially greater health risks, poorer QoL and expense associated with unproven
alternative therapies.5,75,79-83 Clinicians, however, consider CAM to be more likely to help
patients treated palliatively than curatively,75 thus have less difficulty accepting the
patient’s decision to decline conventional treatment in favour of alternative therapies in
palliative contexts.78
How many cancer patients decline conventional treatment is largely unknown, but some
researchers and clinicians (particularly in Australia) appear comfortable in dismissing the
figure as being very low (1-2%) in the absence of any real supportive evidence. The few
studies that have attempted to gauge this, however, suggest that the number is likely to be
substantial enough to demand much greater attention and concern than is currently being
shown, with prevalence estimates ranging from 8% to 14%.84-85
Given the escalating popularity of CAM, it is quite likely that the prevalence of cancer
patients who refuse conventional treatment will increase. Understanding how patients come
to such decisions, however, will allow clinicians to offer them the best possible care and
guidance that will likely prevent them from discontinuing with conventional cancer care
altogether. Fortunately, a number of studies have examined why cancer patients decline
conventional treatment and adopt alternative therapies instead. A qualitative review of these
studies identified prior negative experiences with conventional medicine, the death of close
family or friends to cancer while receiving conventional treatment, pre-existing alternative
15
therapy use, and a strong belief system invested in the holistic approach as the most
important predisposing factors.82 Factors influencing decisions to refuse treatment
following diagnosis include poor doctor-patient communication, psychosocial distress
resulting from diagnosis (e.g. fear, anger), perceived severity of conventional treatment
side-effects, a strong desire for control in decision-making, great belief in holistic
approaches and the mind-body-spirit connection, and beliefs about conventional medicine
(e.g. incompatibility with QoL, treatment of symptoms rather than the underlying disease or
whole person, reduced capacity for cure) and the causes of cancer (e.g. lifestyle factors
such as diet caused their cancer).78,82,86
Few studies have investigated physicians’ responses to cancer patients making decisions to
forego conventional treatment. One study of oncologists and general practitioners,
however, found that physicians naturally adopt a goal-orientated medical viewpoint for
decision-making, whereas patients rely predominantly on personal values and experiences
to make decisions.78 Consequently, a patient’s decision to decline conventional treatment
appears irrational to doctors, especially when the proposed treatment is curative. Besides
the distinctions between curable/non-curable disease and rational/irrational treatment
decisions, physicians differentiate between patients who assume passive and active roles in
decision-making.79 While most patients are fairly passive decision-makers and follow the
medical advice of their doctors, patients who adopt active stances are perceived as being
different and may be inclined to forego conventional treatment and seek alternative
therapies.
Unsurprisingly, patients who reject conventional treatment in favour of alternative therapies
are viewed by some doctors as difficult, irrational, non-compliant, desperate, and in need of
more time to reach a sensible decision. In these circumstances, physicians often experience
much inner conflict in accepting the patient’s decision and about the role they should play,
with interviews of medical and radiation oncologists in one study revealing common
themes of uncertainty (e.g. what approach to take in this situation with patients, about their
ability to effectively communicate with patients); failure (e.g. to understand the patient or
resolve their difference of opinion); helplessness; and concern (i.e. about the patient’s well-
being and the implications of his/her treatment decision).79 The authors concluded that the
tendency of physicians to categorise patient decisions as rational or irrational may
contribute to their feelings of uncertainty and concern, and that this may interfere with their
16
ability to respond with appropriate sensitivity and understanding to patients who decline
conventional treatment in favour of alternative therapies.79
In the search to make informed treatment decisions, family, friends and CAM practitioners
were identified in two qualitative studies as the most valuable sources of support by cancer
patients who declined conventional treatment.82,87 Cancer physicians were also cited, but
more support was forthcoming from general practitioners within the conventional health
realm. Patients who perceived that their oncologist was trying to coerce them into accepting
conventional treatment (i.e. by pressuring them, equating alternative therapies to a “death
sentence”, or making disparaging remarks about CAM) were more likely to cease
conventional cancer care altogether. Conversely, patients highly valued oncologists who
could openly communicate and were open-minded enough to support them and provide
ongoing follow-up care, despite disagreeing with their decision to decline conventional
treatment.
The decision to decline conventional treatment is not necessarily borne from distrust of the
health system or the preceding medical care provided by cancer physicians, but may reflect
the personal characteristics of individual cancer patients. What clinicians must remember is
that treatment decisions are not limited to a single point in time, nor are they absolute.
Patients who substitute conventional treatments with alternative therapies want to keep
their options open,82 and evidence suggests that some patients ultimately decide to utilise
some form of conventional treatment.87 The need for effective, supportive, open-
minded/non-judgmental and respectful communication is the most common and important
theme identified across the studies in this area.86,88 Understanding what categories of
patients are likely to use alternative therapies as surrogates for conventional treatment and
what their motivations are is likely to help improve the communication between cancer
physicians and their patients, and enhance the overall quality of cancer care offered by
oncologists providing conventional treatment.
5. Efficacy and Safety of CAM
Collectively, there is a lack of scientific evidence for the efficacy of CAMs in
oncology.16,89-91 A useful distinction, however, is that between cancer cure and cancer
care.92 Some CAMs (e.g. mind-body techniques, massage and touch therapies) have proven
effective in relieving disease symptoms/treatment side-effects or enhancing
17
QoL/psychosocial functioning and, thus, are important in caring for cancer patients and
alleviating the physical and emotional burden experienced during cancer and its
treatment.4,6,55,56,93,94 To date, however, no CAM has proven effective in reliably curing or
suppressing any form of cancer.6 Nevertheless, with the growing popularity of CAM,
patients have become increasingly aware that commonly used chemotherapy drugs and
other medications used in Western medicine were originally derived from natural sources,95
hence they are investigating natural products in their search to make informed treatment
decisions.
In one population survey, 75% of people agreed that combining conventional medical
treatment and CAMs was preferable to using either alone.96 While use of CAMs may be
problematic, they are often perceived by patients as being more “natural” and, by
association, safer than conventional treatments. CAMs can directly harm patients via toxic
or allergic reactions resulting from their use alone, interactions with chemotherapy agents
and prescribed medications, or contaminants in their manufacturing or from the
environment (e.g. heavy metals, pesticides, bacteria, fungi).57,97 Some herbs, nutritional
supplements and other botanical agents, for instance, have toxic and potentially life-
threatening effects (e.g. kava, comfrey and black cohosh may cause hepatotoxicity,
laetrile/amygdalin cyanide toxicity and dermatitis and high-dose beta-carotene, increases
lung cancer incidence and cancer mortality in smokers).97-99 Other botanical preparations
can interact with chemotherapy and prescription drugs (e.g. St. John’s wort interferes with
drug metabolism via the cytochrome P450 pathway and may result in serotonin syndrome
or lethargy when taken with antidepressants, as well as reducing the efficacy of
chemotherapy drugs, particularly irinotecan and imatinib; botanical agents with oestrogenic
properties including red clover, soy and dong quai/female ginseng may interfere with the
treatment of hormone-sensitive conditions such as breast cancer and endometriosis);57,98 or
cause complications during surgery (e.g. garlic, ginkgo biloba and ginseng may increase
bleeding; ephedrine alkaloids such as ephedra/ma huang may cause cardiovascular events
including hypertension, tachycardia, heart attack and stroke) and radiotherapy (e.g. limited
evidence suggests that high-dose supplementation of antioxidants such as vitamin E and
beta-carotene during radiotherapy may protect tumour cells along with healthy cells, thus
shortening survival of cancer patients).57,100
18
CAMs may also cause indirect harm to patients. Resultant delays in conventional treatment
potentially compromise treatment outcomes, QoL and survival.80,81 Clinical trial outcomes,
particularly those involving advanced disease patients with poor prognosis, may also be
compromised when positive or negative effects of CAM are misattributed to the new
conventional treatment being investigated.101,102 Financial or emotional burden (e.g.
prolonged denial), or the simple squandering of precious, limited time that some patients
have left also constitute indirect harm.
Finally, patients may be harmed as a result of the unsafe practices of CAM practitioners
with inadequate training and competence, often owing to the absence of self-regulatory
bodies and unsatisfactory government legislation protecting health consumers.
Furthermore, harm may be exacerbated by regulatory absence or deficiencies in monitoring
of the biological potency of herbal crops (causing wide variation in therapeutic efficacy) or
the use of incorrect plant species; product standardisation in terms of purity and dosage
(resulting in possible substitution/adulteration and incorrect dosing or preparation); and
product labelling or advertising.103
Acknowledgements
I would like to thank Professor Ian Olver (editor), Professor Peter Drummond and Mr Paul
Katris for their comments on early drafts of this chapter. Finally, I would like to thank my
loved ones for the patience they showed during the writing of this chapter.
References
1. National Center for Complementary and Alternative Medicine (NCCAM), CAM
basics: what is CAM? Available at http://nccam.nih.gov/health/whatiscam/D347.pdf
(accessed 28 July 2009).
2. Cassileth BR. Complementary and alternative cancer medicine. J Clin Oncol 17:
44-52 (1999).
19
3. Cancer Council New South Wales (NSW), Understanding Complementary
Therapies: A Guide for People with Cancer, their Families and Friends. 2nd ed.
(Cancer Council NSW, Woolloomooloo, 2009).
4. Deng G, Cassileth B R, Yeung KS. Complementary therapies for cancer-related
symptoms. J Support Oncol 2:419-426 (2004).
5. Cassileth BR, Deng G. Complementary and alternative therapies for cancer.
Oncologist 9: 80–89 (2004).
6. Deng GE, Frenkel, M, Cohen ML, Cassileth BR, Abrams DI, Capodice JL,
Courneya KS, Dryden T, Hanser S, Kumar N, Labriola D, Wardell DW, Sagar S,
Society for Integrative Oncology. Evidence-based clinical practice guidelines for
integrative oncology: complementary therapies and botanicals. J Soc Integr Oncol
7(3):85-120 (2009).
7. MacLennan AH, Myers SP, Taylor AW. The continuing use of complementary and
alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust
184:27-31 (2006).
8. Australian Bureau of Statistics, Australian Social Trends 1998. (Australian Bureau
of Statistics, Canberra, 1998).
9. National Prescribing Service, NPS National consumer survey no. 5, Available at
http://www.nps.org.au/__data/assets/pdf_file/0009/26874/cons_survey_5_exec.pdf
(accessed 22 January 2010).
10. Xue CC, Zhang AL, Lin V, Da Costa C, Story DF. Complementary and alternative
medicine use in Australia: a national population-based survey. J Altern Complement
Med 13(6):643-650 (2007).
11. Saydah SH, Eberhardt MS. Use of complementary and alternative medicine among
adults with chronic diseases: United States 2002. J Altern Complement Med
12(8):805-812 (2006).
20
12. Mao JJ, Farrar JT, Xie SX, Bowman MA, Armstrong K. Use of complementary and
alternative medicine and prayer among a national sample of cancer survivors
compared to other populations without cancer. Complement Ther Med 5(1):21-29
(2007).
13. Habermann TM, Thompson CA, LaPlant BR, Bauer BA, Janney CA, Clark MM,
Rummans TA, Maurer MJ, Sloan JA, Geyer SM,m Cerhan JR Complementary and
alternative medicine use among long-term lymphoma survivors: a pilot study. Am J
Hematol 84(12):795-798 (2009).
14. Thomas KJ, Nicholl JP, Coleman P Use and expenditure on complementary
medicine in England: a population based survey. Complement Ther Med 9(1):2-11
(2001).
15. Hyodo I, Amano N, Eguchi K, Narabayashi M, Imanishi J, Hirai M, Nakano T,
Takashima S. Nationwide survey on complementary and alternative medicine in
cancer patients in Japan. J Clin Oncol 23(12):2645-2654 (2005).
16. Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in
cancer. Cancer 83:777-782 (1998).
17. Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, Margulies
A, Browall M, Magri M, Selvekerova S, Madsen E, Milovics L, Bruyns I,
Gudmundsdottir G, Hummerston S, Ahmad AM, Platin N, Kearney N, Patiraki E.
Use of complementary and alternative medicine in cancer patients: a European
survey. Ann Oncol 16(4):655-663 (2005).
18. Datamonitor, Complementary and alternative medicines in cancer therapy.
Publication BFHC0462, Available at
http://www.datamonitor.com/all/reports/product_summary.asp?pid=BFHC046
2 (accessed 13 June, 2006).
19. Yates JS, Mustian KM, Morrow GR, Gillies LG, Padmanaban D, Atkins JN, Issell
B, Kirshner JJ, Colman JC. Prevalence of complementary and alternative medicine
use in cancer patients during treatment. Support Care Cancer 13(10):806-811
(2005).
21
20. Sibbritt D, Adams J, Easthope G, Young A. Complementary and alternative
medicine (CAM) use among elderly Australian women who have cancer. Support
Care Cancer 11(8):548-550 (2003).
21. Oh B, Butow P, Mullan B, Clarke S, Tattersall M, Boyer M, Beale P, Vardy J,
Pavlakis N, Larke L. Patient-doctor communication: use of complementary and
alternative medicine by adult patients with cancer. J Soc Integr Oncol 8(2):56-64
(2010).
22. Begbie SD, Kerestes ZL, Bell DR, Patterns of alternative medicine use by cancer
patients. Med J Aust 165(10):545-548 (1996).
23. Miller M, Boyer MJ, Butow PN, Gattellari M, Dunn SM, Childs A. The use of
unproven methods of treatment by cancer patients: frequency, expectations and cost.
Support Care Cancer 6:337-347 (1998).
24. Pirri C, Katris P, Trotter J, Bayliss E, Bennett R, Drummond P. Use of
complementary and alternative therapies by Australian cancer patients. Asia-Pacific
J Clin Oncol 4(3):161-169 (2008).
25. Yates PM, Beadle G, Clavarino A, Najman JM, Thomson D, Williams G, Kenny L,
Roberts S, Mason B, Schlect D. Patients with terminal cancer who use alternative
therapies: their beliefs and practices. Sociol Health Illn 15(2):199-216 (1993).
26. M. G. Sawyer, Gannoni AF, Toogood IR, Antoniou G, Rice M. The use of
alternative therapies by children with cancer. Med J Aust 160:320-322 (1994).
27. Burstein HJ, Gelber S, Guadagnoli E, and Weeks JC. Use of alternative medicine by
women with early-stage breast cancer. N Engl J Med 340:1733-1739 (1999).
28. Girgis A, Adams J, Sibbritt D. The use of complementary and alternative therapies
by patients with cancer. Oncol Res 15:281-289 (2005).
29. Verhoef MJ, Balneaves LG, Boon HS, Vroegindewey A. Reasons for and
characteristics associated with complementary and alternative medicine use among
adult cancer patients: a systematic review. Integr Cancer Ther 4(4):274-286 (2005).
22
30. MacLennan AH, Wilson DH, Taylor AW. The escalating cost and prevalence of
alternative medicine. Prev Med 35(2):166-173 (2002).
31. Fouladbakhsh JM, Stommel M, Given BA, Given CW. Predictors of use of
complementary and alternative therapies among patients with cancer. Oncol Nurs
Forum 32(6):1115-1122 (2005).
32. Söllner W, Maislinger S, DeVries A, Steixner E, Rumpold G, and Lukas P. Use of
complementary and alternative medicine by cancer patients is not associated with
perceived distress or poor compliance with standard treatment but with active
coping behavior: a survey. Cancer 89(4):873-880 (2000).
33. Paltiel O, Avitzour M, Peretz T, Cherny N, Kaduri L, Pfeffer RM, Wagner N,
SoskolneV. Determinants of the use of complementary therapies by patients with
cancer. J Clin Oncol 19(9):2439-2448 (2001).
34. Boon H, Westlake K, Stewart M, Gray R, Fleshner N, Gavin A, Brown JB, Goel V.
Use of complementary/alternative medicine by men diagnosed with prostate cancer:
prevalence and characteristics. Urology 62(5):849-853 (2003).
35. Nagel G, Hoyer H, Katenkamp D Use of complementary and alternative medicine
by patients with breast cancer: observations from a health-care survey. Support
Care Cancer 12(11):789-796 (2004)
36. Cohen L, Cohen MH, Kirkwood C, Russell NC Discussing complementary
therapies in an oncology setting. J Soc Integr Oncol 5(1):18-24 (2007).
37. Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE.
Complementary/alternative medicine use in a comprehensive cancer center and the
implications for oncology. J Clin Oncol 18(13):2505-2514 (2000).
38. Boon H, Stewart M, Kennard MA, Gray R, Sawka C, Brown JB, McWilliam C,
Gavin A, Baron RA, Aaron D, Haines-Kamka T. Use of complementary/alternative
medicine by breast cancer survivors in Ontario: prevalence and perceptions. J Clin
Oncol 18(13):2515-2521 (2000).
23
39. Correa-Velez I, Clavarino A, Barnett AG, Eastwood H. Use of complementary and
alternative medicine and quality of life: changes at the end of life. Palliat Med
17(8):695-703 (2003).
40. Correa-Velez I, Clavarino A, Eastwood H. Surviving, relieving, repairing, and
boosting up: reasons for using complementary/alternative medicine among patients
with advanced cancer: a thematic analysis. Palliat Med 8(5):953-961 (2005).
41. Boon H, Brown JB, Gavin A, Kennard MA, Stewart M. Breast cancer survivors'
perceptions of complementary/alternative medicine (CAM): making the decision to
use or not to use. Qual Health Res 9(5):639-653 (1999).
42. Sparber A, Bauer L, Curt G, Eisenberg D, Levin T, Parks S, Steinberg SM, Wootton
JK. Use of complementary medicine by adult patients participating in cancer
clinical trials. Oncol Nurs Forum 27(4):623-630 (2000).
43. Shen J, Andersen R, Albert PS, Wenger N, Glaspy J, Cole M, Shekelle P. Use of
complementary/alternative therapies by women with advanced-stage breast cancer.
BMC Complement Altern Med 2:8 (2002).
44. Harris P, Finlay IG, Cook A, Thomas KJ, Hood K. Complementary and alternative
medicine use by patients with cancer in Wales: a cross sectional survey.
Complement Ther Med 11(4):249-253 (2003).
45. Scott JA, Kearney N, Hummerston S, Molassiotis A. Use of complementary and
alternative medicine in patients with cancer: a UK survey. Eur J Oncol Nurs
9(2):131-137 (2005).
46. Singh H, Maskarinec G, Shumay DM. Understanding the motivation for
conventional and complementary/alternative medicine use among men with prostate
cancer. Integr Cancer Ther 4(2):187-194 (2005).
47. Ohlén J, Balneaves LG, Bottorff JL, Brazier AS. The influence of significant others
in complementary and alternative medicine decisions by cancer patients. Soc Sci
Med 63(6):1625-1636 (2006).
24
48. Evans M, Shaw A, Thompson EA, Falk S, Turton P, Thompson T, Sharp D.
Decisions to use complementary and alternative medicine (CAM) by male cancer
patients: information-seeking roles and types of evidence used. BMC Complement
Altern Med 7:25 (2007).
49. Bonevski B, Wilson A, Henry DA. An analysis of news media coverage of
complementary and alternative medicine. PLoS One 3(6):e2406 (2008).
50. Mercurio R, Eliott JA. Trick or treat? Australian newspaper portrayal of
complementary and alternative medicine for the treatment of cancer. Support Care
Cancer. DOI: 10.1007/s00520-009-0790-4.
51. Broom A, Tovey P. Therapeutic pluralism? Evidence, power and legitimacy in UK
cancer services. Sociol Health Illn 29(4):551-569 (2007).
52. Eng J, Ramsum D, Verhoef M, Guns E, Davison J, Gallagher R. A population-
based survey of complementary and alternative medicine use in men recently
diagnosed with prostate cancer. Integr Cancer Ther 2(3):212-216 (2003).
53. Hann D, Baker F, Denniston M, Entrekin N. Long-term breast cancer survivors' use
of complementary therapies: perceived impact on recovery and prevention of
recurrence. Integr Cancer Ther 4(1):14-20 (2005).
54. Ernst E. The role of complementary and alternative medicine in cancer. Lancet
Oncol 1:176-180 (2000).
55. Deng G, Cassileth BR. Integrative oncology: complementary therapies for pain,
anxiety, and mood disturbance. CA Cancer J Clin 55(2):109-116 (2005).
56. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults
with cancer: meta-analysis of 116 studies. Oncol Nurs Forum 22(9):1369-1381
(1995).
57. Seely D, Oneschuk D. Interactions of natural health products with biomedical
cancer treatments. Curr Oncol 15(Suppl 2):s109.es81-10.es86 (2008).
25
58. O'Beirne M, Verhoef M, Paluck E, Herbert C. Complementary therapy use by
cancer patients. Physicians' perceptions, attitudes, and ideas. Can Fam Physician
50: 882-888 (2004).
59. Lee RT, Hlubocky FJ, Hu JJ, Stafford RS, Daugherty CK. An international pilot
study of oncology physicians' opinions and practices on complementary and
alternative medicine (CAM). Integr Cancer Ther 7(2):70-75 (2008).
60. Verhoef MJ, Hilsden RJ, O'Beirne M. Complementary therapies and cancer care: an
overview. Patient Educ Couns 38(2):93-100 (1999).
61. Kao GD, Devine P. Use of complementary health practices by prostate carcinoma
patients undergoing radiation therapy. Cancer 88(3):615-619 (2000).
62. Joyce E, Gallagher J, Tenhover J, Binda K. Complementary therapies: knowledge,
attitudes and use among providers. Poster presented at the Association of Oncology
Social Workers Annual Conference, Washington DC (2004).
63. Roberts CS, Baker F, Hann D, Runfola J, Witt C, McDonald J, Livingston ML,
Ruiterman J, Ampela R, Kaw OC, Blanchard C. Patient–physician communication
regarding use of complementary therapies during cancer treatment. Psychosocial
Oncol 23(4):35-60 (2005).
64. Hann DM, Baker F, Denniston MM. Oncology professionals' communication with
cancer patients about complementary therapy: a survey. Complement Ther Med
11(3):184-190 (2003).
65. Schofield PE, Juraskova I, Butow PN. How oncologists discuss complementary
therapy use with their patients: an audio-tape audit. Support Care Cancer
11(6):348-355 (2003).
66. Robinson A, McGrail MR. Disclosure of CAM use to medical practitioners: a
review of qualitative and quantitative studies. Complement Ther Med 12(2-3): 90-98
(2004).
67. Adler S, Fosket J. Disclosing complementary and alternative medicine use in the
medical encounter. J Family Prac. 48(6):453-458 (1999).
26
68. Richardson MA, Mâsse LC, Nanny K, Sanders C. Discrepant views of oncologists
and cancer patients on complementary/alternative medicine. Support Care Cancer
12(11):797-804 (2004).
69. Tasaki K, Maskarinec G, Shumay DM, Tatsumura Y, Kakai H. Communication
between physicians and cancer patients about complementary and alternative
medicine: exploring patients' perspectives. Psychooncology 11(3):212-220 (2002).
70. Roberts C, Benjamin H, Chen L, Gavigan M, Gesme D, McCarthy P, Samuels R,
Baile W. Assessing communication between oncology professionals and their
patients. J Cancer Educ 20(2):113–118 (2005).
71. Broom A, Adams J. Oncology clinicians' accounts of discussing complementary
and alternative medicine with their patients. Health (London) 13(3):317-336 (2009).
72. Hyodo I, Eguchi K, Nishina T, Endo H, Tanimizu M, Mikami I, Takashima S,
Imanishi J. Perceptions and attitudes of clinical oncologists on complementary and
alternative medicine: a nationwide survey in Japan. Cancer 97(11):2861-2868
(2003).
73. Weiger WA, Smith M, Boon H, Richardson MA, Kaptchuk TJ, Eisenberg D.
Advising patients who seek complementary and alternative medical therapies for
cancer. Ann Intern Med 137(11):889-903 (2002).
74. Lerner IJ, Kennedy BJ. The prevalence of questionable methods of cancer treatment
in the United States CA Cancer J Clin 42(3):181-191 (1992).
75. Newell S, Sanson-Fisher RW. Australian oncologists' self-reported knowledge and
attitudes about non-traditional therapies used by cancer patients. Med J Aust
172(3):110-113 (2000).
76. Bourgeault IL. Physicians' attitudes toward patients' use of alternative cancer
therapies. CMAJ 155(12):1679-1685 (1996).
77. van der Weg F, Streuli RA. Use of alternative medicine by patients with cancer in a
rural area of Switzerland. Swiss Med Wkly 133(15-16):233-240 (2003).
27
78. van Kleffens T, van Leeuwen E. Physicians' evaluations of patients' decisions to
refuse oncological treatment. J Med Ethics 31(3):131-136 (2005).
79. Madjar I, Kacen L, Ariad S, Denham J. Telling their stories, telling our stories:
physicians' experiences with patients who decide to forgo or stop treatment for
cancer. Qual Health Res 17(4):428-441 (2007).
80. Bagenal FS, Easton DF, Harris E, Chilvers CE, McElwain,TJ. Survival of patients
with breast cancer attending Bristol Cancer Help Centre. Lancet 336(8715): 606-
610 (1990).
81. Cassileth BR, Lusk EJ, Guerry D, Blake AD, Walsh WP, Kascius L, Schultz DJ.
Survival and quality of life among patients receiving unproven as compared with
conventional cancer therapy. N Engl J Med 324(17):1180-1185 (1991).
82. Verhoef MJ, Rose MS, White M, Balneaves LG. Declining conventional cancer
treatment and using complementary and alternative medicine: a problem or a
challenge? Curr Oncol 15(Suppl 2):s101-s116 (2008).
83. Ernst E. Intangible risks of complementary and alternative medicine. J Clin Oncol
19(8):2365-2366 (2001).
84. Cassileth BR, Lusk EJ, Strouse TB, Bodenheimer BJ. Contemporary unorthodox
treatments in cancer medicine. A study of patients, treatments, and practitioners.
Ann Intern Med 101(1):105-112 (1984).
85. Simmons K, Lindsay S. Psychological influences on acceptance of postsurgical
treatment in cancer patients. J Psychosom Res 51(1):355-360 (2001).
86. Shumay DM, Maskarinec G, Kakai H, Gotay CC, Cancer Research Center of
Hawaii. Why some cancer patients choose complementary and alternative medicine
instead of conventional treatment. J Fam Pract 50(12):1067 (2001).
28
87. White MA, Verhoef MJ, Davidson BJ, Gunn H, Cooke K. Seeking mind, body and
spirit healing: why some men with prostate cancer choose CAM (complementary
and alternative medicine) over conventional cancer treatments. Integr Med Insights
3:1–11 (2008).
88. Montbriand MJ. Abandoning biomedicine for alternate therapies: oncology patients'
stories. Cancer Nurs 21(1):36-45 (1998).
89. Ernst E. A primer of complementary and alternative medicine commonly used by
cancer patients. Med J Aust 174:88-92 (2001).
90. Schraub S. Unproven methods in cancer: a worldwide problem. Support Care
Cancer 8:10-15 (2000).
91. Risberg T, Lund E, Wist E, Kaasa S, Wilsgaard T. Cancer patients use of non-
proven therapy: a 5-year follow-up study. J Clin Oncol 16:6-12 (1998).
92. Ernst E. Complementary cancer treatments: hope or hazard? Clin Oncol (R Coll
Radiol) 7(4):259-263 (1995).
93. Joske DJ, Rao A, Kristjanson L. Critical review of complementary therapies in
haemato-oncology. Intern Med J 36(9):579-586 (2006).
94. Newell SA, Sanson-Fisher RW, Savolainen NJ. Systematic review of psychological
therapies for cancer patients: overview and recommendations for future research. J
Natl Cancer Inst 94(8):558-584 (2002).
95. Coseri S. Natural products and their analogues as efficient anticancer drugs. Mini
Rev Med Chem 9(5):560-571 (2009).
96. Eisenberg DM, Kessler RC, Van Rompay MI, Kaptchuk TJ, Wilkey SA, Appel S,
Davis RB. Perceptions about complementary therapies relative to conventional
therapies among adults who use both: results from a national survey Ann Intern Med
135(5):344-351 (2001).
97. Cassileth B, Yeung KS, Gubili J, Herbs and other botanicals in cancer patient care.
Curr Treat Options Oncol 9(2-3):109-116 (2008).
29
98. Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the
laboratory, animal, and human data for 8 common botanicals. Integr Cancer Ther
8(3):208-227 (2009).
99. Milazzo S, Ernst E, Lejeune S, Schmidt K. Laetrile treatment for cancer. Cochrane
Database Syst Rev 2:CD005476 (2006).
100. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB.
Should supplemental antioxidant administration be avoided during chemotherapy
and radiation therapy? J Natl Cancer Inst 100(11):773-783 (2008).
101. Hlubocky FJ, Ratain MJ, Wen M, Daugherty CK. Complementary and
alternative medicine among advanced cancer patients enrolled on phase I trials: a
study of prognosis, quality of life, and preferences for decision making. J Clin
Oncol 25(5):548-554 (2007).
102. Dy GK, Bekele L, Hanson LJ, Furth A, Mandrekar S, Sloan JA, Adjei AA.
Complementary and alternative medicine use by patients enrolled onto phase I
clinical trials. J Clin Oncol 22(23):4810-4815 (2004).
103. Robotin MC, Penman AG. Integrating complementary therapies into
mainstream cancer care: which way forward? Med J Aust 185(7):377-379 (2006).
104. Balneaves LG, Weeks L, Seely D. Patient decision-making about
complementary and alternative medicine in cancer management: context and
process. Curr Oncol (15 Suppl 2):s94-s100 (2008).
30
2.1 Preface to Study 1
The manuscript describing study 1 underwent peer review and was published in the
Asia-Pacific Journal of Clinical Oncology as a feature article, which formed the basis of
the editorial for that issue. The manuscript in the form in which it was published is
presented overleaf. However, a more detailed methodology chapter is located in Appendix
A for interested readers. Appendix B also contains the battery of questionnaires used to
assess the quality of life and psychological distress of cancer patients in the study. Finally,
an alternative version of Table 1 contained in the study 1 manuscript (p.39), which
summarises the results of a more complex type of statistical analysis (albeit one that
derived identical statistical outcomes), is presented and explained for more discerning
readers in Appendix F.
The manuscript presented overleaf has multiple authors. Drs James Trotter and
Evan Bayliss suggested the idea for study 1 and helped recruit cancer patients for this
study. Together with Paul Katris, they acted as field supervisors and provided consultation
throughout the study. Dr Robert Bennett and Professor Peter Drummond acted as academic
research supervisors and similarly provided consultation throughout the study. Study
design/co-ordination, ethics submissions, patient recruitment, data collection/entry, clinical
audits of participants’ medical records, statistical analysis/interpretation and study
documentation were all performed by the primary author. Finally, all co-authors provided
feedback (including suggestions for improvement) on manuscript drafts and revisions that
were brought to their attention for review.
Original Publication
Pirri, C., Katris P., Trotter J., Bayliss E., Bennett, R., & Drummond, P (2008). Use of
complementary and alternative therapies by Western Australian cancer patients.
Asia-Pacific Journal of Clinical Oncology, 4(3), 161-169.
31
Use of Complementary and Alternative Therapies
by Western Australian Cancer Patients Short Title: Complementary and Alternative Therapy Use by Cancer Patients
Carlo PIRRI1,3,*, Paul KATRIS2, James TROTTER3, Evan BAYLISS3,
Robert BENNETT1 and Peter DRUMMOND1
1Division of Health Sciences (Psychology), Murdoch University, Murdoch, Australia 2Western Australian Clinical Oncology Group, West Perth, Australia 3Department of Medical Oncology, Royal Perth Hospital, Perth, Australia
* Correspondence: Carlo Pirri (PhD Candidate/Psychology Staff), Division of Health
Sciences (Psychology), Murdoch University, South Street, Murdoch WA 6150, Australia.
Email: [email protected]
Tel.: 61 (0) 8 9360 6910 / 2702
Fax: 61 (0) 8 9360 6492
32
Abstract
Background: Many complementary and alternative therapies (CATs) have not been
subjected to controlled clinical trials among cancer patients and some may threaten
patients’ health and interfere with conventional treatments. Nevertheless, CAT use is
becoming increasingly popular and many cancer patients do not discuss it with their
physicians. Consequently, we examined the incidence and type of CAT use, perceived
benefits of use, and the relationship between demographic, clinical or psychological factors
and use in cancer patients who received conventional treatment.
Methods: A heterogeneous cohort of 200 newly-diagnosed cancer patients was recruited
from a large Western Australian public hospital. Health-related quality of life,
psychological adjustment and CAT use were assessed longitudinally at pretreatment, on-
treatment (8 weeks) and post-treatment.
Results: 30% of cancer patients reported CAT use in the course of treatment with
nutritional/ diet therapies and relaxation therapies most common. CAT users were
predominantly younger (p = .004), tertiary educated (p = .016), possessed medical
comorbidities (p = .023), and underwent lengthy treatment (p = .004). Patients who
underwent lengthy treatment (> 6 months) were nearly 3 times more likely to use CATs
than those who did not. 64% of CAT users perceived benefit, primarily citing enhanced
physical and emotional well-being. CAT users, however, did not score significantly better
than non-users on any measure of quality of life, physical health or psychological function.
CAT users generally reported greater psychosocial distress than non-users across treatment,
especially at pretreatment (baseline). However, with ongoing/new CAT use they
significantly reduced their distress levels to that of non-users by 8 weeks on-treatment (p =
.042).
Conclusion: Complementary and alternative therapies enhanced cancer patients’
psychological well-being during the early stages of conventional treatment only, possibly
via a mechanism of empowerment. With patients’ growing interest in CATs, the boundaries
between conventional and non-traditional oncology care are becoming less clear. Use of
CATs by cancer patients may be a clinical marker for psychosocial distress, and should
trigger clinicians to inquire about physical symptoms and concomitant anxiety and
depression.
Key words: complementary and alternative therapies, psychosocial oncology, quality of
life, adjuvant chemotherapy, cancer treatment.
33
INTRODUCTION
‘Alternative therapies’ in oncology have been perceived literally as any clinically unproven
therapy that is promoted to treat cancer in preference to conventional medical treatments.1
‘Complementary therapies’, in contrast, are adjuncts to mainstream cancer treatment, often
used for symptom management and to enhance quality of life (QOL).1 Approximately half
of the Australian general population consume complementary and alternative therapies
(CATs) every year,3 resulting in an incidence at least equivalent to prescription drug use3,4
and costing an estimated AUD$1.8 billion.3 In adult cancer patients, a systematic review of
21 studies worldwide reported an average prevalence of CAT use of 31.4%.5 Among
Australian cancer patients, 22-52% of medical oncology,6,7 40% of palliative,8 and 46% of
pediatric oncology patients9 report CAT use.
Collectively, there is a lack of scientific evidence for the efficacy of CATs.5,10-12 Moreover,
they are potentially harmful to patients either directly through biological activity1 or
indirectly through delay/refusal of traditional oncology care. Popular complementary
therapies (e.g. relaxation, hypnotherapy, aromatherapy, acupuncture) pose minimal risk to
patients’ health10,13 and have proven effective in enhancing psychosocial functioning.14
Popular alternative therapies (e.g. diet therapies, antioxidants, shark cartilage, coffee
enemas, high dose vitamins/minerals and herbal therapies), however, are unproven in
controlled trials, hold potentially greater health risks and may negatively interact with
conventional treatments.10,13 Nevertheless, 25-73% of patients using CATs believe they will
cure their cancer or prolong their lives,6-9,15,16 and 74-86% expect them to assist
conventional treatments.7,16 Oncologists, alternatively, consider CATs to be more likely to
help patients treated palliatively than those treated curatively.13
Further, studies suggest that
CATs are utilized more in palliative or supportive care than other oncology specialties.17
Recent clinical practice guidelines highlight the need for oncologists and general
practitioners to be aware of CATs being used or considered by patients, and to encourage
them to discuss use.18
Research shows that 70% or more of individuals who use CATs do
not inform their physicians.3,19,20 One Australian study found that 40% of cancer patients
using CATs did not tell their oncologists, possibly due to fear of a negative response.6
34
The psychological well-being of patients is fundamental to holistic cancer care.1 Research
has established that 25-33% of cancer patients experience clinically significant levels of
psychosocial distress.21,22
In a study of 480 early-stage breast cancer patients, Burstein and
colleagues23
found that complementary and alternative medicine use was independently
associated with depression, fear of recurrence of cancer, poorer mental health and sexual
satisfaction, and more frequent and intense physical symptoms after 3 months of standard
treatment. The authors suggested that women with breast cancer may start using
complementary and alternative medicine in response to psychological distress following
surgery, and concluded that complementary and alternative medicine use was a clinical
marker of psychosocial distress.
Longitudinal cancer research examining the contribution of psychological, clinical and
demographic factors in explaining CAT use is scant and limited. Most studies examine few
variables and involve homogeneous groups, usually women with breast cancer. What can
be said with some certainty, however, is that cancer patients who use CATs tend to be
female, better educated, of higher socioeconomic status, and younger than those who do
not.1,23-25
The goals of the present study were to determine the proportion of cancer patients using
complementary and alternative therapies in the course of treatment, and the benefits
perceived by patients using them. Additionally, the relationships between an expansive
range of demographic, clinical, or psychological factors and use of CATs were
investigated.
METHOD
A prospective, longitudinal design involving a heterogeneous group of 200 cancer patients
was employed. The ethics committees of the participating institutions approved the study.
All patients provided written and informed consent.
Patients
Participants were recruited from a consecutive series of 287 eligible cancer outpatients,
who were referred to the hospital medical oncology clinic and received multi-modal
35
treatment at Royal Perth Hospital, Western Australia between September 1997 and
December 2002. They were recruited for a larger study evaluating quality of life and
psychosocial distress of cancer patients. 200/287 (70%) eligible patients consented and
completed baseline questionnaires; 178/200 (89%) patients achieved 8 weeks on-treatment
and 153 (76%) progressed to post-treatment. During treatment, 47 patients were withdrawn
due to death (15), study ineligibility triggered by changes in medical care (15), study
withdrawal (15), and loss to follow-up (2).
Eligibility Criteria
Patients were eligible for the larger study if they met the following criteria: histological
confirmation of cancer; age 18 years and over; absence of acute organic psychiatric
symptoms; no prior cancer treatment for the current diagnosis (excluding surgery);
treatment completely overseen at the hospital following presentation to the medical
oncology clinic; and adequate English literacy to complete study questionnaires. Patients
were approached just prior to cancer treatment starting and given an explanation of the
study and an information sheet to help them decide on participation.
Data Collection
Data concerning demographics and clinical characteristics were collected from patients,
oncologists and medical records. Questionnaires were completed by patients at 4 times:
pretreatment (start of chemotherapy and/or radiation therapy), on-treatment (8 weeks), post-
treatment, and follow-up (6 months). Follow-up data will not be reported, however, as
patients reported no change in uptake/relinquishment of CATs in the 6 months following
treatment completion.
Questionnaires
Patients were administered the following questionnaires primarily comprising standardized
instruments assessing psychosocial distress and QOL:
36
(1) The European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire (EORTC QLQ)-C30 V2.0.26
The EORTC QLQ-C30 is a cross-culturally validated, self-report measure of quality of life
intended for use across a range of cancer diagnoses.26,27
It consists of 5 function scales
(physical, role, cognitive, emotional, social); 3 symptom scales (fatigue, nausea/vomiting,
pain); and 6 single items.
(2) Selby Quality of Life (QOL) Uniscale28
and Physical Health (PH) Uniscale.26,28
The Selby QOL Uniscale is a 10-point scale measuring the overall effect of cancer and its
treatment on the lives of patients. The PH Uniscale is a 10-point adaptation of the EORTC
QLQ 7-point global health scale.
(3) Beck Depression Inventory Short Form (BDI-SF).29
This is an abridged 13-item scale measuring the cognitive-affective aspects of clinical
depression while excluding somatic symptoms manifested in medical populations.
(4) Impact of Event Scale- Intrusion Subscale (IES-IS).30
This is a 7-item scale measuring cognitive-emotional distress related to a major stressor,
defined as cancer in the present study.
(5) Eysenck Personality Questionnaire − Revised (EPQ-R) − Neuroticism Short Form
(SF).31
This is an abbreviated 12-item scale used to measure premorbid levels of neuroticism.
(6) Complementary Therapy Items†.
Patients were asked about the use of CATs since cancer diagnosis: a) ’Since your diagnosis
have you tried any complementary and alternative therapies?’ and b) ‘If yes, please state
below what and describe any benefits you get out of them.’ Standard examples of CATs
were provided verbally to patients (e.g. dietary changes, vitamin/herbal supplements,
meditation, psychological therapy). Two independent trained judges categorized patients’
open-ended responses. Interrater disagreement was resolved by deciding judgments from
the first author.
37
Statistical Analysis
The internal consistency of the multi-item scales administered was calculated using
Cronbach’s alpha. Interrater agreement for categorization of patients’ open-ended responses
was assessed via Cohen’s kappa. Differences in demographic and clinical characteristics
between patients who used and did not use CATs were examined via chi-square analyses.
Differences between CAT users and non-users across treatment in quality of life and
psychological function were examined via univariate analyses using split-plot analyses of
variance/covariance. The level of significance was set at p < .05.
RESULTS
Patient Characteristics
Characteristics of the 200 patients are shown in Table 1. The demographic profile of the
cohort included 48% male, 52% female, mean age 56 years (SD = 13), 70% married, 47%
secondary educated, and 85% resided in the Perth metropolitan area. Primary cancer
diagnoses included 29% breast, 28% colorectal and 43% other. Other clinical
characteristics included 64% with localized or locally advanced disease, 51% given
adjuvant/neoadjuvant treatment (56% surgery plus chemotherapy or chemoradiation), and
74% treated for 6 months or less (excluding any initial surgery). Overall, in terms of sex,
age and diagnosis, the sample was quite representative of cancer patients in Western
Australia at the time of the study.32
Reliability
All questionnaires demonstrated acceptable internal consistency (EORTC QLQ-C30: 0.68-
0.87; other scales: 0.74-0.87) except for the EORTC Pain scale (0.68).33 Similarly,
interrater agreement was acceptable for classification of CATs used and perceived benefits
of their use by patients (85-92% concordance; Cohen’s kappa range = 0.70-0.82, p-values <
.001).
Association between Complementary and Alternative Therapy Use and Demographic
/ Clinical Factors
30% (59/200) of cancer patients reported CAT use in the course of treatment. As shown in
Table 1, age (p = .004), education (p = .016), comorbid medical history (p = .023) and
treatment duration (p = .004) were significantly associated with CAT use. More patients
38
than expected adopted CATs if they were aged 18-39 (46.2%), tertiary educated (39.3%),
possessed a comorbid medical condition (41.3% single; 19.8% multiple), or received more
than 6 months of treatment following medical oncology clinic presentation (6-12 months:
44.7%; > 12 months: 60%). Notably, based on an odds ratio, patients who underwent
lengthy treatments (> 6 months) were 2.95 times more likely to engage in CAT use than
those who did not. Conversely, fewer patients than expected adopted CATs if they were
aged 60 or over (15.1%), primary school educated (10%), or received 6 months of
treatment or less after clinic presentation (23.7%).
Breast cancer patients appeared to be overrepresented among CAT users (39.7%), but the
association of primary diagnosis with CAT use fell short of statistical significance (p =
.064). Similarly, no significant associations were found between disease recurrence (p =
.562), disease extent (p = .478), treatment goal/intent (p = .686), or type of treatment
received by patients (p = .629) and CAT use, respectively. Moreover, an analysis of
covariance indicated that primary diagnosis (p = .32), disease recurrence (p = .449) and
disease extent (p = .585) exerted no significant mediating influence on the relationship
between treatment duration and CAT use, which still proved significant after controlling for
the effects of these covariates, F(2, 181) = 4.68, p = .01.
Complementary and Alternative Therapy Practices
Table 2 shows the type of CATs adopted during treatment by 59 cancer patients. At
pretreatment, 53% (31/59) reported using CATs since diagnosis. This increased to 73%
(43/59) by on-treatment (8 weeks), with all 59 patients adopting use by post-treatment.
Furthermore, 53% (31/59) of CAT users tried multiple therapies, 85% (50/59) reported use
more than once during treatment, and only 2% (1/59) relinquished use altogether.
The most frequently reported CAT was nutritional therapy, including the use of food
supplements. This was followed by relaxation/meditation/positive imagery, megavitamins
and minerals, and herbalism. Nutritional therapy involves a diet to treat and prevent illness
and to restore the body to a natural, healthy equilibrium.6 Patients said that they reduced the
amount of fat in their diet, cut out additives and preservatives and reduced the amount of
39
Table 1 Cancer patients’ complementary/alternative therapy use in relation to demographics & clinical factors CAT Users (n=59) Non-Users (n=141) All Patients (N=200) p
Sex n (row %) n (row %) N [column %] Male 25 (26.3) 70 (73.7) 95 [47.5] Female 34 (32.4) 71 (67.6) 105 [52.5]
.433
Age** n (row %) n (row %) N [column %] 18-39yrs** 12 (46.2) 14 (53.8) 26 [13.0] 40-49yrs 14 (37.8) 23 (62.2) 37 [18.5] 50-59yrs 20 (39.2) 31 (60.8) 51 [25.5] 60-69yrs** 7 (15.9) 37 (84.1) 44 [22.0] 70yrs and over** 6 (14.3) 36 (85.7) 42 [21.0]
.004**
Marital Status n (row %) n (row %) N [column %] Married / Defacto 46 (32.9) 94 (67.1) 140 [70.0] Divorced / Separated 6 (20.7) 23 (79.3) 29 [14.5] Widowed 2 (12.5) 14 (87.5) 16 [8.0] Single, Never Married 5 (33.3) 10 (66.7) 15 [7.5]
.244
Education†,* n (row %) n (row %) N [column %] Primary* 2 (10.0) 18 (90.0) 20 [10.2] Secondary 23 (25.3) 68 (74.7) 91 [46.7] Tertiary* 33 (39.3) 51 (60.7) 84 [43.1]
.016*
Residence† n (row %) n (row %) N [column %] Metropolitan 48 (28.4) 121 (71.6) 169 [84.9] Rural 10 (33.3) 20 (66.7) 30 [15.1]
.742
Health Insurance Status n (row %) n (row %) N [column %] Public 51 (29.8) 120 (70.2) 171 [85.5] Private 8 (27.6) 21 (72.4) 29 [14.5]
.981
Primary Diagnosis n (row %) n (row %) N [column %] Breast 23 (39.7) 35 (60.3) 58 [29.0] Colorectal 11 (19.6) 45 (80.4) 56 [28.0] Other 25 (29.1) 61 (70.9) 86 [43.0]
.064
Comorbid Medical History†,* n (row %) n (row %) N [column %] None 21 (33.9) 41 (66.1) 62 [32.0]
Single Condition* 19 (41.3) 27 (58.7) 46 [24.0]
Multiple Conditions* 17 (19.8) 69 (80.2) 86 [44.0]
.023*
Psychiatric History† n (row %) n (row %) N [column %] No Prior History 52 (30.4) 119 (69.6) 171 [88.1] Previous History 5 (21.7) 18 (78.3) 23 [11.9]
.54
Cancer History n (row %) n (row %) N [column %] No Prior History 44 (29.1) 107 (70.9) 151 [75.5] Previous History 15 (30.6) 34 (69.4) 49 [24.5]
.987
Recurrence n (row %) n (row %) N [column %] No 48 (28.4) 121 (71.6) 169 [84.5] Yes 11 (35.5) 20 (64.5) 31 [15.5]
.562
Disease Extent n (row %) n (row %) N [column %] Localised Disease 5 (26.3) 14 (73.7) 19 [9.5] Locally Advanced 29 (26.6) 80 (73.4) 109 [54.5] Metastatic 25 (34.7) 47 (65.3) 72 [46.0]
.478
Treatment Goal n (row %) n (row %) N [column %] Curative 5 (21.7) 18 (78.3) 23 [11.5] Adjuvant / Neoadjuvant 31 (30.7) 71 (69.3) 102 [51.0] Palliative 23 (30.4) 52 (69.6) 75 [37.5]
.686
Treatment Received n (row %) n (row %) N [column %] Chemotherapy + Surgery 21 (31.8) 45 (68.2) 66 [33.0] Chemoradiation + Surgery 17 (32.1) 36 (67.9) 53 [26.5] Chemotherapy 10 (21.7) 36 (78.3) 46 [23.0] Chemoradiation 11 (31.4) 24 (68.6) 35 [17.5]
.629
Treatment Duration†,‡,** n (row %) n (row %) N [column %]
0-6 months** 33 (23.7) 106 (76.3) 139 [74.3] 6-12 months** 17 (44.7) 21 (55.3) 38 [20.3] > 12 months** 6 (60.0) 4 (40.0) 10 [5.4]
.004**
† Patient numbers do not always equal row/column total due to missing data. ‡ Treatment duration excludes any initial surgery received
prior to medical oncology presentation. * p<.05, ** p<.01 by chi-square analysis of CAT users compared to non-users.
40
alcohol they consumed. The vitamins and minerals most commonly used were vitamin E
and C, selenium, and zinc. Individuals engaging in relaxation/meditation most often used
yoga and reiki to reduce feelings of stress and anxiety, as well as to improve their
emotional well-being. Herbalism involves using the curative qualities of plants, flowers,
trees and herbs to stimulate an individual’s own healing system when the body is ill.34
Echinacea, milk thistles, herbal teas and promensil (red clover) were the most frequently
reported herbal items used.
Nearly two thirds of CAT users (38/59) perceived one or more benefits from their use.
Table 3 indicates that the most frequently reported benefits were enhanced physical and
emotional well-being (20), immunological functioning (14) and physical energy (8). Fifteen
individuals indicated that they had not used CATs long enough to perceive any benefit.
Table 2 Complementary/alternative therapies used by cancer patients (n=59)┼ Type of Therapy Number of Patients Nutritional Therapy / Supplements 26 Relaxation / Meditation / Positive Imagery 21 Megavitamins / Minerals 19 Herbalism 15 Homeopathy 5 Naturopathy 3 Faith / Spiritual Healing 2 Acupuncture 1 Other 8
┼ Some patients used multiple complementary/alternative therapies. Responses total 100.
Table 3 Perceived benefits of complementary/alternative therapy use by cancer patients (n=59)┼ Benefits Number of Patients Enhanced physical and emotional well-being 20 Improved immunological functioning 14 Increased (physical) energy 8 Reduced feelings of stress (promote relaxation) 4 Too soon to tell if any benefits have occurred 15 Did not provide a response 10
┼ Some patients specified multiple benefits. Responses total 71.
41
Table 4 Cancer patients’ quality of life and psychological functioning in relation to CAT use† Pretreatment On−treatment Post−treatment p‡
Global Quality of Life: Selby QOL Uniscale (Patients)§ − Mean (SD) CAT users 6.6 (2.3) 6.0 (2.4) 6.5 (2.4) Non-users 7.2 (2.0) 7.0 (2.2) 7.2 (2.2)
.065
Global Health: Physical Health Uniscale (Patients)§ − Mean (SD) CAT users 7.2 (2.0) 6.7 (2.0) 6.6 (2.1) Non-users 7.4 (1.8) 6.7 (2.3) 6.6 (2.3)
.905
Quality of Life: EORTC QLQ−C30 Functional Scales§ − Mean (SD) Physical Functioning CAT users 85.6 (23.4) 83.1 (26.9) 85.0 (27.8) Non-users 91.6 (17.5) 84.4 (25.7) 80.7 (26.4)
.825
Role Functioning CAT users 60.9 (36.1) 71.9 (25.9) 69.3 (29.0) Non-users 66.4 (31.7) 67.6 (33.1) 71.2 (31.2)
.854
Emotional Functioning*
CAT users 74.2 (24.0) 81.0 (20.8) 76.6 (26.3) Non-users 78.5 (20.1) 77.4 (26.8) 78.5 (25.4)
.859
Cognitive Functioning CAT users 75.5 (20.7) 77.1 (16.8) 74.5 (16.9) Non-users 79.4 (18.4) 82.7 (18.4) 82.7 (15.7)
.065
Social Functioning CAT users 70.3 (28.6) 75.5 (25.4) 78.6 (26.5) Non-users 76.5 (29.8) 69.8 (32.7) 71.0 (33.2)
.666
Quality of Life: EORTC QLQ−C30 Symptom Scales / Single Items# − Mean (SD) Fatigue CAT users 29.5 (21.2) 35.8 (22.0) 37.8 (23.8) Non-users 29.1 (17.8) 40.2 (21.0) 43.4 (23.5)
.391
Nausea and Vomiting CAT Users 12.2 (23.5) 16.7 (24.1) 21.2 (25.4) Non-users 11.7 (23.0) 17.8 (23.8) 21.9 (26.8)
.882
Pain CAT users 26.0 (26.4) 17.7 (23.9) 27.6 (28.3) Non-users 27.8 (27.7) 21.3 (25.2) 18.8 (26.1)
.796
Sleep Disturbance CAT users 44.8 (38.4) 31.2 (32.7) 34.4 (36.4) Non-users 35.2 (36.5) 31.5 (36.5) 32.1 (32.0)
.532
Appetite Loss CAT users 17.7 (29.3) 14.6 (25.3) 19.8 (35.8) Non-users 14.5 (26.3) 23.0 (30.0) 23.6 (33.1)
.561
Depression: Beck Depression Inventory Short Form# − Mean (SD) CAT users 3.0 (3.0) 3.2 (3.6) 3.1 (4.0) Non-users 2.2 (2.8) 2.1 (3.2) 2.3 (3.0)
.176
Cognitive Emotional Distress: Impact of Event Scale− Intrusion Subscale# − Mean (SD) CAT users 8.0 (7.6) 5.0 (3.5) 5.1 (4.2) Non-users 5.3 (5.3) 4.7 (6.7) 3.9 (5.2)
.184
Premorbid Neuroticism: EPQ−R Neuroticism Short Form# − Mean (SD) CAT users 3.1 (3.0) − − Non-users 3.0 (2.9) − −
.901
§ Higher scores = healthier functioning. # Higher scores = greater symptomatology/problems. † 47 patients went off-study by post-
treatment, thus analysis involved 48 complementary/alternative therapy (CAT) users and 105 non-users. ‡ p- values for between-
subjects main effects for CAT use (use vs no use) in split-plot ANOVAs are cited only, as within-subjects effects for treatment stage
are secondary. * A significant interaction between Emotional Functioning (EF) and CAT use across treatment was found in split-plot
ANOVA tests of within-subjects effects (p=.042); the main effect for EF was not significant (p=.321).
42
Association between Complementary and Alternative Therapy Use and Health-
Related Quality of Life / Psychological Functioning
Consistent with oncologists’ ratings, CAT users reported poorer global quality of life
(Selby QOL Uniscale) than non-users across treatment. However, statistical significance
was not met in a split-plot analysis of variance (SPANOVA), F(1, 151) = 3.51, p = .065
(see Table 4), nor in a split-plot analysis of covariance controlling for patients’ variable
treatment durations and starting points for CAT use, F(1, 149) = 3.24, p = .076. Similar
findings were also observed for cognitive functioning, F(1, 151) = 3.49, p = .065. A
SPANOVA examining emotional distress (EORTC Emotional Functioning scale) and CAT
use revealed no significant main effect for CAT use, F(1, 151) = .03, p = .859, but a
significant interaction between emotional distress and CAT use over time during treatment,
F(2, 150) = 2.86, p = .043. Simple effects analyses via a oneway repeated measures
ANOVA revealed a significant improvement in emotional functioning of CAT users
between pretreatment and on-treatment (74.2 vs 80.1, p = .042), but that by post-treatment
emotional distress had regressed somewhat to baseline levels (74.2 vs 76.6, p = 1.0). As
expected, the same analysis uncovered no significant differences in emotional distress
across treatment for non-users. Finally, on related measures of depression (BDI-SF) and
cognitive-emotional distress (IES-IS), CAT users again consistently reported higher scores
than non-users, but results did not reach statistical significance (depression: p = .176;
cognitive-emotional distress: p = .184).
DISCUSSION
30% of the 200 medical oncology patients in this study reported use of a diverse range of
complementary and alternative therapies for a variety of reasons. The rate of uptake falls in
the 22-52% range reported by such patients in previous Australian studies.6,7 CAT use was
associated with being younger (18-39 years), tertiary educated, possessing one or more
comorbid medical conditions, and undergoing lengthy cancer treatment (> 6 months).
These results partially confirm earlier findings that CAT users were younger (use
decreasing with age) and more educated,1,24,25 with female gender being a notable omission
in the present study.
Patients used CATs in conjunction with chemotherapy, radiation therapy and surgery.
While use was not associated with the type of cancer treatment received or its intent, it was
43
associated with treatment duration. Patients receiving more than 6 months of treatment
were nearly 3 times more likely to engage in CAT use than those who did not.
Additionally, patients felt that CATs were useful in combating the deleterious physical and
psychological side-effects of cancer and its treatment, particularly if lengthy. As in other
studies,6,9,35 53% of CAT users adopted multiple therapies. The CATs chosen were a mix of
British and American influences, with psychological and nutritional/megavitamin and
mineral approaches, respectively, being most frequently reported. Similar observations
were made in another Australian study.6
Significantly, almost two thirds of patients using CATs perceived benefit, mainly citing
enhanced physical and emotional well-being, and only one patient relinquished use during
cancer treatment. Supportive evidence for benefit, however, was mixed. Compared to non-
users, CAT users did not score significantly better on any measure of physical health,
quality of life or psychological function. In fact, use of CATs may be clinically significant
as a marker for psychosocial distress. Although not statistically significant, CAT users
generally reported higher levels of psychological distress/anxiety and depression than non-
users across treatment, especially at pretreatment. While emotional distress levels of CAT
users significantly declined between pretreatment and on-treatment (8 weeks), no
improvements were observed for non-users across treatment. With ongoing/new CAT use,
these patients reduced their emotional distress to the more desirable levels experienced by
non-users after 8 weeks of cancer treatment (on-treatment). Add to this that most patients
adopting CATs had done so by on-treatment, these results together with the recurring theme
of personal control of one’s disease in patients’ written comments, suggest that
complementary and alternative therapies enhance psychological well-being during the early
stages of cancer treatment for patients who struggle to cope at the outset. This process may
occur via a mechanism of empowerment rather than any direct biological change initiated
by CATs. Randomized controlled trials, however, are required to investigate this further.
Some limitations of this study must be acknowledged. The rate of CAT use in the current
sample may not be generalizable to cancer patients Australia-wide. Patients were recruited
for a larger study not explicitly targeting CAT use; and were self-selected, English-
speaking, chiefly public health patients, and conventionally treated. Also, patients were not
screened for pre-existing CAT use prior to diagnosis, nor given any extensive definitions
44
regarding what CATs were. Despite these shortcomings, the importance of the results of
this longitudinal study cannot be ignored. Few, if any, studies have monitored
complementary and alternative therapy use in tandem with changes in quality of life and
psychological adjustment experienced by cancer patients across treatment.
With the increasing interest of cancer patients in complementary and alternative therapies,
the boundaries between mainstream and unconventional oncology care are becoming less
clear. It would be valuable for oncologists to possess basic knowledge of specific CATs
and their demonstrable benefits or adverse side-effects. However, recent research13,22
indicates that oncologists have self-identified gaps in their knowledge of CATs used by
some patients, and have suggested a need to consider including education about them in
medical training. Currently, complementary and alternative medicine is taught in up to 60%
of US medical schools and is a part of conventional medical practice in Europe.34
Sceptics may question the need for oncologists to increase their knowledge of CATs when
most remain clinically unproven,36,37 but without such knowledge they may be unable to
give adequate advice to their patients about possible health risks of their use. As explained
in the Australian Clinical Practice Guidelines for Management of Early Breast Cancer,18
unsupportive and dismissive attitudes are less likely to discourage patients from using
potentially harmful and costly complementary and alternative therapies than open and
rational discussion. Furthermore, the Australian consumer publication “All about early
breast cancer”, produced by the NHMRC National Breast Cancer Centre38, urges patients
to: ‘discuss with your doctors the complementary and unproven approaches you are using
or thinking about using as some unproven approaches are known to adversely affect
conventional treatments’ (p.82). Indeed, anecdotal evidence suggested that patients in the
present study didn’t do this nearly enough; only 14% (8/59) of those who used CATs were
noted in medical records by oncologists as having disclosed their use. Moreover, a minority
of these patients also commented to the first author that they didn’t advise oncologists of
their CAT use out of fear that conventional treatment would be terminated, or concern that
it would strain the doctor-patient relationship.
Ultimately, cancer patients, for the most part, need to feel empowered in helping to control
and manage their chronic illness, and feel able to discuss CAT use with their oncologist and
45
other health professionals. A clinician who genuinely listens and supports patient choice,
and whose advice minimizes risk rather than dismisses complementary and alternative
therapies is more likely to encourage patients to use them appropriately as an adjunct,
rather than as an alternative that replaces conventional medical treatment.
Newly-reported use of complementary and alternative therapies by cancer patients should
trigger clinicians to inquire about anxiety, depression or physical symptoms, as
recommended in an earlier study.23 This may be difficult given the frequent time constraints
for consultations in increasingly busy oncology outpatient clinics. Chemotherapy nurses,
psychologists, counsellors, and other health professionals may be better-placed to address
these issues and ensure provision of valid and reliable information to cancer patients
contemplating complementary and alternative therapy use. These consultations could also
assist in the identification of patients who may benefit from interventions targeting their
physical and psychological needs. In this way, optimal holistic care will be ensured for
cancer patients by clinicians providing conventional oncology treatment.
ACKNOWLEDGEMENTS
We are grateful to The Cancer Council Western Australia and Murdoch University for their
financial support. We would like to thank Mr Seng Tan and Ms Crystal Laurvick for
assisting in preliminary data analysis and Dr Harold J. Burstein for his comments on an
early draft of this paper. Finally, we would like to thank the patients and staff at the
Department of Medical Oncology, Royal Perth Hospital, as this research would not have
been possible without them.
REFERENCES
1. Cassileth BR. Complementary and alternative cancer medicine. J Clin Oncol 1999; 17:
44-52.
2. Druss BG, Rosenheck RA. Association between use of unconventional therapies and
conventional medical services. JAMA 1999; 282: 651-656.
46
3. MacLennan AH, Myers SP, Taylor AW. The continuing use of complementary and
alternative medicine in South Australia: Costs and beliefs in 2004. Med J Aust 2006;
184: 27-31.
4. Australian Bureau of Statistics. Australian social trends 1998. Australian Bureau of
Statistics, Canberra Australia 1998.
5. Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in
cancer. Cancer 1998; 83: 777-782.
6. Begbie SD, Kerestes ZL, Bell DR. Patterns of alternative medicine use by cancer
patients. Med J Aust 1996; 165(10): 545-548.
7. Miller M, Boyer MJ, Butow PN, Gattellari M, Dunn SM, Childs A. The use of
unproven methods of treatment by cancer patients: Frequency, expectations and cost.
Support Care Cancer 1998; 6: 337-347.
8. Yates PM, Beadle G, Clavarino A, et al. Patients with terminal cancer who use
alternative therapies: Their beliefs and practices. Sociol Health Illn 1993; 15(2): 199-
216.
9. Sawyer MG, Gannoni AF, Toogood IR, Antoniou G, Rice M. The use of alternative
therapies by children with cancer. Med J Aust 1994; 160: 320-322.
10. Ernst E. A primer of complementary and alternative medicine commonly used by
cancer patients. Med J Aust 2001; 174: 88-92.
11. Schraub S. Unproven methods in cancer: A worldwide problem. Support Care Cancer
2000; 8: 10-15.
12. Risberg T, Lund E, Wist E, Kaasa S, Wilsgaard T. Cancer patients use of non-proven
therapy: A 5-year follow-up study. J Clin Oncol 1998; 16: 6-12.
47
13. Newell S, Sanson-Fisher RW. Australian oncologists’ self-reported knowledge and
attitudes about non-traditional therapies used by cancer patients. Med J Aust 2000; 172:
110-113.
14. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with
cancer: Meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22: 1369-1381.
15. Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE.
Complementary/alternative medicine use in a comprehensive cancer center and the
implications for oncology. J Clin Oncol 2000; 18: 2505-2514.
16. Boon H, Stewart M, Kennard MA, et al. Use of complementary/alternative medicine by
breast cancer survivors in Ontario: Prevalence and perceptions. J Clin Oncol 2000; 18:
2515-2521.
17. White P. Complementary medicine treatment of cancer: A survey of provision.
Complement Ther Med 1998; 6: 10-13.
18. National Health and Medical Research Council. Clinical Practice Guidelines. The
Management of Early Breast Cancer, 2nd edn. The Stone Press, Sydney Australia 2001.
19. Montbriand MJ. Freedom of choice: An issue concerning alternate therapies chosen by
patients with cancer. Oncol Nurs Forum 1993; 20: 1195-1201.
20. Kao GD, Devine P. Use of complementary health practices by prostate carcinoma
patients undergoing radiation therapy. Cancer 2000; 88: 615-619.
21. Derogatis LR, Morrow GR, Fetting J, et al. The prevalence of psychiatric disorders
among cancer patients. JAMA 1983; 249: 751-757.
22. Carroll BT, Kathol RG, Noyes R, Wald TG, Clamon GH. Screening for depression and
anxiety in cancer patients using the Hospital Anxiety and Depression Scale. Gen Hosp
Psychiatry 1993; 15: 69-74.
48
23. Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative medicine by women
with early-stage breast cancer. N Engl J Med 1999; 340: 1733-1739.
24. Crocetti E, Crotti N, Feltrin A, Ponton P, Geddes M, Buiatti E. The use of
complementary therapies by breast cancer patients attending conventional treatment.
Eur J Cancer 1998; 34: 324-328.
25. Girgis A, Adams J, Sibbritt D. The use of complementary and alternative therapies by
patients with cancer. Oncol Res 2005; 15: 281-289.
26. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research
and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international
clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365-376.
27. Ringdal GL, Ringdal K. Testing the EORTC Quality of Life Questionnaire on cancer
patients with heterogenous diagnoses. Qual Life Res 1993; 2: 129-140.
28. Selby PJ, Chapman JAW, Etazadi-Amoli J, Boyd NF. The development of a method for
assessing quality of life of cancer patients. Br J Cancer 1984; 50: 13-22.
29. Beck AT, Beck RW. Screening depressed patients in family practice: A rapid technic.
Postgrad Med 1972; 52: 81-85.
30. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: A measure of subjective
stress. Psychosom Med 1979; 41: 209-18.
31. Joseph SA, Williams R, Yule W, Walker A. Factor analysis of the Impact of Event
Scale with survivors of two disasters at sea. Pers Individ Diff 1992; 13: 693-697.
32. Threlfall TJ, Thompson JR. Cancer incidence and mortality in Western Australia, 1998:
A report of the Western Australian Cancer Registry. Health Department of Western
Australia, Perth Australia 2000.
49
33. Guyatt, G, Walters S, Norman G. Measuring change over time: Assessing the
usefulness of evaluative instruments. J Chronic Disease 1987; 40: 171-178.
34. Bensoussan A. Complementary medicine: Where lies its appeal? Med J Aust 1999;
170: 247-248.
35. Crocetti E, Crotti N, Montella M, Musso M. Complementary medicine and
oncologists’ attitudes: A survey in Italy. Tumori 1996; 82: 539-542.
36. Jacobsen JS, Workman, SB, Kronenberg, F. Research on complementary/alternative
medicine for patients with breast cancer: A review of the biomedical literature. Journal
of Clinical Oncology 2000; 18(3): 668-674.
37. Ernst E, Cassileth BR. How useful are unconventional cancer treatments? Eur J Clin
Cancer 1999; 35 (11): 1608-1613.
38. National Breast Cancer Centre. All about early breast cancer. NHMRC National Breast
Cancer Centre, Sydney Australia 1998.
FOOTNOTES
†In hindsight, it may have been preferable to ask patients to describe not only any
benefits they perceived from CAM use, but also any harm or discomfort from CAM use
also. Nonetheless, all 200 cancer patients were given an opportunity in multiple study
questionnaires (proximal to the CAM questions, Appendix B, p.255) to describe any
problem, health-related or otherwise, that they felt was most important in the preceding few
weeks. While some patients reported problems relating to conventional cancer treatment,
none of the 59 patients (30%) who disclosed CAM use described any associated problems.
Furthermore, in a clinical audit of study patients’ medical notes designed to summarise
treatment experiences, CAM use was documented by cancer physicians for 10 patients
(5%) with only one instance of adverse effects (i.e. a recurrent metastatic melanoma patient
receiving palliative radiotherapy reported abdominal pains and flatulence from ingestion of
high dose vitamin A and other preparations, and was advised by his oncologist to
discontinue CAM use).
50
Chapter 3: Complementary and Alternative Medicine Used by Patients with Cancer –
Evidence for Efficacy and Safety
3.1 Preface to Study 2
The manuscript comprising study 2 underwent peer review and was published as an
invited book chapter in the edited publication, Perspectives on Complementary and
Alternative Medicine. The manuscript in the form in which it was published is presented
overleaf. It is followed by a post-publication update of the systematic review that appears in
study 2 (comprising a discussion of more recent and newly-located publications per se not
included in the original review), as well as a commentary article summarising study 2 for
health professionals (see sections 3.2 and 3.8, respectively). However, an earlier revision of
the manuscript is located in Appendix C. It contains summary tables and material that was
otherwise replicated by the authors of other chapters in the edited publication, and
subsequently culled due to space restrictions imposed by the publisher. Appendix D also
contains a detailed methodology of study 2, which provides more detail regarding the
process that underpinned the systematic review performed.
Original Publication
Pirri, C. (2012). Complementary and alternative medicine used by patients with cancer:
Evidence for efficacy and safety. In: I. N. Olver & M. C. Robotin (Eds.),
Perspectives on complementary and alternative medicines (pp. 31-87). London:
Imperial College Press.
51
Chapter 3
CAM Used by Patients with Cancer: Evidence for Efficacy and Safety
Carlo Pirri
Faculty of Health Sciences (Psychology), Murdoch University, Murdoch, Australia
Correspondence: Carlo Pirri (Research Associate/PhD Candidate), Faculty of Health
Sciences (Psychology), Murdoch University, South Street, Murdoch WA 6150, Australia.
Email: [email protected]
Tel.: 61 (0) 8 9360 7382
Fax: 61 (0) 8 9360 6492
Abstract
In Australia the overall prevalence for complementary medicine use is 14% to 65% among
Australian adults diagnosed with cancer (with estimates as high as 80% to 91% in the US
and Europe), and 8% to 14% for alternative medicine use among adult cancer patients.
Given the increasing desire of cancer patients to use CAM, it is important that clinicians
have a good understanding of the levels of evidence available for the efficacy and safety of
specific complementary and alternative therapies. This systematic review aims to evaluate
the efficacy and safety of a range of CAMs in each of five NCCAM/NICM categories used
by cancer patients (upon diagnosis, during conventional treatment, in response to disease
progression or recurrence, or during remission/survivorship) in Australia and elsewhere.
Where possible, evidence from meta-analytic and systematic reviews is utilised. Currently,
there is evidence from high quality clinical trials that some complementary therapies, used
as adjuncts to conventional medical treatments, are beneficial in reducing disease or
treatment symptoms and improving quality of life and psychological functioning. There is
evidence of potential harm also. It is therefore imperative that those involved in the medical
care of cancer patients are equipped with the skills and knowledge to help patients
appropriately evaluate complementary and alternative therapies. Additionally, clinicians are
strongly encouraged to routinely ask patients about complementary and alternative therapy
52
use. Offering evidence-based complementary therapies alongside conventional treatments
in cancer services can influence patients’ decisions to continue with mainstream care and
help avoid any potential harm that may occur with autonomous CAM use.
Key Words: complementary and alternative medicines, efficacy, safety, systematic review
53
1. Popular CAM Approaches and Evidence for Use
1.1 Whole medical systems
Whole medical systems are complete systems of diagnosis and practice, both developed in
Western cultures (e.g. homeopathy), as well as in other cultures (e.g. Traditional Chinese
Medicine, Ayurveda).
1.1.1 Homeopathy
Homeopathy is based on the proposed law of similars that “like cures like”, whereby low
concentrations of substances that cause symptoms in healthy individuals can be used to
treat patients with similar symptoms. Homeopathic medicines are generally safe in terms of
adverse effects and interactions with conventional treatments. A systematic review of 53
studies found that homeopathic medicines prescribed by trained practitioners in low
concentrations are probably safe and unlikely to cause serious adverse events, with the
main risks being indirect, stemming from practitioner inexperience (e.g. misdiagnosis).1
Systematic reviews of controlled trials have found that homeopathic medicines appeared to
improve symptom management during chemotherapy and radiotherapy (specifically
chemotherapy-induced stomatitis and acute radiotherapy-induced dermatitis).2 While
producing encouraging preliminary evidence, the authors of both reviews expressed
concern about the general lack of evidence and the clinical heterogeneity of identified
homeopathy studies and cautioned that further research was required before any definitive
recommendations on use by cancer patients could be made.
1.1.2 Naturopathy
Naturopathy is an alternative medical system based on the core beliefs that nature has the
ability to heal and that the human body has the vital ability to maintain and heal itself.
Naturopaths favour natural remedies and minimally-invasive approaches in preference to
surgery and drugs. Practitioners use a wide variety of treatment modalities, including
dietary and lifestyle changes (e.g. eating more whole and unprocessed foods, abstaining
from alcohol and sugar, stress reduction); using vitamins, minerals and nutritional
supplements; herbal medicine; homeopathy; mind-body techniques (e.g. meditation, yoga,
counselling); and manipulative and body-based therapies (e.g. hydrotherapy, physical
54
exercise). Given the overlap of naturopathic remedies with other categories of CAM, they
will be reviewed in their respective sections below.
1.1.3 Traditional Chinese medicine
Traditional Chinese medicine (TCM) is based upon the concept that the human body is a
dynamic universe of interconnected energy systems and aims to maintain balance, harmony
and order of these systems to ensure healthy body functioning. TCM treatments include
acupuncture and related techniques (e.g. acupressure, moxibustion), Chinese herbal
medicine, massage (e.g. tui na, cupping), exercise and breathing techniques (e.g. Qigong),
and dietary and lifestyle advice.
TCM is predominantly used by cancer patients to improve immune function, for symptom
management (i.e of general constitutional symptoms such as fatigue, pain and depression,
and for specific symptoms such as gastrointestinal distress, or appetite loss) and overall
well-being, as well as to enhance the effects of conventional treatments in chemotherapy
and radiotherapy. In a review of randomised controlled trials (RCTs) and observational
studies of TCM in supportive cancer care,3 the authors concluded that overall there was
sufficient preliminary evidence to suggest that further quality clinical trials were warranted
to evaluate the effects on QoL and survival of integrating TCM into conventional oncology
care (see below for discussion of specific TCM treatments).
1.2 Mind-body techniques
Mind-body techniques involve individuals learning coping strategies to deal with emotional
distress that may be manifest in physical symptoms. Techniques include practitioner-
administered therapies such as hypnotherapy and mindfulness-based stress reduction, and
self-help strategies such as relaxation, meditation and creative therapies (including art,
music and dance therapy). Some techniques that were considered CAM in the past have
become mainstream (e.g. patient support groups), but they are discussed below nonetheless,
because they complement conventional anticancer treatment.
1.2.1 Relaxation
Relaxation techniques originated in the early 1900s in the U.S. and Europe. They are
designed to elicit a state of mental and physical relaxation, most commonly by focusing
55
attention on the sensations associated with systematically tensing and relaxing muscle
groups, as in progressive muscle relaxation (PMR), or to achieve a hypometabolic state of
reduced sympathetic arousal (e.g. via autogenic training, PMR augmented with
diaphragmatic breathing and/or guided imagery). Relaxation techniques often involve
diaphragmatic or deep breathing (slow, deep rhythmic breathing) to aid in the release of
muscle tension, and may incorporate guided imagery/visualisation (evoking images, usually
sensory or affective) to calm the mind. Relaxation is generally safe and adverse events are
rare.
Turning to efficacy, a meta-analysis of 15 RCTs involving patients undertaking acute non-
surgical cancer treatment (chemotherapy, radiotherapy, bone marrow transplantation,
hyperthermia) revealed that relaxation exerted significant positive effects on nausea, pain,
physiological arousal (blood pressure, heart rate), anxiety, depression and hostility.4 A
more recent meta-analysis of 25 controlled trials and observational studies also found
reasonably strong evidence for the efficacy of relaxation-based interventions in reducing
cancer pain,5 while recent systematic reviews derived some support that relaxation reduced
pain,6 nausea and vomiting7 and anticipatory nausea and vomiting,8 respectively.
1.2.2 Meditation
Meditation is an ancient Eastern practice that has been popularly adopted worldwide. It
involves training the mind to focus on breathing or a specific object/image in an effort to
free it of all thought (concentrative meditation), or to focus on sensations experienced in the
present moment in a non-judgmental and accepting manner, to establish a stable, non-
reactive awareness to the physical or psychological symptoms associated with them
(mindfulness meditation).9 Most meditation practices were developed within a religious or
spiritual context and the ultimate goal is to achieve some form of spiritual/personal growth
or transcendental experience and to find a system of values and philosophy of life, whereas
many approaches in behavioural medicine (e.g. relaxation, biofeedback) are designed as
treatments for particular disorders.10 There are many forms of meditation (e.g. Sahaja yoga
meditation, Vipassana meditation), but the two most researched practices are mindfulness
and transcendental meditation [the latter involves a silent word or phrase (a mantra) being
repeated in order to calm (and ultimately transcend) the ordinary flow of internal mental
dialogue].11
56
Meditation is generally safe and serious adverse events are rare, but it is not without some
side-effects. Common adverse effects include relaxation-induced anxiety and panic,
restlessness, frustration, paradoxical increases in tension, depersonalisation or derealisation
(which can recur after meditation), antisocial behaviour and flattened affect.12,13 Other
adverse effects during and after meditation may include reduced motivation, boredom,
difficulty in returning to normal life after meditation retreats, pain, impaired reality testing,
disorientation, feeling “spaced out”, depression, other psychological sequelae and feeling
addicted to meditation.12
In any case, most studies reporting safety concerns about meditation have involved
transcendental or Vipassana meditation and most side-effects have been observed in longer-
term retreats (e.g. 10 days) and/or intensive meditation (e.g. 3 hour sessions). which are not
formally recommended for “novice” patients of some meditation practices such as
mindfulness.14,15 Moreover, only 7.4% of long-term meditators in one study reported severe
adverse effects.12 Nevertheless, meditation practices (transcendental or Vipassana
meditation, in particular) should be used with caution or are best avoided in cancer patients
with (a history of) psychosis, personality/bipolar/dissociative/hypochondrial/somatisation
disorders, or with physical exhaustion.14-16
A meta-analysis of 3 RCTs and 7 observational studies suggested that mindfulness-based
stress reduction (MBSR) may improve breast cancer patients’ psychological adjustment to
illness (i.e. ameliorating anxiety, stress, fatigue, general mood and sleep disturbance), but it
found less convincing evidence to support improvement in physical health.17 Additional
larger RCTs involving other cancer populations were recommended. Similar conclusions
were also drawn in recent systematic reviews involving cancer patients using MBSR or
mindfulness meditation alone.6,18,19
1.2.3 Hypnotherapy
Hypnotherapy is a psychological approach that induces a state of aroused consciousness in
which suggestions are made to an individual to facilitate behaviour change or symptom
relief. An induction procedure, often involving relaxation/imagery techniques, is used prior
to suggestion. The efficacy of hypnotherapy is associated with an individual’s level of
suggestibility, particularly in achieving long-term symptom relief.20 Hypnotherapy is
57
generally safe when administered by qualified practitioners, but some individuals might
experience transient side-effects during or after hypnosis.21,22, These adverse effects include
headaches, drowsiness, confusion, dizziness, or nausea and, less frequently, anxiety or
panic;22 they occur in 5% to 31% of individuals who undertake hypnotherapy.21 Serious
adverse events are rare and typically involve exacerbation of psychological symptoms,
which is usually caused by the misapplication of hypnotherapeutic techniques or poor
clinical practice (e.g. not preparing patients sufficiently).21 Nevertheless, the World Health
Organization and others caution against the use of hypnotherapy in individuals with (a
history of) psychosis, personality disorders or organic psychiatric conditions.23
A meta-analysis of 6 RCTs (one in adults, five in children) has suggested that hypnotherapy
is effective in reducing anticipatory and chemotherapy-induced nausea and vomiting in
paediatric patients alone.24 Furthermore, a more recent systematic review found that
hypnotherapy improved cancer pain without exception in a small number of controlled and
observational studies;6 and systematic reviews of RCTs and observational studies have
demonstrated that hypnotherapy is a potentially valuable treatment for acute procedural
pain and distress in adult and paediatric cancer patients,25,26 although large RCTs are
needed.
1.2.4 Yoga
Yoga is a series of practices that incorporate eight disciplines, including physical poses and
postures, breath control and meditation, with the goal of uniting the mind, body and spirit
for improved physical/mental health and self-awareness. There are many types of yoga,
with Hatha yoga (a gentle form most commonly practiced in Western countries) and
Tibetan yoga being the most studied in recent years. Yoga has been be well-tolerated in
studies and no serious adverse effects. Nevertheless, yoga should be avoided or used in a
gentler, modified form by individuals with balance problems; uncontrolled hypertension,
symptomatic anaemia, postural hypotension; infection or significant thrombocytopenia;
certain eye conditions (e.g. glaucoma); severe osteoporosis and bone injury, vertebral
damage or cervical spondylosis; artificial joints or prothetic devices (e.g. infusaport,
colostomy bag), pregnancy; and psychosis.27
58
Two systematic reviews of RCTs and observational studies provide preliminary support for
the efficacy of yoga interventions in cancer patients and survivors.28,29 Positive effects were
reported for a range of outcomes including sleep quality, mood, stress and overall QoL, but
more RCTs are needed.
1.2.5 Tai chi
Sometimes referred to as “moving meditation”, tai chi is derived from TCM and
incorporates slow movements and postures (similar to aerobic exercise), controlled
breathing and meditation. Tai chi appears to be generally safe and no serious adverse
effects have been reported in cancer and other chronic disease populations.30,31
Tai chi has been used by cancer patients to improve QoL, mood, flexibility, and balance.31
Two systematic reviews of controlled studies in supportive breast cancer care, however,
have found insufficient evidence for the positive impact of tai chi on physical or
psychological outcomes and QoL in patients.30,31 Large RCTs involving breast and other
cancer populations are required.
1.2.6 Music therapy
Music therapy is designed to facilitate communication and achieve therapeutic goals
through the creative use of music alone or in combination with relaxation/imagery
techniques. A recent meta-analysis of 183 studies across 11 medical specialties (with a
heavy emphasis on cancer patients) revealed that music therapy resulted in significant
improvements in pain, well-being, mood, and nausea and vomiting.32 Nevertheless, more
large RCTs are required, although music therapy could be supported for use in cancer
patients in the interim given its association with few (if any) adverse events.
1.2.7 Support groups
Support groups enable patients at any stage of their cancer experience to gain emotional
support from others with similar experiences (and to reciprocate in kind) by sharing. Cancer
support groups include a variety of different approaches (e.g. psychotherapy,
psychoeducation, cognitive-behavioural therapy), types (e.g. face-to-face, telephone or
internet support) and settings (e.g. community centres or hospitals, the patient’s home)
encompassing health professional-led support groups and self-help groups.
59
A meta-analysis of 20 RCTs has suggested that participation in professional-led support
groups results in significant improvements in cancer patients’ emotional well-being
(depression, anxiety), adjustment to illness, QoL and marital satisfaction, but not survival.33
Similarly, a more recent systematic review of 32 RCTs and 12 descriptive studies revealed
that professional-led support groups produced positive effects in psychosocial functioning
(less social isolation, felt more understood and hopeful) and morale and other QoL
dimensions, but not improved survival.34 Further RCTs of professional-led support groups
involving different cancer populations, preferably in community settings, are required.
Benefit from peer/volunteer support programmes, however, is less apparent for cancer
patients. A systematic review of 16 controlled trials and 26 descriptive studies indicated a
high level of satisfaction with individual/group peer support programmes, but mixed
evidence for psychosocial benefit.35 A systematic review of 10 controlled trials and 10
descriptive studies also found a high level of satisfaction among participants in individual
volunteer support programmes, but very limited evidence for psychosocial benefit given the
lack of RCTs performed.36 Again, more large RCTs involving different cancer populations
are needed.
1.2.8 Spirituality, religion and prayer
Spirituality and religion are overlapping concepts that involve a search for the sacred, in
which individuals seek to discover, hold on to, and, when necessary, transform whatever
they hold sacred in their lives.37 Spirituality differs from religion in that religion is a search
for significance in ways related to the sacred38 and, in instances of popular usage, places
spirituality within the context of beliefs, values and practices of an organised institution.39
A systematic review of 7 longitudinal and 10 cross-sectional studies found some evidence
for improved adjustment to illness or reduced distress of religious/spiritual coping with
cancer, but could not draw any firm conclusions,40 A more recent review of 4 longitudinal
and 36 cross-sectional studies drew similar conclusions regarding spirituality and emotional
well-being in cancer patients.41 Further large longitudinal studies are required.
Researchers have argued that prayer can be separated from religion in the same way that
related activities such as meditation have.42 A systematic review of 7 prospective cohort
60
studies, 14 cross-sectional studies and 3 qualitative studies involving hospitalised
populations (including cancer patients) found a positive association between private prayer
and emotional well-being (anxiety, depression), optimism and functioning, respectively, in
patients with religious faith who engage in regular devoted prayer, and some evidence that
prayer out of desperation (e.g. in response to pain, poor prognosis or postoperative trauma)
in the absence of faith is associated with poorer emotional well-being and functioning.43
More rigorous studies involving cancer patients across different religions are needed,
however.
Studies examining the effects of intercessory prayer on well-being are rarer and reported in
another chapter of this book. Additionally, a systematic review of 17 epidemiological
studies (including a subgroup analysis of 11 studies adjusted for demographic and lifestyle
factors) revealed no significant reduction in cancer risk among members of Christian
communities compared to the general population, and concluded that a healthy lifestyle was
the most important mediating factor in explaining any correlation observed between
religious membership and cancer risk.44 Finally, two meta-analyses of randomised trials
involving medical populations (including leukaemia patients) have found insufficient
evidence that distant intercessory prayer has any beneficial effects on clinical outcomes
(health, mortality, hospital re-admission).45,46
1.3 Biologically-based practices
Biologically-based practices involve supplementing a person’s normal diet with additional
extracts, nutrients, herbs and/or certain foods. Examples include, nutritional supplements,
herbal and other plant-based preparations (botanicals), animal-derived extracts, vitamins,
minerals, fatty acids, amino acids, proteins, prebiotics and probiotics (live bacteria often
found in whole grains, yoghurt and functional foods), whole diet therapies, functional
foods, and other so-called natural therapies (e.g. shark cartilage for cancer treatment).47
1.3.1 Nutritional supplements (dietary supplements, food supplements)
Nutrients in dietary supplements may include vitamins, minerals, herbs or other plant-based
substances (botanicals), amino acids, fatty acids, and substances such as enzymes.
Nutritional supplements may be extracts or concentrates sold as tablets/capsules, liquids, or
powders.
61
1.3.1.1 Antioxidants
Free radicals are unstable molecules produced when the body breaks down food, or is
exposed to environmental influences (e.g. tobacco smoke, radiation). While free radicals
are essential for various biological functions including the removal of damaged cells, they
are also highly reactive and can damage healthy cells via oxidation. Excessive free radicals
may play a role in the development and progression of certain diseases, such as cancer,
cardiovascular disease and liver disease.48 Antioxidants neutralise free radicals and may
protect cells in the body from damage caused by oxidative stress.49 Broadly, antioxidants
take the form of nutrients [e.g. vitamins C (ascorbic acid) and E (alpha-tocopherol);
minerals such as selenium and zinc] and non-nutrients (e.g. phytochemicals such as
lycopene, beta-carotene and indole-3-carbinol; zoochemicals in red meat and fish products).
Whilst present in food and beverages, they are commonly taken as nutritional supplements
(capsules/tablets, powders) alone or in combination with vitamins and minerals.
Proponents argue that antioxidants are beneficial to cancer patients because they enhance
the efficacy of chemotherapy, as well as alleviate treatment toxicity and thus allow patients
to tolerate full courses of chemotherapy and/or radiotherapy with fewer dose reductions.50
Others are concerned that antioxidants may not only reduce the efficacy of some
chemotherapy agents and radiotherapy, but may protect cancer cells as well as healthy cells
from oxidative damage.51
A recent systematic review of 33 RCTs found that concurrent use of antioxidants with
chemotherapy resulted in reduced toxicity in the majority of studies (which involved mostly
advanced or recurrent cancer patients), and that patients in 5 studies completed more full
doses of chemotherapy or had fewer dose reductions when receiving antioxidants than
control patients.52 Similarly, another review suggested that antioxidants may mitigate the
adverse effects of radiotherapy,53 while a meta-analysis of 14 RCTs showed that amifostine
(a synthetic antioxidant) significantly reduced the side-effects of radiotherapy.54 In contrast,
however, a systematic review of 22 controlled trials and observational studies involving
breast cancer patients found insufficient evidence that individual antioxidant supplements
reduced toxicity during conventional breast cancer treatment.55 Other systematic reviews
have also revealed insufficient evidence that selenium supplementation alleviates
chemotherapy- or radiotherapy-induced toxicity or postoperative side-effects in cancer
62
patients,56 or that selenium or lycopene supplementation relieves symptoms in prostate
cancer patients.57.58 Similarly, a systematic review of 6 controlled trials found inconclusive
evidence that coenzyme Q10 (synthetic antioxidant) reduced chemotherapy-induced
toxicity.59 Further large, well-designed RCTs are advised.
The formation of free radicals is the primary mechanism by which radiotherapy and many
chemotherapy drugs act in destroying cancer cells. One systematic review of 21
randomised trials and 31 observational studies of antioxidants and chemotherapy observed
such great diversity across studies (study design, cancer diagnoses, chemotherapy
regimens, type/dose/schedule of antioxidant supplementation) that definitive conclusions
could not be made about the efficacy and safety of antioxidant supplementation.60
Similarly, a systematic review of 22 controlled trials and observational studies could not
draw any conclusions regarding the effects of antioxidants during breast cancer treatment
(chemotherapy, radiotherapy and/or hormonal therapy) on tumour response, survival or
recurrence,55 nor could the authors in a systematic review of lycopene supplementation in
prostate cancer patients.58 Another review of 44 randomised trials, however, went further
and concluded that concurrent use of antioxidants with chemotherapy and/or radiotherapy
should be discouraged, due to the possibility of tumour protection and reduced survival,
despite limited evidence of these negative outcomes during radiotherapy and limited
evidence that some antioxidant supplements may actually enhance the efficacy of
chemotherapy.61 In contrast, a systematic review found that the great majority of 19 RCTs
demonstrated either statistically significant or non-significantly greater survival and/or
treatment response for concurrent use of antioxidants with free radical-generating
chemotherapy, in patients with predominantly advanced or recurrent cancer.62 Additionally,
no evidence was found that antioxidant supplementation reduced the efficacy of
chemotherapy. Again, further large, well-designed studies are recommended.
More unequivocal, though, were the results of three meta-analyses. One meta-analysis of 7
RCTs (with no evidence of heterogeneity) found that amifostine (a synthetic antioxidant)
had no effect on tumour response in locally advanced non-small cell lung cancer in patients
treated with radiotherapy ± chemotherapy.63 Another meta-analysis and systematic review
of 38 studies found no support that vitamin E or C supplementation helped treat or prevent
cancer.64 The third meta-analysis of 10 unblinded RCTs (with no evidence of
63
heterogeneity), however, demonstrated consistent positive effects on 1-year survival across
melatonin dose and diagnosis for advanced solid tumour patients receiving melatonin alone
or combined with cancer treatment.65
In regard to chemoprevention, a meta-analysis of 22 RCTs indicated no evidence for the
primary or secondary prevention of cancer through use of antioxidant supplements.66
Another meta-analytic and systematic review of 12 RCTs (predominantly high quality)
revealed that antioxidant supplementation did not significantly reduce total cancer
incidence or mortality or any site-specific cancer incidence in primary prevention.67
Similarly, meta-analytic and systematic reviews do not support the supplementation of
antioxidants (vitamins A, C, E; selenium; beta-carotene) alone or in combination to prevent
colorectal cancer68 or gastrointestinal cancers;69 of vitamin C or E individually to prevent
cancer overall;64,67,70,71 or of vitamin C or E, folate or beta-carotene individually to prevent
lung cancer.72,73 Vitamin E and selenium may have preventative effects for prostate cancer
and gastrointestinal cancers or cancer in men, respectively, although confirmation is
required in further RCTs.67,69,70
Despite the lack of clinical trial data, antioxidants in foods are generally considered safe
and few studies of antioxidant supplements have reported adverse effects. Common minor
adverse effects include mild diarrhoea and gastrointestinal upset for vitamin C,74 and
carotenodermia (yellowish discolouration of the skin) following heavy, chronic intake of
beta-carotene.69 However, high-dose beta-carotene appears to increase lung cancer
incidence and cancer mortality among smokers;67,75 antioxidant supplementation may
increase the risk of bladder cancer;66 and high vitamin E supplementation may increase
bleeding in individuals with drug-induced vitamin K deficiency.74 Given the lack of long-
term safety data, antioxidant supplementation during cancer treatment is not recommended
without guidance from the treating oncology team.
1.3.1.2 Omega-3 fatty acids (n-3 polyunsaturated fatty acids)
Omega-3 fatty acids [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-
linolenic acid (ALA)] influence many physiological functions, including fertility, cell
division, angiogenesis, apoptosis and immune cell function, thus suggesting they may
protect against cancer or alter the response to cancer treatment.76,77 Omega-3 fatty acids are
64
found naturally in fish, fish oil, vegetable oils (mainly canola and soybean), walnuts, wheat
germ, and other foods or as supplements. They are also available as nutritional supplements
in fish oil preparations in both capsule and liquid form. EPA and, to a lesser extent, DHA
have demonstrated anti-cancer and anticachectic effects in human studies.78,79
A meta-analytic and systematic review of 38 studies, involving 20 different prospective
cohorts across 7 countries with different demographics, revealed that data across 11
different types of cancer suggested that nutritional supplementation with omega-3 fatty
acids is unlikely to prevent cancer.80 Additionally, a recent meta-analysis of 5 prospective
studies found a weak protective association between high dietary ALA intake (1.5g/day)
and prostate cancer risk.81 In contrast, two other recent meta-analyses of prospective and
case-control studies revealed that high intake or blood level of ALA (but not EPA or DHA
intake) is weakly associated with an increased risk of prostate cancer.82,83 Clearly, further in
vitro and epidemiological studies are needed.
Many advanced cancer patients develop cachexia and treatment of associated weight loss
and other symptoms has proven difficult. More recently, novel approaches have included
the use of fish oils containing EPA and DHA. A Cochrane meta-analytic review of 5 RCTs
found insufficient data to establish whether oral EPA was better than placebo in improving
symptoms associated with cachexia in advanced cancer patients.78 Similarly, a meta-
analytic and systematic review of 19 studies demonstrated no effect of omega-3 fatty acids
on weight loss, nutritional status, postoperative complications, mortality or length of
hospital stay after surgery for upper gastrointestinal cancers.80 A more recent systematic
review of 17 clinical trials and prospective studies, however, suggested that dietary or
supplemental intake of omega-3 fatty acids (EPA and/or DHA; 1.5g/day) for prolonged
periods (8 weeks) by advanced cancer patients is associated with improved clinical
(nutritional status, tolerance, survival, hospital stays), biological and QoL outcomes.79
Further large RCTs are recommended. Finally, omega-3 fatty acids are generally well-
tolerated and cause few adverse effects in low to moderate doses. Gastrointestinal
symptoms (e.g. diarrhoea, heartburn, bloating, nausea) are the most common side-effects.
65
1.3.1.3 Shark cartilage and AE-941 (Neovastat)
Shark cartilage use by cancer patients became popular in the 1980s after several poor
quality studies claiming “miracle” cancer cures were reported by the US media,84 many of
which were generated by a single manufacturer (Lane Labs-USA, producer of BeneFin).
Use of shark cartilage in cancer patients originally stemmed from and has been perpetuated
by the popular belief that sharks do not develop cancer because of the high proportion of
cartilage in their body (about 6% by body weight).85 Scientifically, this has been shown to
be untrue (several tumours in sharks have subsequently been detailed in a review article).86
Shark cartilage preparations are not standardised and there is no generally accepted
recommended dosage or duration for administration. The only standardised source of shark
cartilage is Neovastat (AE-941, manufactured by AEterna Zentaris), a matrix
metalloproteinase inhibitor specifically developed as a highly purified liquid shark cartilage
extract for evaluation in clinical drug trials. Generally, shark cartilage is well-tolerated. The
most common adverse effects reported are gastrointestinal symptoms (nausea, vomiting,
stomach upset, constipation, diarrhoea, flatulence) and taste alteration.87
While some preclinical studies of shark cartilage and preliminary clinical studies of
Neovastat have demonstrated anti-angiogenic and anti-cancer properties,88 and it has been
observed that cartilage lacks blood vessels and that human cancer rarely invades
cartilage,89,90 no controlled study has demonstrated that crude cartilage extracts are
beneficial in the treatment of cancer in humans (or animals).91,92 In a double-blind RCT of
83 incurable breast and colorectal carcinoma patients (with good performance status and
organ function), no differences in overall survival or QoL were observed between patients
receiving standard conventional care (including chemotherapy for some patients) with
powdered liquid shark cartilage extract (BeneFin nutritional supplement, 3-4 times daily
until unacceptable toxicity developed) versus standard conventional care with placebo.91
These results mirrored those of a previous uncontrolled phase I/II trial involving 60
advanced cancer patients.87
Larger RCTs involving the use of Neovastat in cancer patients have been similarly
disappointing. In a double-blind RCT of 305 metastatic renal cell carcinoma patients
refractory to immunotherapy, no survival advantage was observed in patients treated with
66
Neovastat versus placebo.93 More recently, a comprehensive double-blind RCT of 379
locally advanced non-small cell lung cancer patients (newly-diagnosed, unresectable and
previously untreated) found no differences in overall survival, tumour response rates, time
to disease progression and progression-free survival between patients receiving
chemoradiation with Neovastat (120ml orally, twice daily until disease progression or
unacceptable toxicity developed) versus chemoradiation with placebo.92 It was concluded
that the results do not support the use of shark cartilage-derived products for lung cancer
patients, and this has prompted the pharmaceutical manufacturer of Neovastat to cease
clinical development.
1.3.1.4 Laetrile and amygdalin (Vitamin B17)
Laetrile has been popularly used by cancer patients worldwide since the 1970s in the hope
that it might cure or slow the growth of cancer. The term “laetrile” is an amalgam of
laevorotatory and mandelonitrile, which is used to describe a purified form of amygdalin
(cyanogenic glycoside plant compound).94 Amygdalin is found in the stones of many fruits
and nuts (e.g. almonds, cashews).95 Laetrile may be taken as an oral supplement (dubbed
vitamin B17, although it is not a real vitamin), or injected intravenously, intraperitoneally
or intramuscularly. Despite frequent interchangeable use, the intravenous form of laetrile
(D-mandelonitrile-beta-glucuronide) is a US patented semi-synthetic derivative of
amygdalin, while laetrile produced in Mexico (D-mandelonitrile-beta-gentiobioside) is
usually amygdalin naturally produced from crushed apricot stones.
Laetrile/amygdalin is typically used as an adjunct to conventional anticancer treatments or
in combination with other alternative therapies, such as metabolic therapy.96 In vitro studies
suggest that amygdalin has anti-cancer properties,94,97 but no RCTs have been performed of
amygdalin or laetrile in humans.95 A limited uncontrolled phase II trial, performed by the
US National Cancer Institute in 1982, found that 95 of 178 (53%) of mixed, non-metastatic
cancer patients experienced disease progression and only 1 patient exhibited a partial
tumour response (lasting 10 weeks) following 21 days of intravenous laetrile plus oral
maintenance therapy combined with metabolic therapy (pancreatic enzymes, high vitamin
doses, dietary changes employed by metabolic practitioners).96 Furthermore, all remaining
patients experienced disease progression within 7 months post-treatment, and no significant
67
difference in survival was observed compared to historical controls who had inactive or no
treatment.
Better evidence, however, is offered by a systematic review of 36 studies (25 case reports, 6
best case series of case reports, 3 non-consecutive case series, 2 consecutive case series)
involving 352 cancer patients treated with laetrile/amygdalin.95 Despite the likelihood of
positive bias in case reports, only 3.1% of patients reportedly had a complete response and
9.4% had a partial response (although some of these patients may have received
conventional treatments and no detailed follow-up information was reported for complete
response patients), while 36.4% exhibited disease progression; symptomatic benefits were
also reported in 22.9% of cases. The authors concluded that the claim that laetrile has
beneficial effects for cancer patients is not supported by sound clinical evidence.
Possible adverse effects of laetrile/amygdalin are of particular concern, given the belief that
cyanide produced when it is broken down, kills cancer cells. In the aforementioned
systematic review, 14.4% of patients experienced adverse reactions consisting mainly of
nausea, vomiting, headache, fever and abdominal pain.95 The most important concern with
toxicity, however, involves several reports of cyanide poisoning (including deaths) from the
use of laetrile/amygdalin by cancer patients in North America in the 1970s and 80s, which
prompted the US to ban its use.95
1.3.2 Chinese herbal medicine
Chinese herbal medicine (CHM) is a key part of TCM and is used to normalise imbalanced
energy that runs through invisible meridians in the body. CHM includes any mixture of
herbs (mainly plant-based, but also including minerals or animal extracts) and decoction
(liquid extraction of boiled herbs), which may take the form of tablets/capsules, powders,
tonics, lotions and pastes. There are a number of issues associated with the safety and
quality of CHMs, including herb-drug interactions [via induction or inhibition of enzyme
systems (e.g. cytochrome P450) or by affecting efflux proteins (e.g. P-glycoprotein)],
resulting in a reduced efficacy or increased toxicity of chemotherapy and prescription
medications; direct (pharmacological) or indirect (e.g. free radical-mediated) toxicities;
allergic responses; contamination with heavy metals, pesticides, micro-organisms or other
impurities; deliberate substitution or adulteration with prescription or non-prescription
68
drugs (e.g. corticosteroids, hormones, salicylates, antihistamines, caffeine); and reactivation
of viruses or disease (e.g. hepatitis B or C, herpes simplex, varicella zoster, tuberculosis).98
The safety and quality of CHMs are regulated by the Therapeutic Goods Administration
(TGA) in Australia, but limitations of The Therapeutic Goods Act 1989 do not subject
individual practitioners to the standards that companies selling CHMs are required to
meet.99 Consequently, practitioners can import raw herbs that may not meet the TGA
standards and legally dispense them over the counter, without registering with the TGA.
1.3.2.1 Astragalus (Astragalus membranaceus, Astragalus mongolicus, Astragalus
propinquus, Radix astragali)
Astragalus is usually combined with other Chinese herbs, particularly as part of an
immune-enhancing herbal regimen known in TCM as Fu Zheng therapy. It is typically
administered as a dried root, a powder or in a decoction, although it may be given by
intraperitoneal injection also. Human and in vitro studies have demonstrated the
immunostimulatory properties of astragalus polysaccharides and triterpinoid saponins in
both healthy individuals and cancer patients (e.g. by stimulating macrophage and natural
killer cell activity, and inhibiting T-helper cell type 2 cytokines), as well as anti-cancer
activity.100-102
In China, astragalus-based Chinese herbs (e.g. Jin Fu Kang) combined with platinum-based
chemotherapy is a standard treatment for non-small cell lung cancer. A meta-analysis of 34
Chinese RCTs found evidence that astragalus-based herbal medicine (oral Jin Fu Kang,
Aidi injection, other preparations) may enhance the treatment outcomes (improved survival,
tumour response and performance status) and reduce the toxicity (leukopenia, haemoglobin
toxicity) of standard platinum-based chemotherapy for advanced non-small cell lung cancer
patients.104 Similarly, a more recent meta-analysis and systematic review of 45 RCTs
revealed that oral astragalus-based herbal medicine enhanced complete/partial tumour
response, survival rates and symptom control (abdominal pain, fatigue, appetite loss), and
reduced the risk of disease progression (for astragalus alone also) in unresectable liver
cancer patients receiving transcatheter arterial chemoembolization.105 Another systematic
review of 14 Chinese RCTs suggested that Aidi injection improved the tumour response
and QoL of non-small cell lung cancer patients receiving chemotherapy involving
vinorelbine and cisplatin injections or cobalt-60 (but not etoposide or paclitaxel combined
69
with cisplatin injections).106 Finally, a Cochrane meta-analytic review of 4 RCTs involving
colorectal patients suggested that astragalus (huang qi) compound decoctions as an adjunct
to chemotherapy may decrease chemotherapy toxicity (nausea and vomiting, leukopenia)
and stimulate immunocompetent cells.101 The authors in each review, however, concluded
that larger, more rigorous RCTs were needed to confirm these benefits given the poor
quality of the studies examined.101,104-106
Attributing specific adverse events or drug interactions to astragalus is difficult, however,
given that it is predominantly used in combined herbal preparations. Nevertheless, side-
effects of oral astragalus-based preparations reported in two phase II studies involving
incurable cancer patients receiving standard care (including chemotherapy and
radiotherapy) and incurable non-small lung cancer patients undergoing adjuvant
chemotherapy with paclitaxel, included grade 3 lymphopenia, grade 3/4 hyperglycaemia
and grade 1/2 gastrointestinal symptoms (e.g. diarrhoea, dyspepsia).106,107 Finally, direct
ingestion of certain toxic astragalus plants (locoweed) containing swainsonine and selenium
may cause neurological symptoms, some of which are irreversible.108
1.3.2.2 Ginseng (Panax ginseng, Panax quinquefolium, Eleutherococcus senticosus,
Angelica sinensis)
While the immunostimulatory properties of ginseng (and its ginsenosides) in recent
reviews109,110 have suggested a possible role as an adjuvant or immunotherapeutic agent, to
enhance immunological function and improve QoL in cancer patients during chemotherapy
and radiotherapy, RCTs are yet to be performed to confirm these benefits. Ginseng is
associated with a relatively low incidence of adverse events, with reports being attributed to
adulterated or contaminated preparations.111,112 Common side-effects of ginseng include
insomnia if taken in the evening, and agitation/overstimulation if excessively used.111
Possible contraindications of Asian ginseng (Panax ginseng) and American ginseng (Panax
quinquefolium) include hypertension, diabetes, coagulation disorders and surgery,111,113 and
use of anticoagulants (e.g. warfarin) or antiplatelet medications (aspirin), phenelzine
(monoamine oxidase inhibitor antidepressant), hypoglycaemics, oestrogens, corticosteroids
or alcohol.112-114 Possible contraindications of Siberian ginseng/eleuthero (Eleutherococcus
senticosus) include cardiovascular disease,115 and concomitant use of digoxin (heart drug)
and antihypertensive medications.98 Finally, ginseng, particularly dong quai/female ginseng
70
(Angelica sinensis), has oestrogenic effects, which may interfere with the treatment of
hormone-sensitive conditions, such as breast cancer (e.g. hormonal therapy) and
pregnancy.116
1.3.2.3 Ginger (Zingiber officinale)
Ginger may be used by cancer patients to alleviate postoperative and chemotherapy-
induced nausea and vomiting, as well as gastrointestinal symptoms including diarrhoea. A
meta-analysis of 5 RCTs demonstrated that a fixed dose of ≥1g of ginger is more effective
than placebo in reducing acute postoperative nausea and vomiting.117 Studies examining the
efficacy of ginger for chemotherapy-induced nausea and vomiting, however, have produced
mixed results and are still in their infancy.118 More RCTs comparing ginger to current
antiemetics are required.
Ginger causes few adverse effects when taken in small doses. Gastrointestinal symptoms
(e.g. heartburn, bloating, flatulence) are the most common side-effects. Additionally, ginger
inhibits thromboxane synthase (platelet enzyme) and platelet aggregation, thus the risk of
bleeding is increased in individuals taking anticoagulant/antiplatelet medications (e.g.
warfarin, aspirin), those with coagulation disorders and surgical patients.113
1.3.2.4 Lingzhi/Reishi mushroom (Ganoderma lucidum, Ganoderma tsugae)
Lingzhi is a traditional medicinal mushroom that has been used extensively in cancer
treatment in Asia. Lingzhi polysaccharides have demonstrated anti-cancer and
immunostimulatory properties.119 Reviews of preliminary clinical data suggest that Lingzhi
extracts or powders may have some potential in cancer treatment, but more rigorous RCTs
are required.119,120 Adverse effects from medicinal mushrooms are rare. Dry throat and nose
and gastrointestinal symptoms are the most common side-effects of Lingzhi. Caution is
warranted, however, as Lingzhi causes platelet inhibition, thus the risk of bleeding is
increased in individuals taking anticoagulant/antiplatelet drugs (e.g. warfarin, aspirin),
those with coagulation disorders and surgical patients.121 Additionally, Lingzhi can increase
antioxidant capacity and may interact with chemotherapy agents that rely on free
radicals.122
71
1.3.2.5 Green tea (Camellia sinensis, Thea sinensis)
Green tea and its extracts have a long history of use as a traditional cancer treatment in
Asian cultures. Polyphenols in green tea known as catechins, particularly epigallocatechin
gallate (EGCG), have demonstrated anti-cancer, antioxidant and chemopreventive
properties.123 The US Food and Drug Administration (FDA) in a review of studies
concluded that there is no supportive evidence for green tea decreasing the risk of gastric,
lung, colorectal, oesophageal, pancreatic, ovarian and combined cancers, but weak
evidence for decreased risk in breast and prostate cancer.124 Similarly, more recent
systematic reviews have suggested that green tea may reduce cancer risk and slow or
prevent progression in cancer patients, but found the overall evidence to be
inconclusive125,126 and counselled that use of green tea alone to treat cancer may be ill-
advised given its limited cytotoxic effects.126 Further large prospective cohort studies and
RCTs are recommended.
Green tea is generally safe when consumed in moderate amounts (3-9 cups per day).
Excessive consumption (5-6 litres per day) may cause gastrointestinal and central nervous
system disturbances (e.g. nausea, insomnia, irritability, frequent urination, cardiac
arrhythmia), however, predominantly as a result of the caffeine content, rather than the
tannin content of green tea.127,128 Finally, EGCG and other polyphenols in green tea are
potent blockers of boronic acid-based proteasome inhibitors and can reduce the efficacy of
bortezomib during chemotherapy for multiple myeloma and mantle cell lymphoma.129
1.3.2.6 Ginkgo (Ginkgo biloba, EGb 761)
Ginkgo is one of the most popular herbal medicines worldwide; it is used for a wide range
of conditions including cardiovascular disease, stress, neurodegenerative diseases such as
Alzheimer’s, cognitive impairment including memory loss and psychiatric disorders such
as schizophrenia, as well as cancer. Ginkgo is contained in the leaves and seeds of the
ginkgo tree and is available as a standardised extract (EGb 761), taken orally or, rarely
intravenously. Amongst others, the flavonoids and the terpenoids (gingkolides, bilobalide)
of ginkgo have been reported to have anti-cancer, antioxidant, cardioprotective, antiplatelet,
stress-alleviating, cognitive-improving and sexually-enhancing effects.130 Nonetheless,
RCTs are yet to confirm these benefits in cancer patients.
72
Side-effects of excessive ginkgo consumption include headache, gastrointestinal
disturbances (e.g. nausea, diarrhoea), dizziness, palpitations, convulsions (due to 4-
methoxypyridoxine in ginkgo seeds), allergic skin reactions (by handling ginkgo seeds),
and anaphylaxis-like reactions (intravenous administration only).130 Additionally, ginkgo
enhances anticoagulant/antiplatelet activity and increases the risk of bleeding.113,130
1.3.3 Western herbal medicine
Western herbal medicine (WHM) includes any mixture of herbs that are primarily native to
Europe, which may take the form of tablets/capsules, infusions (teas), concentrated liquid
extracts (requiring dilution) and lotions. WHMs share the same safety and quality issues
associated with TCMs.
1.3.3.1 St. John’s wort (Hypericum perforatum)
St. John’s wort (SJW) is well-known for its antidepressant activity. While a Cochrane
meta-analytic review of 29 RCTs suggests that SJW has similar efficacy to standard
prescription antidepressants and fewer side-effects,131 numerous herb-drug interactions
preclude its safe use in cancer patients and other populations. In fact, SJW is the most
implicated herbal product in herb-drug interactions reported in the literature to date.132
Human studies suggest that SJW can interact with medicines by affecting drug metabolism
(via induction of cytochrome P450 enzymes, particularly cytochrome P450 3A4, and P-
glycoprotein) or levels of neurotransmitters (primarily serotonin).114,123 Consequently, SJW
is contraindicated with the use of opioids, anaesthetics (e.g. fentanyl and propofol),
benzodiazepines (e.g. midazolam) and anticoagulants (e.g. warfarin) in surgical patients,
and opioid use for cancer pain in (palliative) patients (e.g. morphine, fentanyl).123
Additionally, SJW taken in combination with other antidepressants by cancer patients may
result in reduced efficacy of the antidepressants or serotonin syndrome [cognitive,
autonomic and somatic effects ranging from mild symptoms (e.g. hypervigilance, agitation,
muscle twitching) to severe symptoms (e.g. tachycardia and hypertension that may lead to
shock and death)].123 Finally, SJW can reduce the efficacy of imatinib during chemotherapy
for chronic myeloid leukaemia, gastrointestinal stromal tumours and other malignancies,
while having the same effect accompanied by greater myelosuppression in advanced
colorectal and lung cancer patients receiving irinotecan.123
73
1.3.3.2 Garlic (Allium sativum)
Garlic has had a long history of use worldwide for general health, as well as in a variety of
conditions including infections and cancer. Garlic can be eaten raw or cooked, may be dried
or powdered and used in tablets/capsules, or taken in the form of oils and liquid extracts.
Amongst others, garlic has been reported to have antimicrobial, antithrombotic, immune-
enhancing, and anti-cancer/chemopreventive effects.133,134 A meta-analysis of 18
observational studies suggested that high consumption of raw and/or cooked garlic (but not
garlic supplements) may be associated with reduced risk of colorectal and gastric cancers,
although a review of intervention studies was recommended given that many of the studies
identified did not control for dietary differences.135 A more recent meta-analysis of 2 small
RCTs and 8 observational studies also found an inverse relationship between high garlic
intake and colorectal cancer risk, despite great heterogeneity of measures of intake and lack
of control for dietary differences in the studies examined.136 In contrast, a recent large RCT
found that long-term garlic supplementation has no beneficial effects on the incidence of
gastric cancer or the prevalence of precancerous gastric lesions.137 Further large prospective
cohort studies and RCTs are needed.
Garlic appears to be generally safe, but may cause mild to severe gastrointestinal symptoms
(stomach upset, heartburn, bloating) and allergic reactions (e.g. contact dermatitis, garlic
burns and anaphylaxis resulting in possible death with topical or oral use).138 Human
clinical trials using well-established probe drugs have demonstrated that oral garlic inhibits
cytochrome P450 2E1 enzymes (but not 1A2, 3A4 or 2D6 enzymes),139,140 which may
reduce the efficacy of chemotherapy involving dacarbazine (metastatic melanoma,
Hodgkin’s lymphoma and other malignancies) and other drugs (e.g. anaesthetics).114,141
Finally, due to its anticoagulant properties, garlic should be avoided by patients undergoing
surgery and should be used with caution by those taking anticoagulant/antiplatelet
medications (e.g. warfarin, fluindione, aspirin).142
1.3.3.3 Kava (Piper methysticum)
Kava, a psychoactive substance, is derived from the pepper plant and has been traditionally
consumed as a beverage in cultural practices of Pacific countries. It has gained popularity
in Western countries in recent years as a medicinal herb because of its anxiolytic, stress-
relieving and sedative properties.143 The roots and rhizomes of kava are used to prepare
74
beverages, extracts, tablets/capsules, and topical solutions. Complementary medicine
practitioners commonly prescribe kava for anxiety, sleep disorders and menopausal
symptoms. A recent Cochrane meta-analytic review of 7 RCTs suggests that kava extract
(60-280mg of kavalactones) is a safe, effective treatment for anxiety in the short-term (1-24
weeks) compared to placebo, but recommended that more rigorous studies be performed to
clarify uncertainties about long-term efficacy and safety.144
Possible adverse effects of kava are of concern. Chronic and/or heavy use (300-400g per
week) may cause appetite loss, leading to malnutrition and weight loss, shortness of breath,
skin conditions (e.g. dry, scaly skin; yellow or white ulcer-like lesions known as kani or
kava dermopathy), blood and metabolic abnormalities, loss of muscle control
(ataxia/dystonia), and pulmonary hypertension.145 The most important concern with
toxicity, however, involves several reports of hepatotoxicity (including those resulting in
death and liver transplants) from use of concentrated kava extracts (but not beverages) in
Europe and North America, which prompted several European countries to ban its use in
2002 and other countries (including Australia and the US) to issue health warnings to
healthcare professionals and consumers advising of the potential (albeit rare) outcome of
severe liver injury.146
1.3.3.4 Valerian (Valeriana officinalis)
Valerian, although native to Europe and Asia, grows in most parts of the world and has a
long history of use as a sedative for sleep disturbance. The roots and rhizomes of valerian
can be prepared to make supplements including capsules/tablets and liquid extracts, as well
as infusions (teas). Short-term use (≤ 4-6 weeks) of valerian in recommended doses is
generally well-tolerated. Common side-effects include central nervous system (e.g.
headache, nervousness, dizziness) and gastrointestinal symptoms (notably diarrhoea, but
also nausea, heartburn and epigastric pain).147 As with conventional sleep medications,
chronic use of valerian (≥ 2-4 months) may result in insomnia, as well as withdrawal effects
(e.g. delirium, tachycardia) if also used heavily.148
Valerian is often used for the treatment of insomnia, fatigue and anxiety/stress, which are
common symptoms experienced by cancer patients. A Cochrane review found only one
small RCT evaluating the treatment of anxiety disorders using valerian and recommended
75
that more, larger RCTs be performed before drawing any conclusions about its efficacy for
anxiety.149 One systematic review of 29 controlled trials found no significant differences
between valerian pills and placebo, overall, in healthy individuals or in individuals with
general sleep disturbances or insomnia.150 A more recent meta-analysis of 18 RCTs,
however, found that valerian resulted in significant improvement on subjective measures of
sleep quality, but that the effect was not mirrored in objective sleep measures.147 Further
RCTs are required. Overall, short-term use of valerian could be considered for some cancer
patients (e.g. non-surgical patients who prefer not to take conventional sleep medications),
particularly given there is no evidence of potential interactions with chemotherapy agents.
1.3.3.5 Evening primrose oil (Oenothera biennis)
Evening primrose, although native to North America, grows in Europe and parts of the
southern hemisphere. Flowers and seeds are pressed to make evening primrose oil (EPO)
that contains gamma-linolenic acid (GLA), an omega-6 essential fatty acid believed to be
the active ingredient. EPO is commercially available in capsule or liquid form and is widely
used to treat menopausal symptoms, premenstrual syndrome and chronic mastalgia (breast
pain associated with menstruation).151
Breast cancer patients may experience symptoms of (premature) menopause (e.g. hot
flashes, night sweats, vaginal dryness) as a result of chemotherapy, which may be
exacerbated by therapy with tamoxifen in patients with hormone-receptor positive (HR+)
tumours.152 Non-hormonal therapies in the form of herbal medicines such as EPO have
become a popular alternative for women (including breast cancer survivors) for the
treatment of menopausal symptoms, particularly since health risks were cast over prolonged
use (> 5 years) of hormone replacement therapy by the Women’s Health Intervention study
published in 2002.153 The menopausal benefits of EPO, however, have yet to be confirmed
in RCTs involving postmenopausal women or breast cancer patients.154,155 Few studies
examining the safety of EPO have been conducted either. Common adverse effects include
headache and gastrointestinal symptoms (e.g. stomach upset, nausea, mild diarrhoea).156
Limited evidence suggests that EPO may lower the seizure threshold and increase the risk
of seizures in individuals taking phenothiazines (e.g. fluphenazine).151 Finally, despite the
absence of reported herb-drug interactions of EPO, it may be prudent to monitor use by
patients receiving chemotherapy.141
76
1.3.3.6 Black cohosh (Actaea racemosa, Cimicifuga racemosa)
Black cohosh, a member of the buttercup family, was traditionally used by the North
American Indians and in 19th-century America for a variety of conditions ranging from
gynaecological disorders to rheumatism, but has more recently been adopted for use in
Europe and Western countries for the treatment of menopausal symptoms and
dysmenorrhoea. The roots and rhizomes of black cohosh are commonly used fresh or dried
to make infusions (strong teas), capsules, solid extracts used in pills, or liquid extracts.
Like evening primrose oil, black cohosh is used by breast cancer survivors for the treatment
of menopausal symptoms. Alternatively, prostate cancer patients may use black cohosh to
control hot flushes after surgical or medical castration (e.g. hormonal ablation).152
Systematic reviews of RCTs, however, have found inconclusive evidence to support the use
of black cohosh for menopausal symptom relief in peri-/post-menopausal women157,158 and
breast cancer patients.159 More rigorous RCTs of longer duration (> 6 months) are needed.
Black cohosh appears to be relatively safe despite reports that it may be associated with
hepatotoxicity.158 The most important safety concern with black cohosh, however, is the
fear that it has oestrogenic effects and may promote breast or uterine cancer in women.
Early studies suggested an oestrogenic mechanism of action for black cohosh, but this may
have been due to phyto-oestrogen contamination.160 More recent in vitro and human studies
of unadulterated black cohosh extracts, though, have demonstrated no oestrogenic
activity.159 Nevertheless, women with oestrogen-dependent cancers may want to avoid
black cohosh until its long-term effects on breast or uterine tissue are more clearly
established in epidemiological studies. Finally, no herb-drug interactions have been
reported for black cohosh,161
1.3.3.7 Echinacea (Echinacea purpurea, Echinacea angustifolia, Echinacea pallida)
Echinacea is an immunostimulant commonly used by cancer patients to boost their immune
system and to prevent or treat upper respiratory tract infections. RCTs are yet to confirm
these benefits in cancer patients, however.111 Short-term use of echinacea is relatively safe,
although there is some concern about allergic reactions including rashes, increased asthma
and, in rare cases, anaphylaxis.111,162 Echinacea use is contraindicated in individuals with
asthma or atopy (a genetic tendency towards allergic reactions), given greater risk of an
77
allergic reaction.111 Currently, there are no verifiable reports of herb-drug interactions for
any echinacea products.163,164
1.3.3.8 Milk thistle (Silybum marianum, Carduus marianum)
The principal constituent of milk thistle is silymarin, which is a mixture of flavonolignans
(silychristin, silydianin, silybin and others) isolated mainly from the seeds (fruit) of the
plant. The seeds are used to prepare capsules, extracts, and infusions (strong teas).
Evidence suggests that milk thistle has hepatoprotective, anti-cancer, tissue-regenerative,
hypoglycaemic and cardioprotective properties.165,166 Milk thistle is being increasingly used
by cancer patients for liver protection during chemotherapy167 and for detoxification
between chemotherapy cycles or after chemotherapy, as well as an adjuvant treatment and
chemopreventive agent.
A Cochrane meta-analytic review of 13 RCTs involving alcoholic and/or hepatitis B or C
liver disease patients found significant benefits of milk thistle on mortality or hepatic
complications across low quality trials alone, but not across all trials or high quality trials
alone.168 High quality RCTs involving liver disease patients (including those with
chemotherapy-induced hepatotoxicity) are needed. Reviews of preclinical studies and
preliminary clinical trials also suggest that milk thistle extract may potentiate the
antitumour action of certain chemotherapy drugs (e.g. doxorubicin, cisplatin) and
radiotherapy169 and have chemopreventive potential (e.g. skin cancer, colorectal
cancer),169,170 but rigorous RCTs are required to establish its efficacy and safety as an
adjuvant or chemopreventive treatment.
Finally, reviews have established that the chronic use (≤ 41 months) of milk thistle is
generally safe and well-tolerated in recommended doses.168,171 Gastrointestinal problems
are the most common complaint, but are infrequent.172 Allergic reactions, ranging from
itchiness to eczema and anaphylaxis, are rare. Large doses (> 1.5g/day) may cause
diarrhoea, and very high doses (10-20g/day) can result in asymptomatic hepatotoxicity
(hyperbilirubinaemia) in cancer patients.173 Drug interactions do not appear to be
problematic either,165 although further study of milk thistle at higher doses is required.
78
1.3.3.9 European mistletoe (Viscum album L.)
Mistletoe has a long tradition of folk remedy use in Europe, but has been used extensively
in recent years in adjuvant cancer treatment or as a standalone alternative therapy, by and
large, in German-speaking countries (Switzerland, Austria, Germany). Its use in cancer
treatment stems from anthroposophic medicine developed in the early 1900s, which
approaches disease as an imbalance in the biological organism and utilises treatment
strategies designed to restore this balance. Anthroposophic doctors believe that regular
injections of mistletoe will inhibit or stop tumour growth and improve QoL in cancer
patients.174 The stem and leaves of the semi-parasitic mistletoe plant are used to make
commercial preparations (e.g. extracts, pressed sap) that are often administered by
subcutaneous injection (near or directly into the tumour), but may be taken orally,
intravenously or intrapleurally.
In vitro studies indicate that mistletoe or its main constituents (lectins, viscotoxins,
polysaccharides, alkaloids) have anti-angiogenic, anti-cancer and immunostimulatory
properties.175 In 2003, a systematic review of 10 RCTs found some benefits of mistletoe
extract as adjuvant or standalone treatment for cancer patients, particularly in relation to
QoL, across low quality trials alone; however, no benefits in terms of QoL, survival and
other outcomes were demonstrated in higher quality trials.176 In contrast, another systematic
review in 2003 involving 16 RCTs and 7 quasi-/non-randomised controlled trials of
mistletoe preparations revealed that 12 studies exhibited significantly positive results on at
least one clinically-relevant outcome measure, 7 studies indicated a positive trend on at
least one measure, 3 showed no significant results and 1 demonstrated a negative trend.177
In 2007, a systematic review of 16 RCTs and 9 non-RCTs involving mistletoe use as
adjuvant or standalone treatment found arguable benefits for cancer survival, but better
evidence for the efficacy of anthroposophic mistletoe preparations in improving QoL and
reducing toxicity of conventional treatments.178 Despite similar observations, a 2008
Cochrane meta-analytic review of 21 RCTs found weak evidence to support that mistletoe
extract improves survival and QoL or reduces the adverse effects of chemotherapy and
radiotherapy, although the conclusions for QoL were qualified by stating that a small
number of higher quality trials suggested possible benefits for breast cancer patients during
chemotherapy.179
79
Seeking to minimise the problems of previous reviews (e.g. heterogeneity), a more recent
systematic review limited to 18 RCTs and observational studies180 found inconsistent
evidence for the efficacy of mistletoe preparations as adjuvant or standalone treatment in
increasing cancer survival and tolerance to chemotherapy and radiotherapy, but concluded
that there was clear evidence for enhanced QoL and that these benefits were not limited to
specific mistletoe preparations or cancer populations. The latest systematic review (26
RCTs, 10 non-RCTs) has further confirmed the QoL benefits also.181 Nevertheless, more
high quality prospective trials are needed to consolidate the positive QoL effects of
mistletoe preparations in cancer patients.
Mistletoe preparations are usually well-tolerated and that serious adverse effects are rare
(cf. mistletoe plants and berries, which are poisonous) when used as directed under the
supervision of health professionals.179,180 Depending on the dose, local reactions (e.g.
pruritus, erythema or induration at the injection site) have been observed in 0.9-43% of
cancer patients182 and systemic reactions (e.g. headaches, fever, influenza-like symptoms)
in up to 10% of patients.179 Allergic reactions (e.g. breathing difficulties, anaphylaxis) have
been reported, but are rare (< 1%).182 Also, long-term use of mistletoe extracts may reduce
T-cell function in cancer patients without local reactions, thus use should be suspended
periodically to allow T-cell reactivity to recover.183 Finally, herb-drug interaction studies
involving mistletoe use in cancer patients are required, given their virtual non-existence.
1.4 Manipulative and body-based practices
Manipulative and body-based practices focus primarily on body structures and systems
including bones and joints, soft tissue, and the circulatory and lymphatic systems.184 They
involve manipulation or movement of one or more parts of the body in order to heal the
body and achieve good health. Examples include massage, acupuncture/acupressure,
chiropractic and osteopathic manipulation, tui na, reflexology, and Bowen therapy. There is
considerable variation in the level of formal training and approaches taken by practitioners
both across and within modalities (e.g. chiropractic and osteopathic manipulation primarily
involve rapid movements, whereas massage therapy involves slower application of force).
Despite this heterogeneity, manipulative and body-based practices share some common
principles (e.g. the human body is self-regulating, parts of the body are interdependent) and
features (e.g. therapies tend to be tailored to the specific needs of patients).
80
1.4.1 Massage therapy
Massage therapy involves the systematic manipulation of soft tissues of the body; examples
include Swedish massage, aromatherapy, shiatsu, reflexology and acupressure. The
common goal of most massage techniques is to promote relaxation and general well-being.
Overall, therapeutic massage administered by trained practitioners is very safe. Two
reviews, one focusing on cancer patients, found few reported adverse events.185,186 While
there is no evidence that massage therapy can spread cancer, applying direct pressure over
known tumours is best avoided. Reduced pressure and/or avoidance of direct or deep tissue
massage is also advisable for cancer patients with coagulation disorders (and those using
anticoagulant/antiplatelet medications, such as warfarin and aspirin), bone metastases or
severe osteoporosis, open wounds or radiation dermatitis, and prosthetic devices (e.g.
infusaport, colostomy bag, stents).186 Additionally, caution is advised with use of
aromatherapy essential oils in cancer patients with renal or liver disorders, and direct
application should be avoided in those with wounds, skin conditions or allergies to essential
oils.187
A Cochrane meta-analytic review of 8 RCTs found limited evidence for short-term benefits
of massage/aromatherapy on anxiety in cancer patients, but inconclusive results for other
symptoms.188 More recent systematic reviews of RCTs and observational studies have also
suggested that massage may alleviate anxiety, as well as other symptoms such as pain,
nausea, depression and stress.186,189 Larger RCTs are required, but massage therapy should
be supported for use by patients in the interim given the encouraging evidence for symptom
control and safety.
1.4.2 Acupuncture
Acupuncture, a key aspect of TCM, is a family of procedures that involves the application
of needles, pressure, heat and other treatments to the skin at particular sites called
acupuncture points for therapeutic purposes. Acupuncture performed by competent and
experienced practitioners is safe.190,191
Systematic reviews revealed that there is no convincing evidence that acupuncture
alleviates cancer pain192,193 or hot flushes in breast and prostate cancer patients,194,195
although further randomised controlled trials (RCTs) were recommended. In contrast, a
81
Cochrane meta-analytic review of 11 RCTs concluded that acupuncture-point stimulation
(manual acupuncture, electroacupunture, self-/practitioner-administered acupressure) in
combination with antiemetics demonstrated benefits for acute chemotherapy-induced
nausea and/or vomiting and complemented the positive evidence for postoperative nausea
and vomiting.196 Additionally, an exploratory meta-analysis of 11 Chinese non-randomised
clinical trials of poor quality found that acupuncture was associated with an increase in
leukocytes during chemotherapy and chemoradiation, suggesting that acupuncture may be
effective in reducing leukopenia in patients undertaking such treatments.197 Finally, several
pilot studies suggest that acupuncture may improve radiation-induced xerostomia in head
and neck cancer patients (e.g. [Cho et al, Garcia et al]),198,199 although RCTs are needed to
further confirm these promising results.
1.4.3 Exercise interventions
There are two broad categories of exercise. Aerobic or cardiorespiratory exercise involves
large muscle groups performing continuous or intermittent physical activity over an
extended period of time, while anabolic or resistance exercise involves performing sets of
repetitive movements against a resistance during which neuromuscular fatigue occurs
within 6-12 repetitions.200 Exercise may be home-based or take the form of highly
structured, supervised interventions. Cancer survivors and patients undergoing treatment
are generally prescribed aerobic and/or resistance exercise of low to moderate intensity and
regular frequency (3-5 times per week) for at least 20 minutes per session.201
Aerobic and resistance exercise appear to be relatively safe in cancer patients during
treatment or survivorship, even in home-based programmes and older or advanced cancer
patients.202,203 Recent meta-analytic and systematic reviews have found that serious adverse
events (e.g. back injury; falls; development or exacerbation of lymphoedema, anaemia or
cachexia) are rare, and that the most common minor adverse effects (e.g. hip/calf pain,
pulled hamstring, shoulder tendonitis) of exercise interventions were no more frequent
compared to control interventions in RCTs.203-205
A meta-analysis and systematic review of exercise-based and psychological interventions
revealed in a subgroup analysis of 17 RCTs that there were no significant decreases in
cancer-related fatigue (CRF) during treatment or survivorship for predominantly non-
82
metastatic cancer patients who completed various exercise-based interventions.206 In
contrast, a Cochrane meta-analytic review of 28 RCTs found a small beneficial effect of
exercise in reducing symptoms of CRF during treatment or survivorship in patients
(predominantly diagnosed with breast cancer) who completed various exercise-based
interventions compared to control interventions.207 A more recent meta-analysis of 18
RCTs examined the effects of different exercise parameters on CRF symptoms experienced
during cancer treatment.208 Overall, exercise produced small significant reductions in CRF
for breast cancer patients and moderate significant reductions in prostate cancer patients.
Supervised aerobic exercise interventions proved more effective in reducing CRF during
breast cancer treatment than home-based programmes, which did not significantly decrease
CRF. Clearly, further large RCTs comparing different forms of exercise interventions
across settings and patient populations with CRF are needed.
Looking beyond CRF, a meta-analysis of 16 randomised and 14 non-randomised trials
found that exercise interventions resulted in small positive effects on clinical and QoL
outcomes (physical functioning, symptoms other than fatigue, body composition, fatigue,
mood, overall QoL) during cancer treatment, although larger effects were generally
contributed by poorer quality studies.209 Similarly, a systematic review of 3 RCTs and 5
non-randomised trials found positive effects on QoL and physical outcomes in metastatic
cancer patients, although heterogeneity was problematic and limited the generalisability of
results.210 Also, a Cochrane meta-analytic review of 9 RCTs revealed a moderate positive
effect of exercise interventions on physical functioning during adjuvant breast cancer
treatment (and insufficient evidence for other outcomes, such as fatigue, mood disturbance,
immune function and weight gain), although heterogeneity again was problematic.211 A
more recent meta-analysis of exercise and behavioural interventions revealed in a subgroup
analysis of 17 RCTs that physical exercise produced small positive effects on fatigue,
depression, body image and QoL in breast cancer survivors or patients receiving
treatment.212
Finally, in the most comprehensive evaluation to date, a meta-analysis and systematic
review of 74 RCTs and 8 non-randomised trials (including 66 judged to be of high quality)
showed a large beneficial effect of exercise interventions for cancer survivors on lower and
upper body strength and moderate effects on fatigue and breast cancer-specific concerns.205
83
Small to moderate positive effects in cancer patients undergoing treatment were observed
for physical activity level, aerobic fitness, muscular strength, functional QoL, anxiety and
self-esteem. More large RCTs, as prescribed for CRF, are recommended in evaluating
exercise interventions targeting other clinical and QoL outcomes.
1.5 Energy therapies
Energy therapies involve the use of two types of energy fields. Veritable energy fields,
which can be measured, employ mechanical vibrations (e.g. sound) and electromagnetic
forces including visible light, magnetism, monochromatic radiation (e.g. laser beams), and
rays from other parts of the electromagnetic spectrum. Specific, measurable wavelengths
and frequencies are used to treat individuals.213 In contrast, putative energy fields or
biofields are theorised to surround the body and have yet to be scientifically measured.
Biofield therapies are based on the concept that humans are infused with a subtle form of
energy or life force (termed differently in different cultures; for example, qi in TCM, ki in
the Japanese Kampo system, doshas in Ayurvedic medicine, and elsewhere as prana,
etheric energy and other names) that can be manipulated to effect changes in the physical
body and influence health.214,215
1.5.1 Biofield therapies
Biofield therapies refer to techniques which use energy fields that purportedly surround the
human body to stimulate one’s own healing (internal practices; e.g. internal Qigong) or
healing in others (external practices; e.g. external Qigong, therapeutic touch, healing touch,
Reiki, Johrei, polarity therapy). Energy fields are sometimes manoeuvred by manipulating
the body using light touch or placing the hands above the body. The broad goal of biofield
therapies is to heal mental or physical disorders by rebalancing the energy fields in the
body or by drawing upon spiritual energies for such healing. Cancer patients may use them
to improve general well-being and QoL (e.g. pain relief), particularly in palliative and
supportive care settings. Biofield therapies are generally safe when administered by trained
practitioners. Although few (if any) adverse events have been reported for touch therapies
(healing touch, therapeutic touch, Reiki),216 use of Reiki is not advised for individuals with
(a history of) psychosis, personality disorders or bipolar disorder.
84
1.5.1.1 Qigong
Qigong is the most studied biofield therapy among cancer patients and refers to a whole
host of different meditative exercises (sometimes combined with breathing techniques,
imagery and/or vocalisation of sounds) from traditional Chinese medicine used to prevent
or slow disease and maintain health. Medical Qigong, however, has been specifically
developed for the treatment and cure of disease (e.g. hypertension, arthritis, cancer, HIV),
and may be used as an adjunct to conventional medical treatments. Given its utilisation of
meditation, imagery and breathing techniques and dependence on regular practice, Qigong
has many parallels to Western behavioural medicine.
Qigong is generally safe for most individuals when instructed by qualified practitioners and
practiced correctly according to standard moderate principles.217-219 Abnormal
psychosomatic responses and culture-bound psychiatric disorders (specific to individuals of
Chinese or other Asian ethnicities, even when living in Western countries) may be induced,
however, when Qigong is practiced inappropriately, excessively and/or unguided,
particularly by psychologically vulnerable individuals.218-220 Serious adverse events are
rare, but Qigong-induced psychiatric disorders are becoming more prevalent in China.221
Adverse effects may include sensory or somatic disturbances (e.g. headache, dizziness,
chest tightness, tachycardia, breathlessness); motor disturbances (e.g. muscle twitching,
tremors, odd limb movements, uncontrolled motor activity); cognitive impairment (e.g.
memory, attention); psychological symptoms (e.g. anxiety, irritability, hypochondriasis,
obsessive thoughts or images, delusions, visual/auditory hallucinations, disorganised
speech, dissociation, altered consciousness, disorientation, mania, depression, suicidal or
bizarre behaviour); and allergic skin reactions.217,220,222,223
An exploratory review of 21 Chinese studies (mostly controlled) revealed that cancer
patients predominantly treated with internal Qigong and conventional medical treatment
exhibited a consistent tendency for greater improvement on biological indicators and/or
longer survival time than those who received conventional treatment alone, but concluded
that there was much need for replication and improved methodological quality in future
studies.224 A more recent systematic review of 9 controlled studies involving
palliative/supportive care cancer patients, however, was less positive and concluded that the
efficacy of internal Qigong (alone or combined with conventional medical treatment) in
85
cancer care is not yet supported due to the poor methodological quality of existing studies,
and recommended that large-scale RCTs be performed along with studies investigating
possible scientific mechanisms.225 Finally, a systematic review of 66 RCTs and
observational studies examining a variety of practitioner-administered biofield therapies
(external Qigong, therapeutic touch, Reiki, spiritual healing, healing touch and others) in
different medical populations found moderate (level 2) evidence for their efficacy in
reducing acute pain in cancer patients and postoperative and hospitalised patients, but
mixed (level 4) evidence for chronic pain, fatigue, physiological arousal (heart/respiratory
rate, blood pressure) and QoL in cancer patients.226 Again, larger high-quality studies were
advised.
1.5.2 Bioelectromagnetic-based therapies
Bioelectromagnetic-based therapies involve the unconventional use of electromagnetic
fields, such as magnetic, pulsed or alternating-/direct-current fields.214 Examples include
magnetic, millimetre wave, sound energy (vibrational or frequency), and light therapy.
1.5.2.1 Microwave (UHF radiowave)/Tronado therapy
Microwave or ultra high frequency (UHF) therapy is designed to treat cancer via exposure
of tumorous tissue to electromagnetic radiation delivered using frequencies ranging
300MHz-3GHz (although super high and extra high frequencies ranging up to 300GHz
have reportedly been utilised also).227 UHF frequencies commonly used include 200-
300MHz, 434MHz, 915MHz and 2450MHz.228 Microwave therapy is generally thought to
exert therapeutic effects via direct or indirect heating of cancer cells, thus thermometry is
typically undertaken at the time of treatment to measure intra-tumour temperature.
Microwave therapy is usually combined with conventional radiotherapy or uncommonly
with infusions of glucose-blocking agents (e.g. cyclophosphamide, cystine disulphide or
penicillamine disulphide), and is often administered 5 days per week over a period of
weeks.228
A systematic review of 58 controlled and uncontrolled studies (mostly poor quality due to
the absence of single or double-blind RCTs and inadequate patient follow-up, and
exhibiting significant clinical heterogeneity), largely comparing microwave therapy and
radiotherapy combined to microwave therapy alone in relation to tumour response and
86
overall survival, found minimal evidence to support the routine use of microwave therapy
for cancer treatment.228 Additionally, in the same review, a limited clinical audit of the
medical records of 179 cancer patients treated in Western Australia suggested that
microwave therapy with radiotherapy resulted in greater toxicity than radiotherapy alone or
microwave therapy with glucose-blocking agents for patients with bladder or other invasive
cancers. Some of the more common adverse effects associated with microwave therapy
appear to be pain, erythema, fibrosis, necrosis, ulcerations, blisters and thermal burns. Third
degree burns, arterial rupture and development of fistulae have been reported on occasions,
as have deaths (often related to inadvertent heating of blood vessels or infections following
invasive thermometry).228,229
2. Summary Conclusions
The complementary and alternative therapies used by cancer patients are diverse in their
origin, premise (including proposed or actual mechanisms of action), practice, efficacy and
safety. Cancer patients and other members of the public are mostly unaware of distinctions
between conventional drugs registered by the Therapeutic Goods Administraion (TGA) and
may believe that a CAM listed by the TGA has been assessed as both effective and safe and
approved for such use by the Federal Government. Additionally, many complementary and
alternative therapies have long histories as components of ancient traditional medical
practices, but have only been subjected to rigorous scientific investigation in the last 10-20
years. More research is required to evaluate or confirm the efficacy and safety of many of
these therapies.
Currently, however, there is evidence from high quality clinical trials that some
complementary therapies, used as adjuncts to conventional medical treatments, are
beneficial in reducing disease or treatment symptoms and improving QoL and
psychological functioning (e.g. relaxation). There is evidence of potential harm also.
Nutritional supplements, herbal preparations, and other natural therapies among the
biologically-based practices may pose direct safety risks because of their potential adverse
effects or interactions with conventional anticancer treatments (chemotherapy,
radiotherapy, surgery, hormonal therapies) and other medications. Some should not be used
under any circumstances in cancer patients, irrespective of potential benefit (e.g. St. John’s
wort), while others may be beneficial when patients are not undergoing these treatments
87
and have no other contraindications (e.g. valerian for short-term amelioration of sleep
problems in non-surgical cancer patients). Alternative therapies promoted as “cures” in
place of conventional treatments (e.g. shark cartilage) have the potential to cause patients
(and their loved ones) the most harm, however, when they forego evidence-based cancer
treatments that are likely to be more effective.
In conclusion, whether termed complementary medicine or integrative oncology, cancer
physicians in Australia should strongly consider offering evidence-based complementary
therapies (or at least safe forms of them) alongside conventional treatments through their
own cancer services.230 Conceivably, this may influence patients to continue with
mainstream care and help them avoid any potential harm that may occur with autonomous
CAM use. In this way, optimal holistic care will be ensured for cancer patients by clinicians
providing conventional oncology treatment and care.
3. Acknowledgements
I would like to thank Professor Ian Olver (editor), Professor Peter Drummond and Mr Paul
Katris for their comments on early drafts of this chapter. Finally, I would like to thank my
loved ones for the patience they showed during the writing of this chapter.
4. References
1. Dantas F, Rampes H, Do homeopathic medicines provoke adverse effects? A
systematic review. Br Homeopath J 89(Suppl 1):S35-S38 (2000).
2. Kassab S, Cummings M, Berkovitz S, van Haselen R, Fisher P. Homeopathic
medicines for adverse effects of cancer treatments. Cochrane Database Syst Rev. 2:
CD004845 (2009).
3. Wong R, Sagar CM and Sagar SM. Integration of Chinese medicine into supportive
cancer care: a modern role for an ancient tradition. Cancer Treat Rev. 27(4): 235-
246 (2001).
4. Luebbert K, Dahme B, Hasenbring M. The effectiveness of relaxation training in
reducing treatment-related symptoms and improving emotional adjustment in acute
non-surgical cancer treatment: a meta-analytical review. Psychooncology. 10(6):
490-502 (2001).
88
5. Devine EC, Meta-analysis of the effect of psychoeducational interventions on pain
in adults with cancer. Oncol Nurs Forum 30(1): 75-89 (2003).
6. Kwekkeboom KL, Cherwin CH, Lee JW, Wanta B, Mind-body treatments for the
pain-fatigue-sleep disturbance symptom cluster in persons with cancer. J Pain
Symptom Manage 39(1): 126-138 (2010).
7. Lotfi-Jam K, M. Carey M, Jefford M, Schofield MP, Charleson C, Aranda S.
Nonpharmacologic strategies for managing common chemotherapy adverse effects:
a systematic review. J Clin Oncol 26(34): 5618-5629 (2008).
8. Figueroa-Moseley C, Jean-Pierre P, Roscoe JA, Ryan JL, Kohli S, Palesh OG,
Ryan EP, Carroll J, Morrow GR, Behavioral interventions in treating anticipatory
nausea and vomiting. J Natl Compr Canc Netw 5(1): 44-50 (2007).
9. Shapiro DH Jr., Overview: clinical and physiological comparison of meditation
with other self-control strategies. Am J Psychiatry 139(3): 267-274 (1982).
10. Astin JA, Shapiro SL, Eisenberg DM, Forys KL. Mind-body medicine: state of the
science, implications for practice. Mind-Body Med 16(2): 131-147 (2003).
11. Alexander CN, Robinson P, Orme-Johnson DW, and Schneider RH, The effects of
transcendental meditation compared to other methods of relaxation and meditation
in reducing risk factors, morbidity, and mortality. CIANS-ISBM Satellite
Conference Symposium: Lifestyle changes in the prevention and treatment of
disease (1992, Hannover, Germany). Homeostasis Health Dis 35: 243-263 (1994).
12. Shapiro DH Jr. Adverse effects of meditation: A preliminary investigation of long-
term meditators. Int J Psychosom. 39: 62-67 (1992).
13. Castillo RJ. Depersonalization and meditation. Psychiatry. 53: 158-168 (1990).
14. Melbourne Academic Mindfulness Interest Group, Mindfulness-based
psychotherapies: a review of conceptual foundations, empirical evidence and
practical considerations. ANZ J Psychiatry 40: 285-294 (2006).
15. Kuijpers HJH, van der Heijden FMMA, Tuinier S, Verhoeven WMA, Meditation-
induced psychosis. Psychopathol 40: 461-464 (2007).
16. Shapiro DH Jr., Examining the content and context of meditation: a challenge for
psychology in the areas of stress management. Psychother Religious Values 34(4):
101-135 (1994).
17. D. Ledesma D, Kumano H, Mindfulness-based stress reduction and cancer: a meta-
analysis. Psychooncology 18(6):571-579 (2009).
89
18. Smith JE, Richardson J, Hoffman C. Pilkington K. Mindfulness-based stress
reduction as supportive therapy in cancer care: systematic review J Adv Nurs. 52(3):
315-327 (2005).
19. Ott MJ, Norris RL, Bauer-Wu SM. Mindfulness meditation for oncology patients: a
discussion and critical review, Integr Cancer Ther 5(2): 98-108 (2006).
20. Patterson DR, and Jensen MP. Hypnosis and clinical pain. Psychol Bull 129(4):
495-521 (2003).
21. Lynn SJ, Martin DJ, Frauman DC. Does hypnosis pose special risks for negative
effects? A master class commentary. Int J Clin Exp Hypn 44: 7-19 (1996).
22. MacHovec F. Hypnosis complications, risk factors, and prevention. Am J Clin
Hypn 31: 40-49(1988).
23. Vickers A, Zollman C. ABC of complementary medicine. Hypnosis and relaxation
therapies. BMJ 319(7221): 1346-1349 (1999).
24. Richardson J, Smith JE, McCall G, Richardson A, Pilkington K, Kirsch I. Hypnosis
for nausea and vomiting in cancer chemotherapy: a systematic review of the
research evidence. Eur J Cancer Care (Engl) 16(5): 402-412 (2007).
25. Flory N, Lang E. Practical hypnotic interventions during invasive cancer diagnosis
and treatment. Hematol Oncol Clin North Am 22(4): 709-725 (2008).
26. Richardson J, Smith JE, McCall G, Pilkington K. Hypnosis for procedure-related
pain and distress in pediatric cancer patients: a systematic review of effectiveness
and methodology related to hypnosis interventions. J Pain Symptom Manage 31(1):
70-84 (2006).
27. Oestreicher P. Help patients integrate yoga into cancer care. ONS Connect 23(4):
20-21 (2008).
28. Bower JE, Woolery A, Sternlieb B, Garet D. Yoga for cancer patients and
survivors. Cancer Control 12(3): 165-171 (2005).
29. Smith KB, Pukall CF. An evidence-based review of yoga as a complementary
intervention for patients with cancer. Psychooncology 18(5): 465-475 (2009).
30. Lee MS, Pittler MH, Ernst E. Is tai chi an effective adjunct in cancer care? A
systematic review of controlled clinical trials. Support Care Cancer 15(6): 597-601
(2007).
31. Lee MS, Choi TY, Ernst E. Tai chi for breast cancer patients: a systematic review.
Breast Cancer Res Treat 120(2): 309-316 (2010).
90
32. Dileo C. Effects of music and music therapy on medical patients: a meta-analysis
of the research and implications for the future. J Soc Integr Oncol 4(2): 67-70
(2006).
33. Zabalegui A, Sanchez S, Sanchez PD, Juando C. Nursing and cancer support
groups. J Adv Nurs 51(4): 369-381 (2005).
34. Gottlieb BH, Wachala ED. Cancer support groups: a critical review of empirical
studies. Psychooncology 16(5): 379-400 (2007).
35. Hoey LM, Ieropoli SC, White VM, Jefford M. Systematic review of peer-support
programs for people with cancer. Patient Educ Couns 70(3): 315-337 (2008).
36. Macvean ML, White VM, Sanson-Fisher R. One-to-one volunteer support
programs for people with cancer: a review of the literature. Patient Educ Couns
70(1): 10-24 (2008).
37. Pargament KI. The psychology of religion and spirituality? Yes and no. Int J Psych
Religion 9: 3-16 (1999).
38. Pargament KI, The Psychology of Religion and Coping: Theory, Research,
Practice, (Guilford Press, New York, 1997).
39. Belzen JA. Spirituality, culture and mental health: prospects and risks for
contemporary psychology of religion. J Religion Health 43: 291-316 (2004).
40. Thuné-Boyle IC, Stygall JA, Keshtgar MR, Newman SP. Do religious/spiritual
coping strategies affect illness adjustment in patients with cancer? A systematic
review of the literature. Soc Sci Med 63(1): 151-164 (2006).
41. Visser A, Garssen B, Vingerhoets A. Spirituality and well-being in cancer patients:
a review, Psychooncology. 19(6): 565-572 (2010).
42. Rossiter-Thornton JF. Prayer in your practice. Complement Ther Nurs Midwifery
8(1): 21-28 (2002).
43. Hollywell C, Walker J. Private prayer as a suitable intervention for hospitalised
patients: a critical review of the literature. J Clin Nurs 18(5): 637-651 (2009).
44. Hoff A, Johannessen-Henry CT, Ross L, Hvidt NC, Johansen C. Religion and
reduced cancer risk: what is the explanation? A review, Eur J Cancer. 44(17):
2573-2579 (2008).
45. Masters KS, Spielmans GI. Prayer and health: review, meta-analysis and research
agenda J Behav Med 30(4): 329-338 (2007).
91
46. Roberts L, Ahmed I, Hall S, Davison A. Intercessory prayer for the alleviation of ill
health. Cochrane Database Syst Rev 15(2): CD000368 (2009).
47. National Center for Complementary and Alternative Medicine (NCCAM),
Biologically based practices: an overview (NCCAM Publication No. D237),
Available at http://www.umbwellness.org/PDF_files/biobasedprac.pdf (accessed 15
June 2010).
48. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl
Acad Sci USA 92(12): 5258-5265 (1995).
49. Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic
disease. Crit Rev Food Sci Nutr 44(4): 275-295 (2004).
50. Conklin KA. Cancer chemotherapy and antioxidants. J Nutr 134(11): 3201S-3204S
(2004).
51. D'Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should
be avoided. CA Cancer J Clin 55(5): 319-321 (2005).
52. Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of
antioxidant supplementation on chemotherapeutic toxicity: a systematic review of
the evidence from randomized controlled trials. Int J Cancer 123(6): 1227-1239
(2008).
53. Moss RW. Do antioxidants interfere with radiation therapy for cancer? Integr
Cancer Ther 6(3): 281-292 (2007).
54. Sasse AD, Clark LG, Sasse EC, Clark OA. Amifostine reduces side effects and
improves complete response rate during radiotherapy: results of a meta-analysis. Int
J Radiat Oncol Biol Phys 64(3): 784-791 (2006).
55. Greenlee H, Gammon MD, Abrahamson PE, Gaudet MM, Terry MB, D. L.
Hershman DL, Desai M, Teitelbaum SL, Neugut AI, Jacobson JS. Prevalence and
predictors of antioxidant supplement use during breast cancer treatment: the Long
Island Breast Cancer Study Project. Cancer 115(14): 3271-3282 (2009).
56. Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy,
radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev 3:
CD005037 (2006).
57. Tabassum A, Bristow RG, Venkateswaran V. Ingestion of selenium and other
antioxidants during prostate cancer radiotherapy: a good thing? Cancer Treat Rev
36(3): 230-234 (2010).
92
58. Haseen F, Cantwell MM, O'Sullivan JM, Murray LJ. Is there a benefit from
lycopene supplementation in men with prostate cancer? A systematic review.
Prostate Cancer Prostatic Dis 12(4): 325-332 (2009).
59. Roffe L, Schmidt K, Ernst E. Efficacy of coenzyme Q10 for improved tolerability
of cancer treatments: a systematic review. J Clin Oncol 22(21): 4418-4424 (2004).
60. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM,
Antioxidants and cancer therapy: a systematic review, J Clin Oncol. 22(3): 517-528
(2004).
61. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should
supplemental antioxidant administration be avoided during chemotherapy and
radiation therapy? J Natl Cancer Inst 100(11): 773-783 (2008).
62. Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of
antioxidant supplementation on chemotherapeutic efficacy: a systematic review of
the evidence from randomized controlled trials. Cancer Treat Rev 33(5): 407-418
(2007).
63. Mell LK, Malik R, Komaki R, Movsas B, Swann RS, Langer C, Antonadou D,
Koukourakis M, Mundt AJ. Effect of amifostine on response rates in locally
advanced non-small-cell lung cancer patients treated on randomized controlled
trials: a meta-analysis. Int J Radiat Oncol Biol Phys 68(1): 111-118 (2007).
64. Coulter ID, Hardy ML, Morton SC, Hilton LG, Tu W, Valentine D, Shekelle PG.
Antioxidants vitamin C and vitamin e for the prevention and treatment of cancer. J
Gen Intern Med 21(7): 735-744 (2006).
65. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a
systematic review of randomized controlled trials and meta-analysis. J Pineal Res
39(4): 360-366 (2005).
66. Myung SK, Kim Y, Ju W, Choi HJ, Bae WK. Effects of antioxidant supplements
on cancer prevention: meta-analysis of randomized controlled trials Ann Oncol
21(1): 166-179 (2010).
67. Bardia A, Tleyjeh IM, Cerhan JR, Sood AK, Limburg PJ, Erwin PJ, Montori VM.
Efficacy of antioxidant supplementation in reducing primary cancer incidence and
mortality: systematic review and meta-analysis. Mayo Clin Proc 83(1): 23-34
(2008).
93
68. Papaioannou D, Cooper K, Carroll CC, Hind D, Pilgrim H, Tappenden P, Logan
RF. Antioxidants in the chemoprevention of colorectal cancer and colorectal
adenomas in the general population: a systematic review and meta-analysis.
Colorectal Dis DOI: 10.1111/j.1463-1318.2010.02289.x.
69. Bjelakovic B, Nikolova D, Simonetti RG, Gluud C. Systematic review: primary
and secondary prevention of gastrointestinal cancers with antioxidant supplements.
Aliment Pharmacol Ther 28(6): 689-703 (2008).
70. Alkhenizan A, Hafez K. The role of vitamin E in the prevention of cancer: a meta-
analysis of randomized controlled trials. Ann Saudi Med 27(6): 409-414 (2007).
71. Pham DQ, Plakogiannis R. Vitamin E supplementation in cardiovascular disease
and cancer prevention: part 1. Ann Pharmacother 39(11): 1870-1878 (2005).
72. Cho E, Hunter DJ, Spiegelman D, Albanes D, Beeson WL, van den Brandt PA,
Colditz GA, Feskanich D, Folsom AR, Fraser GE, Freudenheim JL, Giovannucci E,
Goldbohm RA, Graham S, Miller AB, Rohan TE, Sellers TA, Virtamo J, Willett
WC, Smith-Warner SA. Intakes of vitamins A, C and E and folate and
multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J
Cancer 118(4): 970-978 (2006).
73. Gallicchio L, Boyd K, Matanoski G, Tao XG, Chen L, Lam TK, Shiels M,
Hammond E, Robinson KA, Caulfield LE, Herman JG, Guallar E, Alberg AJ.
Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin
Nutr 88(2): 372-383 (2008).
74. Hathcock JN, Azzi A, Blumberg J, Bray T, Dickinson A, Frei B, Jialal I, Johnston
CS, Kelly FJ, Kraemer K, Packer L, Parthasarathy S, Sies H, Traber MG. Vitamins
E and C are safe across a broad range of intakes. Am J Clin Nutr 81(4): 736-745
(2005).
75. World Cancer Research Fund and American Institute for Cancer Research (AICR),
Food, nutrition, physical activity, and the prevention of cancer: a global
perspective (AICR, Washington DC, 2007).
76. Avula CPR, Lawrence RA, Jolly CA, Fernandes G. Role of n-3 polyunsaturated
fatty acids (PUFA) in autoimmunity, inflammation, carcinogenesis, and apoptosis.
Recent-Research-Developments-in-Lipids 4(2): 303-319 (2000).
77. Johnson IT, Anticarcinogenic effects of diet-related apoptosis in the colorectal
mucosa. Food Chem Toxicol. 40(8): 1171-1178 (2002).
94
78. Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid (EPA,
an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane
Database Syst Rev 24(1): CD004597 (2007).
79. Colomer R, Moreno-Nogueira JM, García-Luna PP, García-Peris P, García-de-
Lorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. N-3 fatty
acids, cancer and cachexia: a systematic review of the literature Br J Nutr 97(5):
823-831 (2007).
80. MacLean CH, Newberry SJ, Mojica WA, Khanna P, Issa AM, Suttorp MJ, Lim
YW, Traina SB, Hilton L, Garland R, Morton SC. Effects of omega-3 fatty acids on
cancer risk: a systematic review. JAMA 295(4): 403-415 (2006).
81. Carayol M, Grosclaude P, Delpierre C. Prospective studies of dietary alpha-
linolenic acid intake and prostate cancer risk: a meta-analysis. Cancer Causes
Control 21(3): 347-355 (2010).
82. Simon JA, Chen YH, Bent S. The relation of alpha-linolenic acid to the risk of
prostate cancer: a systematic review and meta-analysis. Am J Clin Nutr 89(5):
1558S-1564S (2009).
83. Brouwer IA. Omega-3 PUFA: good or bad for prostate cancer. Prostaglandins
Leukot Essent Fatty Acids 79(3-5): 97-99 (2008).
84. Mathews J. Media feeds frenzy over shark cartilage as cancer treatment. J Natl
Cancer Inst 85(15): 1190-1191 (1993).
85. Lane IW, Comac L, Sharks Don’t Get Cancer. (Avery Publishing, New York,
1992).
86. Ostrander GK, Cheng KC, Wolf JC, Wolfe MJ. Shark cartilage, cancer and the
growing threat of pseudoscience. Cancer Res 64(23): 8485-8491 (2004).
87. Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D. Phase I/II trial of the
safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin
Oncol 16(11): 3649-3655 (1998).
88. Gingras D, Renaud A, Mousseau N, Béliveau R. Shark cartilage extracts as
antiangiogenic agents: smart drinks or bitter pills? Cancer Metastasis Rev 19(1-2):
83-86 (2000).
89. Pauli BU, Memoli VA, Kuettner KE. Regulation of tumor invasion by cartilage-
derived anti-invasion factor in vitro. J Natl Cancer Inst. 67: 65-73 (1981).
95
90. Kuettner KE, Pauli BU, Inhibition of tumor invasion by tissue-derived proteinase
inhibitors. Monogr Pathol 27: 1711-1782 (1986).
91. Loprinzi CL, Levitt R, Barton DL, Sloan JA, Atherton PJ, Smith DJ, Dakhil SR,
Moore DF Jr, Krook JE, Rowland KM Jr, Mazurczak MA, Berg AR, Kim GP,
North Central Cancer Treatment Group. Evaluation of shark cartilage in patients
with advanced cancer: a North Central Cancer Treatment Group trial. Cancer
104(1): 176-182 (2005).
92. Lu C, Lee JJ, Komaki R, Herbst RS, Feng L, Evans WK, Choy H, Desjardins P,
Esparaz BT, Truong MT, Saxman S, Kelaghan J, Bleyer A, Fisch MJ.
Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer:
a randomized phase III trial. J Natl Cancer Inst 102(12): 859-865 (2010).
93. AEterna Zentaris, AEterna Laboratories reports phase III trial results in renal cell
carcinoma with Neovastat, Available at
http://www.aeternazentaris.com/en/page.php?p=60&q=46 (accessed 22 June 2010).
94. Fukuda T, Ito H, Mukainaka T, Tokuda H, Nishino H, Yoshida T. Anti-tumor
promoting effect of glycosides from Prunus persica seeds. Biol Pharm Bull 26(2):
271-273 (2003).
95. S. Milazzo, S. Lejeune and E. Ernst, Laetrile for cancer: a systematic review of the
clinical evidence, Support Care Cancer. 15(6): 583-595 (2007).
96. Moertel CG, Fleming TR, Rubin J, Kvols LK, Sarna G, Koch R, Currie VE, Young
CW, Jones SE, Davignon JP. A clinical trial of amygdalin (Laetrile) in the treatment
of human cancer. N Engl J Med 306(4): 201-206 (1982).
97. Syrigos KN, Rowlinson-Busza G, Epenetos AA. In vitro cytotoxicity following
specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-
associated monoclonal antibody. Int J Cancer 78(6): 712-719 (1998).
98. Chiu J, Yau T, Epstein RJ. Complications of traditional Chinese/herbal medicines
(TCM): a guide for perplexed oncologists and other cancer caregivers. Support Care
Cancer. 17(3): 231-240 (2009).
99. Li GQ, Duke CC, Roufogalis BD. The quality and safety of traditional Chinese
medicines. Aust Prescr 26:128-130 (2003).
100. Wu T, Munro AJ, Guanjian L, Liu GJ. Chinese medical herbs for
chemotherapy side effects in colorectal cancer patients. Cochrane Database Syst
Rev 1: CD004540 (2005).
96
101. Wei H, Sun R, Xiao W, Feng J, Zhen C, Xu X, Tian Z. Traditional Chinese
medicine Astragalus reverses predominance of Th2 cytokines and their up-stream
transcript factors in lung cancer patients. Oncol Rep 10(5): 1507-1512 (2003).
102. Zwickey H, Brush J, Iacullo CM, Connelly E, Gregory WL, Soumyanath A,
Buresh R. The effect of Echinacea purpurea, Astragalus membranaceus and
Glycyrrhizaglabra on CD25 expression in humans: a pilot study. Phytother Res
21(11): 1109-1112 (2007).
103. McCulloch M, See C, Shu XJ, Broffman M, Kramer A, Fan WY, Gao J,
Lieb W, Shieh K, Colford JM Jr, Astragalus-based Chinese herbs and platinum-
based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of
randomized trials. J Clin Oncol. 24(3): 419-430 (2006).
104. Wu T, Munro AJ, Guanjian L, Liu GJ. Chinese medical herbs for
chemotherapy side effects in colorectal cancer patients. Cochrane Database Syst
Rev 1: CD004540 (2005).
105. Ma WH, Duan KN, Feng M, She B, Chen Y, Zhang RM. Aidi Injection as
an adjunct therapy for non-small cell lung cancer: a systematic review. Zhong Xi Yi
Jie He Xue Bao 7: 315-324 (2009).
106. Cassileth BR, Rizvi N, Deng G, Yeung KS, Vickers A, Guillen S, Woo D,
Coleton M, Kris MG. Safety and pharmacokinetic trial of docetaxel plus an
Astragalus-based herbal formula for non-small cell lung cancer patients. Cancer
Chemother Pharmacol 65(1): 67-71 (2009).
107. Lee JJ, Lee JJ. A phase II study of an herbal decoction that includes
Astragali radix for cancer-associated anorexia in patients with advanced cancer.
Integr Cancer Ther 9(1): 24-31 (2010).
108. Shi Y, Li M, Xu F. A review of the study on swainsonine – toxic elements
of locoweed. Zhong Yao Cai 22(1): 47-49 (1999).
109. Jia L, Zhao Y, Liang XJ. Current evaluation of the millennium
phytomedicine- ginseng (II): Collected chemical entities, modern pharmacology,
and clinical applications emanated from traditional Chinese medicine. Curr Med
Chem 16(22): 2924-2942 (2009).
97
110. Wu P, Dugoua JJ, Eyawo O, Mills EJ. Traditional Chinese Medicines in the
treatment of hepatocellular cancers: a systematic review and meta-analysis. J Exp
Clin Cancer Res 28: 112 (2009).
111. Block KI, Mead MN. Immune system effects of echinacea, ginseng, and
astragalus: a review. Integr Cancer Ther 2(3): 247-267 (2003).
112. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and
drug interactions. Drug Saf 25(5): 323-344 (2002).
113. Kumar NB, Allen B, Bell H. Perioperative herbal supplement use in cancer
patients: potential implications and recommendations for presurgical screening.
Cancer Control 12(3): 149-157 (2005).
114. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed
drugs: an updated systematic review. Drugs 69(13): 1777-1798 (2009).
115. Smith M, Boon HS. Counseling cancer patients about herbal medicine.
Patient Educ Couns. 38(2): 109-120 (1999).
116. Liu J, Burdette JE, Xu H, Gu C, van Breemen RB, Bhat KP, Booth N,
Constantinou AI, Pezzuto JM, Fong HH, Farnsworth NR, Bolton JL. Evaluation of
estrogenic activity of plant extracts for the potential treatment of menopausal
symptoms. J Agric Food Chem 49(5): 2472-2479 (2001).
117. Chaiyakunapruk N, Kitikannakorn N, Nathisuwan S, Leeprakobboon K,
Leelasettagool C. The efficacy of ginger for the prevention of postoperative nausea
and vomiting: a meta-analysis. Am J Obstet Gynecol 194(1): 95-99 (2006).
118. Zick SM, Ruffin MT, Lee J, Normolle DP, Siden R, Alrawi S, Brenner DE.
Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced
nausea and vomiting. Support Care Cancer 17(5): 563-572 (2009).
119. Yang AK, He SM, Liu L, Liu JP, Wei MQ, Zhou SF. Herbal interactions
with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem
17(16): 1635-1678 (2010).
120. Mahajna J, Dotan N, Zaidman BZ, Petrova RD, Wasser SP.
Pharmacological values of medicinal mushrooms for prostate cancer therapy: the
case of Ganoderma lucidum. Nutr Cancer 61(1): 16-26 (2009).
121. Cassileth B. Complementary therapies, herbs, and other OTC agents: Reishi
mushroom. Oncology (Williston Park) 23(8): 728 (2009).
98
122. Wachtel-Galor S, Tomlinson B, Benzie IF. Ganoderma lucidum ("Lingzhi"),
a Chinese medicinal mushroom: biomarker responses in a controlled human
supplementation study. Br J Nutr 91(2): 263-269 (2004).
123. Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the
laboratory, animal, and human data for 8 common botanicals. Integr Cancer Ther
8(3): 208-227 (2009).
124. Food and Drug Administration (FDA), Letter responding to health claim
petition dated January 27, 2004: green tea and reduced risk of cancer health claim
(docket number 2004Q-0083) (docket number 2004Q-0083), Available at
http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/u
cm072774.htm (accessed 1 May 2010).
125. Sturgeon JJ, Williams M. van Servellen G. Efficacy of green tea in the
prevention of cancers. Nurs Health Sci 11(4): 436-446 (2009).
126. Liu J, Xing J, Fei Y. Green tea (Camellia sinensis) and cancer prevention: a
systematic review of randomized trials and epidemiological studies. Chin Med 3: 12
(2008).
127. Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK,
Glisson BS, Lee JS. Phase I trial of oral green tea extract in adult patients with solid
tumors. J Clin Oncol 19(6): 1830-1838 (2001).
128. Laurie SA, Miller VA, Grant SC, Kris MG, Ng KK. Phase I study of green
tea extract in patients with advanced lung cancer. Cancer Chemother Pharmacol
55(1): 33-38 (2005).
129. Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis
NA, Chen TC, Schönthal AH. Green tea polyphenols block the anticancer effects of
bortezomib and other boronic acid-based proteasome inhibitors. Blood 113(23):
5927-5937 (2009).
130. Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba
L.: chemistry, efficacy, safety, and uses. J Food Sci 73(1): R14-R19 (2008).
131. Linde K, Berner MM, Kriston L. St John's wort for major depression.
Cochrane Database Syst Rev 4: CD000448 (2008).
132. Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (Hypericum
perforatum): an update on clinical observations. AAPSJ 11(4): 710-727 (2009).
99
133. Ariga T, Seki T. Antithrombotic and anticancer effects of garlic-derived
sulfur compounds: a review. Biofactors 26(2): 93-103 (2006).
134. Iciek M, Kwiecień I, Włodek L. Biological properties of garlic and garlic-
derived organosulfur compounds. Environ Mol Mutagen 50(3): 247-265 (2009).
135. Fleischauer AT, Poole C, Arab L. Garlic consumption and cancer
prevention: meta-analyses of colorectal and stomach cancers. Am J Clin Nutr 72(4):
1047-1052 (2000).
136. Ngo SN, Williams DB, Cobiac L, Head RJ. Does garlic reduce risk of
colorectal cancer? A systematic review. J Nutr 137(10): 2264-2269 (2007).
137. You WC, Brown LM, Zhang L, Li JY, Jin ML, Chang YS, Ma JL, Pan KF,
Liu WD, Hu Y, Crystal-Mansour S, Pee D, Blot WJ, Fraumeni JF Jr, Xu GW, Gail
MH. Randomized double-blind factorial trial of three treatments to reduce the
prevalence of precancerous gastric lesions J Natl Cancer Inst 98(14): 974-983
(2006).
138. Borrelli F, Capasso R, Izzo AA. Garlic (Allium sativum L.): adverse effects
and drug interactions in humans. Mol Nutr Food Res 51(11): 1386-1397 (2007).
139. B. J. Gurley, S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry,
Y. Cui and C. Y. Ang, Cytochrome P450 phenotypic ratios for predicting herb-drug
interactions in humans, Clin Pharmacol Ther. 72(3): 276-287 (2002).
140. J. S. Markowitz, C. L. Devane, K. D. Chavin, R. M. Taylor, Y. Ruan and J.
L. Donovan, Effects of garlic (Allium sativum L.) supplementation on cytochrome
P450 2D6 and 3A4 activity in healthy volunteers, Clin Pharmacol Ther. 74(2): 170-
177 (2003).
141. Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the
United States: potential adverse interactions with anticancer agents. J Clin Oncol.
22(12): 2489-2503 (2004).
142. Saw JT, Bahari MB, Ang HH, Lim YH. Potential drug-herb interaction with
antiplatelet/anticoagulant drugs. Complement Ther Clin Pract 12(4): 236-241
(2006).
143. Singh YN. Potential for interaction of kava and St. John's wort with drugs. J
Ethnopharmacol 100(1-2): 108-113 (2005).
144. Pittler MH, Ernst E. Kava extract versus placebo for treating anxiety.
Cochrane Database Syst Rev 1: CD003383 (2003).
100
145. Mathews JD, Riley MD, Fejo L, Munoz E, Milns NR, Gardner ID, Powers
JR, Ganygulpa E, Gununuwawuy BJ. Effects of the heavy usage of kava on
physical health: summary of a pilot survey in an aboriginal community. Med J Aust
148(11): 548-555 (1988).
146. Robinson V, Bergfeld WF, Belsito DV, Klaasen CD, Marks Jr JG, Shank
RC, Slaga TJ, Snyder PW, Cosmetic Ingredient Review Expert Panel, Andersen
FA. Final report on the safety assessment of Piper Methysticum leaf/root/stem
extract and Piper Methysticum root extract. Int J Toxicol 28(6S): 175S-188S (2009).
147. Fernández-San-Martín MI, Masa-Font R, Palacios-Soler L, Sancho-Gómez
P, Calbó-Caldentey C, Flores-Mateo G. Effectiveness of valerian on insomnia: a
meta-analysis of randomized placebo-controlled trials. Sleep Med 11(6): 505-511
(2010).
148. Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium
associated with valerian root withdrawal. JAMA 280(18): 1566-1567 (1998).
149. Miyasaka LS, Atallah AN, Soares BG. Valerian for anxiety disorders.
Cochrane Database Syst Rev 4: CD004515 (2006).
150. Taibi DM, Landis CA, Petry H, Vitiello MV. A systematic review of
valerian as a sleep aid: safe but not effective. Sleep Med Rev 11(3): 209-230 (2007).
151. Bayles B, Usatine R. Evening primrose oil. Am Fam Physician 80(12):
1405-1408 (2009).
152. Adelson KB, Loprinzi CL, Hershman DL. Treatment of hot flushes in breast
and prostate cancer. Expert Opin Pharmacother 6(7): 1095-1106 (2005).
153. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg
Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM,
Ockene J, Writing Group for the Women's Health Initiative Investigators. Risks and
benefits of estrogen plus progestin in healthy postmenopausal women: principal
results from the Women's Health Initiative randomized controlled trial. JAMA
288(3): 321-333 (2002).
154. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-
menopausal vasomotor symptoms: a structured evidence-based review. Arch
Gynecol Obstet 276(5): 463-469 (2007).
101
155. Rock E, DeMichele A. Nutritional approaches to late toxicities of adjuvant
chemotherapy in breast cancer survivors. J Nutr 133(11 Suppl 1): 3785S-3793S
(2003).
156. Seibel MM, Treating hot flushes without hormone replacement therapy. J
Fam Pract 52: 291-296 (2003).
157. Shams T, Setia MS, Hemmings R, McCusker J, Sewitch M Ciampi A.
Efficacy of black cohosh-containing preparations on menopausal symptoms: a
meta-analysis. Altern Ther Health Med 16(1): 36-44 (2010).
158. Palacio C, Masri G, Mooradian AD. Black cohosh for the management of
menopausal symptoms: a systematic review of clinical trials. Drugs Aging 26(1):
23-36 (2009).
159. Walji R, Boon H, Guns E, Oneschuk D, Younus J. Black cohosh
(Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients. Support
Care Cancer 15(8): 913-921 (2007).
160. Kennelly EJ, Baggett S, Nuntanakorn P, Ososki AL, Mori SA, Duke J,
Coleton M, Kronenberg F. Analysis of thirteen populations of black cohosh for
formononetin. Phytomedicine 9(5): 461-467 (2002).
161. Huntley A. The safety of black cohosh (Actaea racemosa, Cimicifuga
racemosa). Expert Opin Drug Saf 3(6): 615-623 (2004).
162. Huntley AL, Thompson Coon J, Ernst E. The safety of herbal medicinal
products derived from Echinacea species: a systematic review. Drug Saf 28(5): 387-
400 (2005).
163. Basch E, Ulbricht C, Basch S, Dalton S, Ernst E, Foppa I, Szapary P,
Tiffany N, Orlando CW, Vora M. An evidence-based systemic review Echinacea E.
angustifolia DC, E. pallida, E. purpurea by the Natural Standard Research
Collaboration. J Herb Pharmacother 5: 57-88 (2005).
164. Freeman C, Spelman K. A critical evaluation of drug interactions with
Echinacea spp. Mol Nutr Food Res 52(7): 789-798 (2008).
165. Tamayo C, Diamond S. Review of clinical trials evaluating safety and
efficacy of milk thistle (Silybum marianum [L.] Gaertn.). Integr Cancer Ther 6(2):
146-157 (2007).
166. Sagar SM. Future directions for research on Silybum marianum for cancer
patients. Integr Cancer Ther 6(2): 166-173 (2007).
102
167. Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of chemotherapy.
Semin Oncol 33: 50-67 (2006).
168. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis
B or C virus liver diseases. Cochrane Database Syst Rev 4: CD003620 (2007).
169. Greenlee H, Abascal K, Yarnell E, Ladas E. Clinical applications of
Silybum marianum in oncology. Integr Cancer Ther 6(2): 158-165 (2007).
170. Ladas EJ, Kelly KM. Milk thistle: is there a role for its use as an adjunct
therapy in patients with cancer? J Altern Complement Med 9(3): 411-416 (2003).
171. Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for
the treatment of liver disease: a systematic review and meta-analysis. Am J Med
113(6): 506-515 (2002).
172. Mulrow C, Lawrence V, Jacobs B, Dennehy C, Sapp J, Ramirez G, Aguilar
C, Montgomery K, Morbidoni L, Arterburn JM, Chiquette E, Harris M, Mullins D,
Vickers A, Flora K. Milk thistle: effects on liver disease and cirrhosis and clinical
adverse effects. Evid Rep Technol Assess (Summ) 21: 1-3 (2000).
173. Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS,
Pierson AS, Agarwal R, Glodé LM. A phase I and pharmacokinetic study of
silybin-phytosome in prostate cancer patients. Invest New Drugs 25(2): 139-146
(2007).
174. Kienle S, Kiene H, Albonico HU, Anthroposophic Medicine: Effectiveness,
Utility, Costs, Safety. (Schattauer Verlag, Stuttgart, 2006).
175. Hajto T, Hostanska K, Berki T, Palinkas L, Boldizsar F, Nemeth P.
Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I):
overview of recent results from in vitro experiments and in vivo animal models, and
their possible relevance for clinical applications. Evid Based Complement Alternat
Med 2: 59-67 (2005).
176. Ernst E, Schmidt K, Steuer-Vogt MK. Mistletoe for cancer? A systematic
review of randomised clinical trials. Int J Cancer 107(2): 262-267 (2003).
177. Kienle GS, Berrino F, Büssing A, Portalupi E, Rosenzweig S, Kiene H.
Mistletoe in cancer - a systematic review on controlled clinical trials. Eur J Med Res
8(3): 109-119 (2003).
103
178. Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of
prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res
12(3): 103-119 (2007).
179. Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe
therapy in oncology. Cochrane Database Syst Rev 2: CD003297 (2008).
180. Melzer J, Iten F, Hostanska K, Saller R. Efficacy and safety of mistletoe
preparations (Viscum album) for patients with cancer diseases. A systematic review,
Forsch Komplementmed 16(4): 217-226 (2009).
181. Kienle GS, Kiene H. Influence of Viscum album L (European mistletoe)
extracts on quality of life in cancer patients: a systematic review of controlled
clinical studies. Integr Cancer Ther 9(2): 142-157 (2010).
182. Saller R, Kramer S, Iten F, Melzer J. Unerwünschte wirkungen der
misteltherapie bei tumorpatienten – eine systematische übersicht. In: Fortschritte in
der Misteltherapie. Aktueller Stand der Forschung und klinische Anwendung eds. R.
Scheer, R. Bauer, H. Becker, V. Fintelmann, F. Kemper and H. Schilcher (KVC,
Essen, 2005), pp. 367-403.
183. Büssing A, Stumpf C, Tröger W, Schietzel M. Course of mitogen-stimulated
T lymphocytes in cancer patients treated with Viscum album extracts. Anticancer
Res 27(4C): 2903-2910 (2007).
184. National Center for Complementary and Alternative Medicine (NCCAM),
Manipulative and body-based practices: an overview (NCCAM Publication No.
D238), Available at http://www.fvpt.com/manipulative.pdf (accessed 15 June
2010).
185. Ernst E. The safety of massage therapy. Rheumatology (Oxford) 42(9):
1101-1106 (2003).
186. Corbin L. Safety and efficacy of massage therapy for patients with cancer.
Cancer Control 12(3): 158-164 (2005).
187. Maddocks-Jennings W, Wilkinson JM. Aromatherapy practice in nursing:
literature review. J Adv Nurs 48(1): 93-103 (2004).
188. Fellowes D, Barnes K, Wilkinson S. Aromatherapy and massage for
symptom relief in patients with cancer. Cochrane Database Syst Rev 2: CD002287
(2004).
104
189. Ernst E, Massage therapy for cancer palliation and supportive care: a
systematic review of randomised clinical trials. Support Care Cancer 17(4): 333-
337 (2009).
190. Chao LF, Zhang AL, Liu HE, Cheng MH, Lam HB, Lo SK. The efficacy of
acupoint stimulation for the management of therapy-related adverse events in
patients with breast cancer: a systematic review Breast Cancer Res Treat 118(2):
255-267 (2009).
191. Melchart D, Weidenhammer W, Streng A, Reitmayr S, Hoppe A, Ernst E,
Linde K. Prospective investigation of adverse effects of acupuncture in 97 733
patients. Arch Intern Med 164(1): 104-105 (2004).
192. Lee H, Schmidt K, Ernst E. Acupuncture for the relief of cancer-related
pain–a systematic review. Eur J Pain 9(4): 437-444 (2005).
193. Robb KA, Bennett MI, Johnson MI, Simpson KJ, and Oxberry SG,
Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults.
Cochrane Database Syst Rev 3: CD006276 (2008).
194. Lee MS, Kim KH, Choi SM, Ernst E. Acupuncture for treating hot flashes in
breast cancer patients: a systematic review. Breast Cancer Res Treat 115(3): 497-
503 (2009).
195. Lee MS, Kim KH, Shin BC, Choi SM, Ernst E. Acupuncture for treating hot
flushes in men with prostate cancer: a systematic review. Support Care Cancer
17(7): 763-770 (2009).
196. Ezzo JM, Richardson MA, Vickers A, Allen C, Dibble SL, Issell BF, Lao L,
Pearl M, Ramirez G, Roscoe J, Shen J, Shivnan JC, Streitberger K, Treish I, Zhang
G. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting,
Cochrane Database Syst Rev 2: CD002285 (2006).
197. Lu W, Hu D, Dean-Clower E, Doherty-Gilman A, Legedza AT, Lee H,
Matulonis U, Rosenthal RS. Acupuncture for chemotherapy-induced leukopenia:
exploratory meta-analysis of randomized controlled trials. J Soc Integr Oncol 5(1):
1-10 (2007).
198. Cho JH, Chung WK, Kang W, Choi SM, Cho CK, Son CG. Manual
acupuncture improved quality of life in cancer patients with radiation-induced
xerostomia. J Altern Complement Med 14(5): 523-526 (2008).
105
199. Garcia MK, Chiang JS, Cohen L, Liu M, Palmer JL, Rosenthal DI, Wei Q,
Tung S, Wang C, Rahlfs T, Chambers MS. Acupuncture for radiation-induced
xerostomia in patients with cancer: a pilot study. Head Neck 31(10): 1360-1368
(2009).
200. Newton RU, Galvão DA. Exercise in prevention and management of cancer.
Curr Treat Options Oncol 9(2-3): 135-146 (2008).
201. Hayes SC, Spence RR, Galvão DA, Newton RU. Australian association for
exercise and sport science position stand: optimising cancer outcomes through
exercise. J Sci Med Sport 12: 428-434 (2009).
202. Morey MC, Snyder DC, Sloane R, Cohen HJ, Peterson B, Hartman TJ,
Miller P, Mitchell DC, Demark-Wahnefried W. Effects of home-based diet and
exercise on functional outcomes among older, overweight long-term cancer
survivors: RENEW: a randomized controlled trial. JAMA 301(18): 1883-1891
(2009).
203. De Backer IC, Schep G, Backx FJ, Vreugdenhil G, Kuipers H. Resistance
training in cancer survivors: a systematic review. Int J Sports Med 30(10): 703-712
(2009).
204. Cheema B, Gaul CA, Lane K, Fiatarone Singh FA, Progressive resistance
training in breast cancer: a systematic review of clinical trials. Breast Cancer Res
Treat 109(1): 9-26 (2008).
205. Speck RM, Courneya KS, Mâsse LC, Duval S, Schmitz KH. An update of
controlled physical activity trials in cancer survivors: a systematic review and meta-
analysis. J Cancer Surviv 4(2): 87-100 (2010).
206. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ. Systematic review
and meta-analysis of psychological and activity-based interventions for cancer-
related fatigue. Health Psychol 26(6): 660-667 (2007).
207. Cramp F, Daniel J. Exercise for the management of cancer-related fatigue in
adults. Cochrane Database Syst Rev 2: CD006145 (2008).
208. Velthuis MJ, Agasi-Idenburg SC, Aufdemkampe G, Wittink MH. The effect
of physical exercise on cancer-related fatigue during cancer treatment: a meta-
analysis of randomised controlled trials. Clin Oncol (R Coll Radiol) 22(3): 208-221
(2010).
106
209. Conn VS, Hafdahl AR, Porock DC, McDaniel R, Nielsen PJ. A meta-
analysis of exercise interventions among people treated for cancer. Support Care
Cancer 14(7): 699-712 (2006).
210. Beaton R, Pagdin-Friesen W, Robertson C, Vigar C, Watson H, Harris SR.
Effects of exercise intervention on persons with metastatic cancer: a systematic
review. Physiother Can 61(3): 141-153 (2009).
211. Markes M, Brockow T, Resch KL. Exercise for women receiving adjuvant
therapy for breast cancer. Cochrane Database Syst Rev 4: CD005001 (2006).
212. Duijts SF, Faber MM, Oldenburg HS, van Beurden M, Aaronson NK.
Effectiveness of behavioral techniques and physical exercise on psychosocial
functioning and health-related quality of life in breast cancer patients and survivors-
a meta-analysis. Psychooncology DOI: 10.1002/pon.1728.
213. Vallbona C, Richards T. Evolution of magnetic therapy from alternative to
traditional medicine. Phys Med Rehabil Clin N Am 10(3): 729-75 (1999).
214. National Center for Complementary and Alternative Medicine (NCCAM),
Energy medicine: an overview (NCCAM Publication No. D235), Available at
http://www.umbwellness.org/PDF_files/energymed.pdf (accessed 15 June 2010).
215. Hintz KJ, Yount GL, Kadar I, Schwartz G, Hammerschlag R, Lin S.
Bioenergy definitions and research guidelines Altern Ther Health Med 9(suppl 3):
A13-A30 (2003).
216. So PS, Jiang Y, Qin Y. Touch therapies for pain relief in adults Cochrane
Database Syst Rev 4: CD006535 (2008).
217. Ng B, Qigong-induced mental disorders: a review. ANZ J Psychiatry 33:
197-206 (1999).
218. Shan HH. Culture-bound psychiatric disorders associated with Qigong
practice in China. Hong Kong J Psychiatry 10(3): 12-14 (2000).
219. Ulbricht C, Bent S, Chao W, Costa D, Che W, Lee D, Liebowitz R, Shan H,
Sollars D, Tanguay-Colucci S. An evidence-based review of Qi Gong by the
Natural Standard Research Collaboration. Natural Med J 2(5): 7-15 (2010).
220. Lee S. Cultures in psychiatric nosology: the CCMD-2-R and international
classification of mental disorders. Cult Med Psychiatry 20: 421-472 (1996).
221. Zhang TL Xu TH. Correcting Deviations from the Path of Qigong,
(Publishing House of People's Health, Beijing, 1997).
107
222. C. M. Han and W. J. Ji, Qigong induced mental disorders, Chinese Qigong,
1: 37-38 (1997).
223. H. Ryu, H. Y. Mo, G. D. Mo, B. M. Choi, C. D. Jun, C. M. Seo, H. M. Kim
and H. T. Chung, Delayed cutaneous hypersensitivity reactions in Qigong (chun do
sun bup) trainees by multitest cell mediated immunity, Am J Chin Med. 23(2): 139-
144 (1995).
224. Chen K, Yeung R. Exploratory studies of Qigong therapy for cancer in
China. Integr Cancer Ther 1(4): 345-370 (2002).
225. Lee MS, Chen KW, Sancier KM, Ernst E. Qigong for cancer treatment: a
systematic review of controlled clinical trials. Acta Oncol 46(6):717-722 (2007).
226. Jain S, Mills PJ. Biofield therapies: helpful or full of hype? A best evidence
synthesis. Int J Behav Med 17(1): 1-16 (2010).
227. University of New South Wales Department of Physics, The electromagnetic
spectrum, Available at http://www.phys.unsw.edu.au/~jw/EMspectrum.html
(accessed 16 June 2010).
228. Review Committee on Microwave Cancer Therapy and National Health and
Medical Research Council, Review of the use of microwave therapy for the
treatment of patients with cancer, Available at
http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/nh67.pdf
(accessed 16 June 2010).
229. Wust P, Gellermann J, Harder C, Tilly W, Rau B, Dinges S, Schlag P,
Budach V, Felix R. Rationale for using invasive thermometry for regional
hyperthermia of pelvic tumors. Int J Radiat Oncol Biol Phys 41: 1129-1137 (1998).
230. Lowenthal RM. Integrative oncology in Australia. J Soc Integr Oncol 4(2):
82-85 (2006).
108
3.2 Post-Publication Update to the Systematic Review in Study 2
This literature update of the systematic review of CAMs used by cancer patients
that comprised study 2 will follow the same structure observed in the preceding manuscript.
3.3 Whole Medical Systems
3.3.1 Homeopathy
Two subsequent reviews evaluating the efficacy and/or safety of homeopathy in
cancer patients have been published. Consistent with the systematic review in study 2,
Frenkel (2010) concluded in a narrative review of randomised controlled trials (RCTs) and
observational studies that while homeopathic medicines appear to be safe and may offer
symptom relief and concomitant improvement in QoL for cancer patients, the outcomes
were equivocal and further clinical trials were required. Additionally, the author noted that
no controlled trials to date had demonstrated anticancer effects. Furthermore, in a recent
systematic review of 57 meta-analytic/systematic reviews (including 11 relating to cancer)
involving homeopathic controlled clinical trials, the Australian National Health and
Medical Research Council (2013) found insufficient evidence that homeopathy is an
effective treatment for any of the 68 health conditions considered. Endemic of the great
majority of studies evaluated, there was a paucity of large, good-quality studies amongst
the 7 RCTs of homeopathic management of cancer treatment-related symptoms (adverse
effects of venous cannulation, chemotherapy-induced nausea/vomiting and stomatitis, hot
flushes in women with a history of breast cancer, radiodermatitis in breast cancer patients
undergoing radiotherapy); all of which were assigned a very low or low level of confidence
rating for the weight of evidence provided.
3.3.2 Naturopathy
Given the overlap of naturopathic remedies with other categories of CAM, updates
will be reviewed in their respective sections below.
3.3.3 Traditional Chinese Medicine
Three subsequent reviews evaluating the efficacy and/or safety in cancer care of
traditional Chinese medicine (TCM) in general have been published. In a systematic review
of 2385 Chinese RCTs and 579 non-randomised controlled trials / observational studies
evaluating the efficacy of TCM (predominantly herbal medicine and acupuncture-point
109
stimulation) ± conventional treatment (72% combined), 756 (26%) studies recommended
TCM be incorporated into standard treatment based on efficacy and safety (Li et al., 2013).
However, the review authors assessed only 5 of those studies as well-designed RCTs
exhibiting significantly improved survival, and recommended further studies and improved
reporting of randomisation and blinding procedures in future Chinese controlled trials to
meet international standards. Similar conclusions were also drawn in systematic reviews of
Chinese retrospective case series reports (Yang et al., 2012) and case studies (Liu et al.,
2011) evaluating TCM in cancer care. These outcomes are consistent with the systematic
review in study 2.
3.4 Mind-Body Techniques
3.4.1 Relaxation
Two subsequent reviews evaluating the efficacy of relaxation techniques in cancer
care have been published. Consistent with the systematic review in study 2, a large meta-
analytic/systematic review of psychological-based interventions revealed that relaxation
training (± imagery techniques) demonstrated significant small-medium effect sizes for
emotional distress, anxiety, depression and QoL in cancer patients at post-treatment (based
on 46 RCTs; Faller et al., 2013). The authors concluded that beneficial effects of relaxation
training were evident in the short-term, although the effects on emotional distress and
anxiety outcomes may have been more pronounced due to possible publication bias (i.e. the
disproportionate contribution of larger effect sizes by small studies). Additionally, in a
review of pharmacological/non-pharmacological interventions for hot flushes, Morrow and
colleagues (2011) concluded that relaxation techniques (two trials of post-menopausal
women, a systematic review of psychoeducational interventions including 9 RCTs
involving breast cancer survivors) appeared to alleviate hot flushes and should be
considered as an alternative or as a complement to non-hormonal medications in
individuals with cancer. However, further studies were recommended given the poor
methodological quality of the evidence.
3.4.2 Meditation
Two subsequent reviews evaluating the safety of meditation practices have been
published or newly-located. Consistent with the systematic review in study 2, serious
adverse events were found to be rare in two meta-analytic/systematic reviews of RCTs
110
involving medical patients and trait anxiety-prone populations, respectively (Arias,
Steinberg, Banga, & Trestman, 2006; Orme-Johnson & Barnes, 2014). Furthermore, Arias
and colleagues (2006) concluded that the outcomes supported the safety of meditation
practices for treating medical patients (including emotional disturbance in cancer patients),
particularly those with non-psychotic mood and anxiety disorders. This further reinforces
the recommendation of study 2 that, first and foremost, meditation practices (transcendental
or Vipassana meditation, in particular) should be used with caution or are best avoided in
cancer patients with (a history of) psychosis or related symptomatology.
Eight subsequent reviews (and one RCT of transcendental meditation) evaluating
the efficacy of meditation practices in cancer care have been published or newly-located.
Consistent with study 2, meta-analytic/systematic reviews of mindfulness-based stress
reduction (MBSR) involving 3 RCTs and 3 controlled trials plus 6 observational studies,
respectively, suggested that MBSR compared to standard care may decrease anxiety, stress
and depressed mood in breast cancer patients and survivors (Cramer, Lauche, Paul, &
Dobos, 2012; Zainal, Booth, & Huppert, 2012). Similar outcomes were reported in other
systematic reviews of breast cancer patients and survivors (Casellas-Grau, Font, & Vives,
2014; Matchim, Armer, & Stewart, 2011), as well as recent meta-analytic/systematic
reviews of MSBR ± other mindfulness-based therapies involving mixed cancer patients and
survivors (Piet, Würtzen, & Zachariae, 2012; Musial, Büssing, Heusser, Choi, &
Ostermann, 2011; Shennan, Payne, & Fenlon, 2011; Hofmann, Sawyer, Witt, & Oh, 2010).
The general consensus among the review authors, however, was that the methodology
employed was poor and more large, high-quality RCTs were required involving male and
other non-breast cancer populations (preferably diagnosed with psychological disorders to
be targeted), active treatment control groups (e.g. relaxation training), standardised
treatment protocols and measures of mindfulness and longer follow-up periods.
Finally, in the only controlled trial of transcendental meditation (TM) in the cancer
literature to the author’s knowledge, a single-blind RCT involving 130 older,
predominantly early-stage breast cancer patients revealed significant improvements in
overall QoL and emotional and social well-being after a median 18 months of TM when
compared with standard care (Nidich et al., 2009). Improvements in functional and spiritual
well-being were not exhibited by TM patients, however. As with mindfulness, further
RCTs are required involving larger samples of different cancer patients and survivors
(preferably diagnosed with psychological disorders to be targeted), active treatment control
111
groups, standardised treatment protocols and longer follow-up periods. Adverse effects
should also be monitored given previous concerns raised about the safety of intensive TM
(refer to study 2).
3.4.3 Hypnotherapy
One subsequent review evaluating the efficacy of hypnotherapy in cancer
prevention and care has been published (Montgomery, Schnur, & Kravits, 2013). In a
comprehensive narrative review, Montgomery and colleagues (2013) found mixed evidence
for the efficacy of hypnotherapy in cancer prevention based on previous meta-
analytic/systematic reviews. While overweight/obesity is a risk factor for cancer and
hypnotherapy has the capacity to double weight loss when combined with cognitive-
behavioural therapy in weight loss programmes, the authors overlooked the necessity of
presenting meta-analytic findings of such programmes that actually show significant
reduction of cancer risk or mortality. Additionally, they found insufficient evidence from
several meta-analytic/systematic reviews to support the use of hypnotherapy for smoking
cessation, and recommended more rigorous RCTs examining the additive effect of
hypnotherapy combined with other treatments and potential moderators of any beneficial
treatment effects (e.g. social support).
In relation to cancer diagnosis, based on 4 RCTs and a cost-benefit study, the
review authors found that hypnotherapy may be effective in controlling acute pain and
distress in breast and other cancer patients undergoing diagnostic procedures (as per study
2), with significant overall cost savings being delivered for breast biopsies alone. Identical
outcomes were revealed for surgical procedures and percutaneous cancer treatment also,
with clinical benefits extending to reduced recovery and treatment time in the former and
less pain medication in the latter compared to standard care or empathic attention control
groups. Large-scale RCTs of hypnotherapy involving non-breast cancer patients (curative
and palliative) undergoing chemotherapy or radiotherapy as well as cancer survivors, and
including longer follow-up periods and cost-benefit analyses were recommended.
3.4.4 Yoga
Twelve subsequent reviews evaluating the efficacy and/or safety of yoga in cancer
care have been published. Several systematic/meta-analytic and narrative reviews provide
preliminary support for the efficacy of yoga interventions in breast cancer patients and
112
survivors. Positive short-term benefits were demonstrated for a range of outcomes
including (overall) QoL, general, physical/functional, emotional and social well-being,
anxiety, depression, mood and stress (Shneerson, Taskila, Gale, Greenfield, & Chen, 2013;
Sadja & Mills, 2013; Zhang, Yang, Tian, & Wang, 2012; Cramer, Lange, Klose, Paul, &
Dobos, 2012a; Buffart et al., 2012; Harder, Parlour, & Jenkins, 2012; Culos-Reed,
Mackenzie, Sohl, Jesse, Zahavich, & Danhauer, 2012; Levine & Balk, 2012; Lin, Hu,
Chang, Lin, & Tsauo, 2011). Mixed preliminary evidence was reported for fatigue (Sadja &
Mills, 2013; Zhang et al., 2012; Cramer et al., 2012b; Harder et al., 2012; Buffart et al.,
2012; Culos-Reed et al., 2012; Boehm, Ostermann, Milazzo, & Büssing, 2012), while no
significant benefits were detected for sleep quality (Zhang et al., 2012; Buffart et al., 2012).
Long-term benefits of yoga in breast cancer patients and survivors, however, were difficult
to ascertain as few studies included long-term follow-up.
Overall, the great majority of studies included in these reviews suffered from a
number of limitations, including small sample sizes, biased sampling (e.g. mostly
Caucasian women), poor screening (e.g. few fatigue studies, if any, purposely recruited
patients or survivors suffering cancer-related fatigue), poor blinding practices (e.g. few
studies reported blinding of outcome assessors), heterogeneity of yoga intervention type,
components and duration/length, no use of objective measures where appropriate (e.g.
physiological measures for fatigue, such as haemoglobin levels), no inclusion of active
treatment control groups (e.g. physical activity intervention group), and no long-term
follow-up or assessment of adverse effects. Larger, high-quality RCTs addressing these
limitations are required.
Finally, a recent Cochrane meta-analytic review found inconclusive evidence to
support the use of yoga interventions in haematological cancer patients, and advised that
large, high-quality RCTs were needed (Felbel, Monsef, Engert, & Skoetz, 2014). Only one
small RCT met criteria for inclusion, which revealed no benefit of Tibetan yoga over and
above standard care for distress, depression, anxiety and fatigue and only low quality
evidence supporting improved sleep quality. Adverse effects were not addressed either.
3.4.5 Tai Chi
Two subsequent reviews evaluating the efficacy of tai chi in breast cancer care have
been published. Consistent with study 2, two small meta-analytic/systematic reviews of
RCTs provided insufficient support for the positive impact of tai chi on physical and
113
psychological outcomes in breast cancer patients and survivors (Zeng, Luo, Xie, Huang, &
Cheng, 2014; Yan, Zhang, Sun, & Cui, 2013). Non-significant effect sizes were reported
for several outcomes (physical, social/family and functional well-being, other QoL
concerns, body mass index, body fat mass, bone mineral density, muscle strength), while
only a small effect size was identified for emotional well-being in the latter study. Again,
large high-quality RCTs examining the efficacy and safety of tai chi in breast and other
cancer populations are required to address the same limitations observed in the yoga
literature reported above.
3.4.6 Music-Related Therapies
Since study 2, a distinction in nomenclature has been made more apparent in the
cancer literature between “music therapy” and “music medicine”. Music medicine involves
passive listening, usually prerecorded music selected by medical staff (with or without a
background in music therapy) that may or may not consider patient preferences (Trondalen
& Bonde, as cited in MacDonald, Kreutz, & Mitchell, 2012; Bradt, Dileo, & Shim, 2013).
In contrast, music therapy comprises prerecorded, live and/or interactive music that is
individually tailored by a music therapist that engages in a therapeutic process with patients
(Bradt et al., 2013). Either may be used alone or in combination with relaxation/imagery
techniques. Fifteen subsequent reviews evaluating the efficacy and/or safety of music-
related interventions (music therapy, music medicine) in cancer care have been published
or newly-located.
In relation to cancer diagnosis and surgical procedures, two meta-analytic studies
examining RCTs involving colonoscopy (a screening method for colon cancer) found that
music medicine was a safe, effective technique for reducing procedure time, anxiety and
sedative medication (Bechtold et al., 2009; Tam, Wong, & Twinn, 2008), but not
procedural pain (Bechtold et al., 2009) Similarly, a small systematic review of RCTs
involving colposcopy (a diagnostic test for cervical cancer following an abnormal pap
smear) suggested that anxiety and pain levels may be reduced by listening to music during
the procedure (Galaal, Bryant, Deane, Al-Khaduri, & Lopes, 2011). Additionally, a large
Cochrane meta-analytic review and two systematic/narrative reviews of controlled trials
(Bradt et al., 2013; Gooding, Swezey, & Zwischenberger, 2012; Nilsson, 2008), albeit of
poor methodological quality overall, suggested that self-reported pre-operative anxiety may
be reduced by music-related interventions (predominantly passive listening compared to
114
standard care), but this may not translate to physiological indicators (heart/respiratory rate,
systolic/diastolic blood pressure, skin temperature; Bradt et al., 2013). No adverse effects
were identified either (Bradt et al., 2013). Similarly, a Cochrane meta-analytic review and
three systematic/narrative reviews of controlled trials (Cepeda, Carr, Lau, & Alvarez, 2006;
Cole & LoBiondo-Wood, 2014; Gooding et al., 2012; Engwall & Duppils, 2009), albeit of
poor methodological quality overall, suggested that music-related interventions could be
used as an adjuvant to pain medication to reduce postoperative pain and analgesic use.
Further high-quality RCTs are required examining the impact on procedural and pre-
/postoperative outcomes of specific music-related interventions, alone and in comparison to
or combination with other active treatments (e.g. relaxation/imagery, psychoeducation,
pharmacotherapy). Ideally, they would incorporate both homogeneous and heterogeneous
samples of cancer patients, more music therapy interventions, standardised types and
durations of music intervention, a combination of standardised self-report measures and
physiological measures, baseline measures of medication intake and cost-benefit analyses
of any reduced medication use.
In cancer care per se, a Cochrane meta-analytic review of 30 controlled trials
(including two paediatric studies) and a meta-analytic/systematic review of 32 RCTs
provided preliminary support for the efficacy of music-related interventions relative to
standard care or other active treatment control groups (Bradt et al., 2011; Zhang et al.,
2012). Benefits were demonstrated for a range of psychological and physiological
outcomes, including self-reported (coping) anxiety, mood, pain, heart/respiratory rate and
blood pressure. Mixed evidence was found for depression and none for the amelioration of
fatigue, physical status or QoL. These two reviews have since been criticised for
unnecessarily including heterogeneous and ambiguous data from studies not only of poor
methodological quality, but also from several studies predating guidelines for reporting
clinical trials established in the mid-1990s (Tsai et al., 2014; Nightingale, Rodriguez, &
Carnaby, 2013). Furthermore, a limited re-analysis of the aforementioned Cochrane review
indicated that music-related interventions did, indeed, have a significant impact on QoL
following the removal of one problematic study (Archie, Bruera, & Cohen, 2013).
In a more contemporary meta-analytic review of 21 higher-quality controlled trials
and a large comprehensive narrative review of controlled/observational studies, evidence
suggested that music-related interventions may have positive effects on self-reported
anxiety, depression, mood, pain, fatigue and QoL in cancer patients (Tsai et al., 2014;
115
Archie et al., 2013). Subgroup analyses in the meta-analytic review also revealed that
music-related interventions were more effective when patients rather than medical staff or
researchers selected the music. In contrast, a meta-analytic/systematic review of 13 higher-
quality RCTs suggested a positive impact on self-reported anxiety in cancer patients in the
systematic review, but then revealed a non-significant effect size when 4 amenable RCTs
were subjected to meta-analysis and subsequent subgroup analysis (Nightingale et al.,
2013). The authors argued that the high quality study selection combined with study
heterogeneity (variable samples and music intervention approaches) accounted for the
disparity of their results from previous meta-analytic reviews. Nevertheless, despite the
merits of these two most recent meta-analytic reviews, both were still limited by the
omission of studies that contained active treatment control groups and analyses examining
physiological measures of anxiety. Consequently, the conclusions of study 2 still hold –
that is, only preliminary evidence for efficacy exists and larger, high-quality RCTs are
required (as specified for procedural and pre-/postoperative outcomes above), but use of
music-related interventions in cancer patients could be supported in the interim given its
very good safety profile and economy in terms of time and expense.
3.4.7 Support Groups
Since study 2, the concept of internet cancer support groups (ICSGs) has gained in
popularity, so much so that it has been the subject of two published or newly-located
reviews. Briefly defined, ICSGs enable cancer patients and survivors to share experiences
and opinions and to seek, receive and provide information (diagnosis, treatment, other
cancer-related resources), advice or emotional support online (Griffiths, Calear, & Banfield,
2009). The online resources utilised include chat rooms, bulletin boards, mailing
lists/newsgroups/online web forums, instant messaging and blogs (Griffiths et al., 2009; Im
& Chee, 2008).
Two subsequent reviews evaluating the efficacy of ICSGs in cancer care have been
published. Griffiths and colleagues (2009) in their systematic review of 28 studies
examined the effects on depression of internet support groups (ISGs) in a range of
populations (e.g. patients, caregivers, adolescents) including breast cancer patients (6
studies, 2 RCTs). While the poor methodological quality and heterogeneity of the studies
precluded meta-analysis, they found that breast cancer ISGs were more likely to report
reduced depression than studies of other populations (Griffiths et al., 2009). Nevertheless,
116
these results were rendered inconclusive by the low quality of the studies and the majority
being performed by one research group. In a more comprehensive systematic review of 24
studies evaluating ICSGs and related online resources in cancer patients and survivors
(mostly small studies of Caucasian breast cancer survivors, 4 RCTs), Hong and colleagues
(2012) found that most studies reported psychosocial benefits. However, evidence was
deemed inconclusive as none of the RCTs reported significant benefits (Hong, Peña-Purcell
NC, & Ory, 2012). Large, high-quality RCTs involving homogeneous and heterogeneous
cancer populations (e.g. treated patients vs survivors, non-breast cancer and ethnically
diverse samples) are required, comparing ICSGs to active treatment control groups (e.g.
more traditional support groups) across both psychosocial and physical/QoL outcomes and
including long-term follow-up.
3.4.8 Spirituality, Religion and Prayer
Three subsequent reviews evaluating the role of spirituality and religion in cancer
prevention and care have been published. In a large, comprehensive systematic review
examining the relationship between religion/spirituality and health, 123 of 137 studies (and
90% of the 83 methodologically most rigorous of these studies) demonstrated a significant
inverse relationship between religion/spirituality and cigarette smoking, while none
reported significant positive associations (Koenig, 2012). Given the causative relationship
between cigarette smoking and lung cancer, the author concluded that decreased cigarette
smoking associated with religion/spirituality will lead to a reduction in lung cancer and
concomitant chronic obstructive pulmonary disease, not to mention reduced risk for cancer
in general. More equivocally, 16 of 29 studies (and 60% of the 20 methodologically most
rigorous of these studies) also revealed a significant inverse relationship between
religion/spirituality and cancer risk or poor prognosis, while none reported elevated cancer
risk or poorer prognosis among the methodologically most rigorous studies. Nevertheless,
consistent with study 2, the systematic review was unfortunately compromised by
associations observed in the (predominantly cross-sectional, observational) studies being
confounded by individuals being more likely to become religious/spiritual following
significant life events (e.g. bereavement), no adjustment being made for relevant
demographic and lifestyle factors, and poor conceptualisation and/or measurement of
religiosity/spirituality (Stefanek, McDonald, & Hess, 2005; de Jager et al., 2010; Masters &
Hooker, 2013).
117
In relation to adjustment to and coping with cancer, two detailed systematic and
narrative reviews found limited evidence for a positive relationship between adaptive
religious or spiritual coping and psychological, spiritual and general well-being in cancer
patients and breast cancer survivors/patients, and poorer well-being for negative religious
or spiritual coping (Masters & Hooker, 2013; Schreiber & Brockopp, 2012). As
recommended in study 2, more large longitudinal studies are required that compare
spirituality and/or religion (across faiths) as primary endpoints to other coping strategies
(e.g. social support) in specific cancer populations, and adequately control for potential
confounding variables (e.g. the aforementioned variables above, stage of illness,
prognosis).
3.5 Biologically-Based Practices
3.5.1 Nutritional Supplements (Dietary/Food Supplements)
3.5.1.1 Antioxidants
Twenty-five subsequent reviews evaluating the efficacy and/or safety of
antioxidants in cancer prevention and care have been published. With respect to
chemoprevention, a meta-analysis of 20 RCTs indicated that antioxidant supplements
(vitamins A, C, E; selenium; beta-carotene) alone or in combination did not significantly
reduce colorectal cancer incidence, colorectal adenoma recurrence or cancer-related/overall
mortality (Pais & Dumitrascu, 2013). Vitamin C combinations were the only exception and
significantly reduced colorectal cancer incidence, but not mortality. Similar outcomes were
revealed in a Cochrane meta-analytic review of 8 controlled and cohort studies evaluating
the effects of dietary flavonoid intake on colorectal cancer and adenoma incidence (Jin,
Leng, & Li, 2012). A meta-analysis of 13 observational studies examining antioxidant
intake (vitamins A, C, E; beta-carotene), however, found limited evidence that dietary
intake of vitamin C and beta-carotene, but not vitamins A and E, reduced the risk of
colorectal adenoma (precursor of colorectal cancer), although more large, high-quality
studies were recommended (Xu et al., 2013). Similarly, results were mixed when both
antioxidant intake and supplementation were examined in reviews of breast cancer and
prostate cancer risk. A meta-analysis of 51 RCTs, cohort studies and case-control studies
indicated that total vitamin A and total retinol intake significantly reduced breast cancer
risk across different study designs, but not total vitamin E or dietary vitamin A or E intake
(Fulan et al., 2011). Additionally, a meta-analysis of 33 cohort and case-control studies
118
revealed that dietary intake of alpha- or beta-carotene, but not dietary or total intake of
other carotenoids (including lycopene), significantly reduced breast cancer risk (Hu et al.,
2012). Finally, a systematic review of RCTs, cohort and observational studies found
inconclusive evidence for the use of dietary intake or supplementation of antioxidants
(vitamins C and E; selenium; carotenoids) in reducing prostate cancer risk and
recommended further studies (Vance, Su, Fontham, Koo, & Chun, 2013).
Several reviews have also focused exclusively on specific antioxidants in relation to
cancer prevention. A meta-analysis of 6 RCTs indicated that there was no evidence for the
primary or secondary prevention of cancer through use of beta-carotene supplementation,
and that it significantly increased the risk of urothelial malignancies (especially bladder
cancer) and marginally increased the risk of cancer among current smokers (Jeon et al.,
2011). Similar outcomes were also observed in a meta-analysis of 6 RCTs evaluating the
effects of vitamin A on lung cancer risk (Fritz et al., 2011a). A Cochrane meta-analytic
review of 3 RCTs and a meta-analysis of 17 cohort and case-control studies found
insufficient support for lycopene consumption or supplementation preventing prostate
cancer, and recommended more rigorous studies be performed in light of marked clinical
heterogeneity (Ilic, Forbes, & Hassed, 2011; Chen, Song, & Zhang, 2013). Similar
outcomes also were reported in a meta-analysis of 17 cohort and case-control studies for
gastric cancer risk (T. Yang, X. Yang, X. Wang, Y. Wang, & Song, 2013).
A Cochrane meta-analytic review found lower cancer incidence and cancer
mortality associated with selenium exposure in 55 observational studies, but no such
evidence for selenium supplementation in 8 RCTs (Vinceti et al., 2014). Nevertheless, the
authors advised that outcomes of the observational studies should be interpreted with
caution given several methodological limitations (e.g. assessment issues with selenium
exposure, heterogeneity). In contrast, a meta-analysis of 9 RCTs found qualified support for
selenium supplementation preventing cancer (Lee et al., 2011). Subgroup analyses
indicated that preventative effects were exerted for liver cancer and in populations with
high-risk for cancer or a low baseline serum selenium level. Discrepancies may be
explained by more liberal inclusion criteria for studies in the latter meta-analysis (e.g.
combined selenium protocols, high-risk liver cancer populations) introducing bias that may
have inflated efficacy outcomes. Nevertheless, a meta-analytic/systematic review also
found qualified support for selenium supplementation in the prevention of lung cancer,
such that lung cancer risk may be reduced in low baseline selenium level populations (Fritz
119
et al., 2011b). However, given its association with elevated risk of diabetes at higher
baseline selenium levels, the authors suggested that use of selenium supplementation be
limited until further studies are performed.
Turning to adjuvant cancer treatment, two meta-analyses (21 RCTs and 8 RCTs,
respectively) have demonstrated a range of positive treatment outcomes in solid tumour
patients of using melatonin as an adjunct to chemotherapy ± radiotherapy or
supportive/palliative care (Seely et al., 2012; Wang et al., 2012). They included significant
improvements in 1-year survival, complete/partial tumour response, stable disease and
various toxicities due to chemotherapy ± radiotherapy (thrombocytopenia, leukopenia,
fatigue, asthenia, neurotoxicity, nausea and vomiting, hypotension). Additionally, no
adverse effects were reported. Furthermore, a meta-analysis of 10 prospective observational
studies involving breast cancer patients and survivors suggested that vitamin C
supplementation and dietary intake may be associated with significantly increased breast
cancer survival and reduced overall mortality, although several limitations of the included
studies (e.g. non-adjustment of confounding demographic and/or lifestyle factors including
pre-diagnosis vitamin C use; self-reporting of dietary intake) and the review itself (e.g.
safety was not considered) require more large high-quality studies be performed (Harris,
Orsini, & Wolk, 2014).
More equivocally, a systematic review examining intravenous vitamin C in 37
studies (2 RCTs, 15 uncontrolled trials, 6 observational studies, 14 case studies) found very
limited evidence suggesting that high-dose intravenous vitamin C (≥ 5g) combined with
chemotherapy may enhance survival, tumour response, time to relapse, QoL, physical
functioning and and various chemotherapy- or cancer-related symptoms (fatigue, nausea,
insomnia, constipation, depression); however, no evidence exists for its efficacy as a
standalone anticancer treatment (Frtitz et al., 2014). Additionally, limited evidence was
demonstrated for the safety of intravenous vitamin C when adequate precautions are taken
(e.g. use of graduated dosing schedules; concomitant administration with
calcium/potassium/magnesium chloride to offset electrolyte imbalances, and reduce kidney
stone risk in patients with such a history; Frtitz et al., 2014; Stephenson, Levin, Spector, &
Lis, 2013; Riordan et al., 2005). The most commonly reported adverse effects of
intravenous vitamin C include transient nausea (due to osmotic load during infusion),
headaches, lightheadedness and dry mouth, while high-dose administration has also been
associated with more serious, dose-limiting adverse events in electrolyte imbalances [e.g.
120
grade 3/4 hypokalaemia (low blood potassium) and hypernatraemia (high sodium blood
concentration); Stephenson et al., 2013; Welsh et al., 2013; Monti et al., 2012; Riordan et
al., 2005]. Contraindications of high-dose intravenous vitamin C include cancer patients
with (a history of) acute/chronic renal dysfunction, glucose-6-phosphate (G6PD) deficiency
due to risk of haemolysis (red blood cell breakdown) or haemochromatosis (iron overload;
Riordan et al., 2003, 2004), or those at increased risk of tumour necrosis (e.g. brain
metastasis, aggressive malignancies; Campbell & Jack, 1979). Finally, trials of low-dose
intravenous vitamin C combined with various chemotherapy/symptom control regimens
(paclitaxel/carboplatin, gemcitabine, arsenic trioxide, melphalan, bortezomib,
dexamethasone) also suggested few concerns with drug interactions (Fritz et al., 2014),
with the exception of bortezomib used to treat multiple myeloma or mantle cell lymphoma
(Perrone et al., 2009). Nevertheless, the review authors acknowledged that the outcomes are
far from conclusive due to the poor quality of the studies (e.g. lack of control groups, small
sample sizes, use of heterogenous trial methodologies and populations), which precluded
meta-analysis and limitations of the review itself (e.g. no assessment of publication bias).
Further well-designed RCTs evaluating the efficacy and safety of intravenous vitamin C
(including optimal dosing schedules) as an adjunct to cancer therapy, and involving active
treatment control groups and long follow-up periods are advised.
In contrast, a subgroup meta-analysis of 6 RCTs found that the use of amifostine
(synthetic antioxidant) as an adjunct to radiotherapy ± chemotherapy had no significant
effect on complete/partial response in head and neck cancer patients compared to placebo
or clinical observation (Gu et al., 2014). Furthermore, a meta-analysis of 12 high-quality
RCTs, predominantly involving lung and head and neck cancer patients with locally
advanced disease, revealed that the use of amifostine as an adjunct to radiotherapy ±
chemotherapy conferred no significant benefit for overall survival or progression-free
survival in studies with a median follow-up of 5.2 years (Bourhis et al., 2011). The most
common adverse effects of intravenous amifostine reported were nausea/vomiting, transient
hypotension and allergic reactions (grade 3/4: 4-6% average incidence; Gu et al., 2014; cf.
subcutaneous amifostine: nausea/vomiting; Jensen et al., 2010), which can lead to cessation
in up to 25% of patients (Rades et al., 2004). Concerns regarding the cytoprotective effects
of amifostine extending beyond normal tissue to tumours and therefore compromising
survival appear unfounded, although the authors of the latter review recommended further
RCTs designating survival as a primary endpoint rather than a secondary one to provide a
121
more definitive answer.
Finally, in regard to treatment toxicity per se, the American Society of Clinical
Oncology has recommended in clinical practice guidelines that amifostine’s cytoprotective
properties may lend its possible use to the prevention of cisplatin-induced nephrotoxicity
and the reduction of acute/late xerostomia among head and neck cancer patients receiving
fractionated radiotherapy, as well as grade 3/4 neutropenia in general (Hensley et al., 2009).
A recent meta-analytic/systematic review of 17 RCTs involving head and neck cancer
patients treated with radiotherapy ± chemotherapy provided qualified support for this
position (Gu et al., 2014). Subgroup analyses revealed that the use of amifostine
significantly reduced grade 2-4 acute or late xerostomia and grade 3-4 mucositis in head
and neck cancer patients receiving radiotherapy alone (and not concurrent
chemoradiotherapy), but not grade 3/4 leukopenia, anaemia and thrombocytopenia across
treatments. Significant improvement was also observed for grade 3/4 dysphagia, but
extreme heterogeneity observed in the 5 RCTs examined rendered these results
inconclusive. In contrast, the Multinational Association of Supportive Care in Cancer
(MASCC) found insufficient evidence to support the use of amifostine to reduce acute/late
xerostomia among (chemo)radiotherapy patients (Jensen et al., 2010). In their systematic
review of 16 studies (9 RCTs, 6 cohort studies, 1 cross-sectional study; predominantly head
and neck cancer patients), whilst most studies exhibited beneficial effects on xerostomia,
amifostine failed to demonstrate in most studies that it also mitigated reductions in salivary
flow rate secondary to radiotherapy. The authors also held that most studies were of
questionable methodological quality (e.g. no placebo use in control arms), thus further
high-quality RCTs are recommended.
The MASCC has also determined that there is insufficient support for the use of
amifostine in the prevention/management of oral mucositis in cancer patients (Nicolatou-
Galitis et al., 2013). In their systematic review of 30 studies (organised by type of cancer
treatment and amifostine administration), the authors observed that all studies suffered from
major flaws (e.g. no double-blinding or use of placebo in control arms, use of historical
controls) and clinical heterogeneity (e.g. variable time/dose schedules of amifostine
administration and type/intensity of cancer treatments). Similarly, a Cochrane meta-analytic
review, based on 11 RCTs involving predominantly head and neck cancer patients
receiving radiotherapy ± chemotherapy, found weak unreliable evidence that amifostine
may prevent oral mucositis in cancer patients (Worthington et al., 2011). Large, well-
122
designed RCTs, involving homogeneous cancer populations, standardised time/dose
administration schedules and placebo or active control treatments, are required to clarify
the role of amifostine (alone and in combination with other preventative strategies) as an
intervention for oral mucositis.
Amifostine has also been evaluated in the prevention/management of chemotherapy
toxicities related to platinum-based agents. A Cochrane meta-analytic review, based on 7
small controlled trials involving cancer patients treated with platinum-based chemotherapy
(cisplatin, carboplatin, oxaliplatin), revealed that amifostine received as an adjunct
modestly reduced or prevented neurotoxicity assessed post-treatment (0-6 months)
compared to placebo, but that the evidence was inconclusive given the trials lacked
methodological rigour (i.e. omission of primary measures, such as the proportion of
patients who received increased dosing of platinum-based chemotherapy due to reduced
neurotoxicity; no objective measures of neurotoxicity; Albers, Chaudhry, Cavaletti, &
Donehower, 2014). The most commonly reported adverse effects were transient
hypotension (8-62% incidence) and hypocalcaemia (11%). Similarly, a meta-analysis of 4
RCTs found insufficient support for the use of amifostine as an adjunct to cisplatin in
reducing or preventing ototoxicity (symptoms include sensorineural hearing loss, tinnitus,
dizziness; Duval & Daniel, 2012). Reported adverse effects included hypocalcaemia,
hypotension, vomiting and sneezing. Further large RCTs are needed to clarify the role (if
any) of amifostine in the prevention and/or management of chemotherapy toxicities
secondary to platinum-based chemotherapy.
3.5.1.2 Omega-3 Fatty Acids (n-3 Polyunsaturated Fatty Acids)
Eight subsequent reviews evaluating the efficacy and/or safety of omega-3 fatty
acids in cancer prevention and care have been published. With respect to chemoprevention
(and consistent with study 2), a meta-analysis of 19 RCTs revealed that omega-3 fatty acid
supplementation had no significant effect on cancer incidence or overall mortality
compared to placebo (Zhang, Gao, Hou, & Zhou, 2014). Several recent meta-
analytic/systematic reviews have examined the association of dietary intake of omega-3
fatty acids or fish and cancer risk in epidemiological studies (prospective cohort/case-
control studies), with few positive outcomes. No significant associations were observed for
risk of breast, prostate, colorectal or gastric cancer (Zheng, Hu, Zhao, Yang, & Li, 2013;
Chua, Sio, Sorongon, & Dy, 2012; Shen, Zhou, Dong, Ding, & Wu, 2012; Qin, Xun, & He,
123
2012; Wu et al., 2011). Partly consistent with study 2, however, weak protective
associations were found between high alpha-linolenic acid (ALA) dietary intake and
prostate cancer risk (Chua et al., 2012), as well as breast cancer risk (Zheng et al., 2013).
Nevertheless, further large epidemiological studies are warranted given the many
challenges involved in evaluating the association between dietary fat and cancer risk (e.g.
adjusting for confounding dietary, lifestyle and/or reproductive/genetic factors across
populations, quantifying ALA and other different fats classified as omega-3 fatty acids, the
effect of potential contaminants contained in fish and other dietary sources of omega-3 fatty
acids; Khaw, 2013).
In relation to supportive care (and broadly consistent with study 2), a systematic
review of 38 studies (including 10 controlled trials) involving omega-3 fatty acids, fish oil
and/or eicosapentaenoic acid (EPA) indicated that omega-3 fatty acid treatment is unlikely
to be effective in ameliorating refractory cachexia in advanced cancer patients (Ries et al.,
2012). In fact, the authors suggested that the 8 week treatment duration recommended in
several studies may render omega-3 fatty acid treatment burdensome for advanced cancer
patients with poor prognosis, particularly if any of the reported mild adverse effects (e.g.
abdominal discomfort, nausea, diarrhoea, belching) that may occur prove dose-limiting
over time. More positively, however, the authors observed promising outcomes (faster
wound healing, fewer postoperative complications) in the use of parenteral/enteral omega-3
fatty acid supplementation following cancer surgery. Similarly, another systematic review
based on 5 RCTs suggested that postoperative parenteral supplementation may reduce the
length of hospital stay of surgical oncology patients (van der Meij, van Bokhorst-de van der
Schueren, Langius, Brouwer, & van Leeuwen, 2011). Further large RCTs are required to
confirm the efficacy of omega-3 fatty acid supplementation in the surgical oncology
setting.
3.5.1.3 Shark Cartilage and AE-941 (Neovastat®)
No subsequent reviews or controlled trials evaluating the efficacy and/or safety of
shark cartilage products that are of relevance to the cancer field were located.
3.5.1.4 Laetrile and Amygdalin (Vitamin B17)
One subsequent review evaluating the efficacy and safety of laetrile or amygdalin in
cancer treatment has been published. Consistent with study 2, the authors of a Cochrane
124
meta-analytic review were unable to locate any RCTs or quasi-RCTs meeting the inclusion
criteria, and concluded that there was no reliable evidence for the alleged curative effects of
laetrile or amygdalin in cancer patients (Milazzo, Ernst, Lejeune, Boehm, & Horneber,
2011). Moreover, laetrile/amygdalin were associated with a high risk of developing serious
adverse effects due to cyanide poisoning (especially after oral ingestion), which may be
further compounded by concomitant high vitamin C intake, a genetically predisposed,
diminished capacity to detoxify cyanide or vegetarianism coupled with vitamin B12
deficiency (Chan, 2006).
3.5.2 Chinese Herbal Medicine
3.5.2.1 Astragalus [Astragalus Membranaceus, Astragalus Propinquus, Radix Astragali,
Huang Qi, Astragalus Mong(h)olicus, Milk Vetch]
Four subsequent reviews evaluating the efficacy and/or safety of astragalus or
astragalus-based Chinese herbal medicines in cancer treatment and care have been
published or newly-located. A meta-analysis of 65 RCTs (mostly small Chinese studies)
suggested that astragalus-based herbal medicines used as an adjunct to platinum-based
chemotherapy significantly improved survival (1-, 2-, 3-year), complete/partial tumour
response and performance status in advanced non-small lung cancer patients (Duguoa, Wu,
Seely, Eyawo, & Mills, 2010). A more recent meta-analysis of 26 Chinese RCTs revealed
identical outcomes for astragalus-based herbal medicines used as an adjunct to radiotherapy
in non-small-lung cancer patients, but also found significantly reduced radiotherapy
toxicity (radiation pneumonia, white blood cell toxicity; He, Zhou, Wang, & Zhao, 2013).
Positive outcomes were also observed for survival, complete/partial response and risk of
progressive disease in a meta-analysis of RCTs involving liver cancer patients receiving
adjuvant transcatheter arterial chemoemolization / astragalus-based herbal medicines (Wu,
Dugoua, Eyawo, & Mills, 2009), and for complete response, chemo toxicity
(nausea/vomiting, grade 3/4 leukopenia) and QoL in a meta-analysis of RCTs involving
gastric cancer patients treated with adjuvant chemotherapy (5-fluorouracil +
leucovorin/oxaliplatin) / astragalus polysaccharides (Wang, Tian, Ge, Gan, & Yang, 2014).
The major drawback acknowledged by the authors of each of these reviews, however, is
that most RCTs were not only small, but performed in China and therefore highly prone to
suspect randomisation procedures (amongst other methodological limitations) and
publication bias. Consequently, as per study 2, larger and more rigorous RCTs are needed
125
to confirm the efficacy and safety of astragalus-based herbal medicines, and preferably
involving comparisons to adjunctive astragalus monopreparations in addition to standard
anticancer therapy.
3.5.2.2 Ginseng (Panax Ginseng, Radix Ginseng, Asian Ginseng, Red Ginseng, Ren
Shen, Panax Quinquefolium, American Ginseng, White Ginseng, Eleutherococcus
Senticosus, Siberian Ginseng, Angelica Sinensis, Female Ginseng, Dong Quai)
Ginseng products are available in many forms including fresh slices (raw form),
extracts (tincture or boiled), powder, tea, juices, and tablets/capsules. In Asian countries,
ginseng is widely used as an adjunct to conventional anticancer treatments (Qi et al., 2010).
The traditional Chinese herbal preparation widely used for such clinical purposes is
Shengmai, which is a mixture extracted from ginseng, ophiopogon and schisandra (Zhou et
al., 2014). Mass production is based on a standardised formula and it is available in
different forms including capsules (Shenyi), powder, oral liquids and injection (Shenmai).
Recent in vitro and in vivo studies of ginseng polysaccharides, ginsenosides and active
metabolites (e.g. compound K) have demonstrated anticancer, anti-proliferative, anti-
angiogenic, apoptotic and radioprotective properties (Nag et al., 2012; Zong, Cao, & Wang,
2012; He et al., 2011; Ming et al., 2011; Jeong et al., 2010; Lee, Johnke, Allison, O'Brien,
& Dobbs, 2005).
Five subsequent reviews (and two RCTs) evaluating the efficacy and/or safety of
ginseng and ginseng-based Chinese herbal medicines in cancer prevention and care have
been published or newly-located. Regarding chemoprevention, a systematic review of 65
randomised trials involving healthy and medical populations (including 2 cancer studies)
revealed insufficient evidence for ginseng preventing gastric cancer incidence or recurrence
(Shergis, Zhang, Zhou, & Xue, 2013). Despite positive outcomes, the authors observed
several methodological (e.g. suspect randomisation/blinding procedures, small samples)
and heterogeneity issues (e.g. the type, method of preparation, dose and standardised active
ingredients of ginseng used). Large RCTs addressing these limitations are advised.
In relation to cancer treatment, a comprehensive narrative review based on 6
Chinese controlled trials found insufficient evidence for enhanced clinical outcomes
(complete response, survival, disease progression, immune response, haematological
toxicity, QoL) when Shengmai or ginsenoside Rg3 (Shenyi capsules) was used as an
adjunct to chemotherapy in cancer patients (Chen et al., 2014). Similar conclusions were
126
also drawn in a systematic review based on 4 Korean RCTs that evaluated the effects of red
ginseng versus standard care/treatment on immune response and nutritional status in gastric
and colon cancer patients (J. Choi, Kim, T. Y. Choi, & Lee, 2013). Further large high-
quality RCTs are required.
Turning to symptom management, two recent RCTs investigating the effect of
ginseng on cancer-related fatigue have produced encouraging results. In a good quality,
dosing-finding, double-blind pilot RCT of 290 patients with cancer-related fatigue, no
significant differences were found between three collective American ginseng arms (750-,
1000- and 2000-mg/day) and placebo (matching capsules) with respect to activity
interference and self-reported fatigue (or toxicity) at 4- and 8-weeks post-baseline (Barton
et al., 2010). However, subset analyses revealed a trend for higher doses (1000- and 2000-
mg/day) exerting greater effects on fatigue, QoL and satisfaction with fatigue management.
In a follow-up double-blind RCT of 364 patients and survivors with cancer-related fatigue,
no significant differences were observed on any measure (including toxicity) between the
ginseng (2 x 1000mg doses per day) and placebo arms at 4 weeks post-baseline; however,
significant improvements were observed in self-reported fatigue and physical functioning
with ginseng after 8 weeks of treatment (Barton et al., 2013). Furthermore, subgroup
analysis revealed that patients receiving active cancer treatment reported significant
improvements in fatigue at both 4 and 8 weeks compared to placebo, but cancer survivors
did not. Nevertheless, further large RCTs are recommended involving not only both
homogeneous and heterogeneous cancer populations, but also objective as well as
subjective measures of fatigue, physical functioning and activity levels in comparing
ginseng to active control treatments (e.g. physical exercise). Special attention should also
be paid to the methodological challenges of ginseng studies in cancer (e.g. difficulties in
double-blinding due to the potent odour of ginseng capsules or aftertaste following
ingestion; conditions that are possible contraindications of ginseng use or are fatigue-
inducing but unrelated to cancer; Elam, Carpenter, Shu, Boyapati, & Friedmann-Gilchrist,
2006).
Finally, consistent with study 2, ginseng has not been associated with any serious
adverse events in recent systematic reviews of studies involving healthy, cancer and other
medical populations (Choi et al., 2013; Shergis et al., 2013; Qi et al., 2011). The most
commonly reported adverse effects included gastrointestinal upset, constipation and
insomnia. Divergently, however, studies observed no herb-drug interactions between Asian
127
ginseng and warfarin (S. H. Lee, Y. M. Ahn, S. Y. Ahn, Doo, & B. C. Lee, 2008; Y. H. Lee
et al., 2010), and variable inhibition on platelet aggregation of ginsenosides isolated from
processed ginseng (J. G. Lee et al., 2009, 2010). Nevertheless, given the potential
irreversibility of such effects, patients should discontinue ginseng use at least one week
prior to surgery (Ang-Lee, Moss, & Yuan, 2001). Furthermore, recent case reports suggest
that Asian ginseng may interact with imatinib (used to treat chronic myeloid leukaemia,
gastrointestinal stromal tumors and other malignancies) and raltegravir (antiretroviral) to
produce hepatotoxicity via inhibition of the cytochrome P450 C3A4 enzyme (Bilgi, Bell,
Ananthakrishnan, & Atallah, 2010; Mateo-Carrasco, Gálvez-Contreras, Fernández-Ginés,
& Nguyen, 2012). Consequently, Asian ginseng should be avoided or used with caution
with these and other drugs metabolised by the cytochrome P450 C3A4 enzyme, and in
patients with (a history of) liver dysfunction.
3.5.2.3 Ginger (Zingiber Officinale)
Three subsequent reviews evaluating the efficacy and safety of ginger in the
prevention/management of chemotherapy-induced nausea and vomiting (CINV) have been
published. A meta-analytic/systematic review of 5 double-blind RCTs comparing ginger to
placebo or conventional antiemetics (predominantly metoclopramide or ondansetron)
revealed insufficient support for the use of ginger in CINV control (Lee & Oh, 2013).
Subgroup meta-analysis of 4 RCTs indicated that the incidence of acute nausea and acute
vomiting, and the severity of acute nausea did not differ significantly between the ginger
and control groups. Mixed supportive evidence was also observed in a systematic and
narrative review of 7 RCTs (including 3 crossover trials; Marx et al., 2013; Haniadka,
Rajeev, Palatty, Arora, & Baliga, 2012). In each case, the conflicting study outcomes were
attributed to various methodological limitations (double-blinding difficulties due to the
potent odour of ginger capsules and aftertaste following ingestion; variations in the active
compounds, dosages and treatment initiation periods of the ginger used; inadequate control
over potentially confounding variables including pre-existing anticipatory nausea/vomiting,
gender, chemotherapy emetogenicity and antiemetic/ginger use and compliance, as well as
order effects in crossover trials; use of different study endpoints for ginger effects;
subjective nature of nausea combined with the diverse standardised measures used; small
samples). Consequently, more large rigorous studies of CINV control were recommended
comparing ginger to current standard antiemetics (e.g. aprepitant) and placebo.
128
Finally, consistent with study 2, few adverse effects of ginger were observed in the
CINV studies. Reported side-effects included mild gastrointestinal symptoms (heartburn,
stomach upset, diarrhoea), bruising or flushing, rash, dizziness, drowsiness/sleepiness, dry
mouth, thirst and restlessness, but generally incidence was not significantly greater
compared to the control groups in these studies (Ryan et al., 2012; Manusirivithaya et al.,
2004; Pace, 1986). Interestingly, however, and consistent with trends in previous cancer-
unrelated ginger research (e.g. Arfeen et al., 1995), two studies reported a significant
decline in CINV control at higher doses of ginger (1.5-2g per day) compared to lower doses
of ginger (0.5-1g per day) or the placebo (Ryan et al., 2012; Zick et al., 2009) when
combined with conventional antiemetics. Ryan and colleagues (2012) suggested that ginger
may compete with antiemetics for the same receptors when used in tandem, thus reducing
the uptake of such medications and lowering antiemetic coverage.
3.5.2.4 Lingzhi / Reishi Mushroom (Ganoderma Lucidum, Ganoderma Tsugae)
One subsequent review (and a case series study) evaluating the efficacy and/or
safety of Lingzhi in cancer treatment have been published. A Cochrane meta-analytic
review of 5 Chinese RCTs found insufficient evidence for the use of commercially
prepared Lingzhi as a standalone cancer treatment, and inconclusive evidence for enhanced
tumour response when combined with chemotherapy or radiotherapy in lung cancer
patients (Jin, Ruiz Beguerie, Sze, & Chan, 2012). Additionally, there was inconclusive
evidence for enhanced immune reponse (leukocyte count, natural killer cell activity) with
the exception of increased T-cell counts (CD3, CD4 and CD8, but not CD4/CD8 ratio), and
very limited evidence that it enhanced performance status at post-treatment compared to
placebo or conventional treatment. Overall, given the poor methodological quality of the
studies (i.e. mostly small studies, all performed in China and prone to suspect
randomisation/blinding procedures), the authors suitably recommended that large, high-
quality double-blind RCTs be performed to evaluate the long-term survival benefit (among
others, as well as safety) of Lingzhi when combined with conventional anticancer treatment
and preferably in non-Asian populations.
Turning to safety, consistent with study 2, few adverse effects (nausea and insomnia
in one study only) of commercially prepared Lingzhi were experienced by cancer patients
in the above review, with no study reporting haematological or liver toxicity (Jin et al.,
2012). Curiously, however, a recent case series of 5 Chinese gastric cancer patients
129
observed that Ganoderma lucidum spore (Lingzhi spore) herbal supplementation (generally
1.8g/day over 1-2 months) was associated with elevated CA 72-4 serum tumour marker
levels (sans clinical symptoms or objective evidence of disease progression) when
combined with chemotherapy or different Chinese herbal medicines (Yan et al., 2014).
Given CA 72-4 levels may be used as an indicator of disease progression in gastric cancer
(e.g. Ucar et al., 2008) and trigger clinicians to modify cancer treatment, Ganoderma
lucidum spore supplementation should be used with caution or perhaps best avoided in such
patients.
3.5.2.5 Green Tea (Camellia Sinensis, Thea Sinensis, Polyphenon E)
Twenty subsequent reviews evaluating the efficacy and/or safety of green tea in
cancer prevention have been published or newly-located. A Cochrane meta-analytic review
of 51 studies (21 case-control, 23 cohort, 1 RCT), predominantly involving Asian
populations (n = 47), found insufficient and conflicting evidence to make any firm
recommendations regarding green tea consumption for cancer prevention (Boehm et al.,
2009). Recent meta-analytic reviews of case-control and cohort studies produced mixed
results regarding the protective effects of green tea for oesophageal cancer in Asian
populations, but consistently suggested that green tea consumption may reduce oesophageal
cancer risk in Asian women (Zheng et al., 2013; Sang, Chang, Li, & Jiang, 2013; P. Zheng,
H. M. Zheng, Deng, & Zhang, 2012). Similar mixed outcomes were observed in meta-
analyses of green tea consumption for bladder cancer (Wu et al., 2013; Wang et al., 2013)
and prostate cancer risk in Asian populations (Lin et al., 2014; Zheng et al., 2011), as were
gender effects on gastric cancer risk in Japan in a meta-analytic/systematic review of 6
cohort studies (Sasazuki et al., 2012). However, the observed gender effects may be due to
higher smoking rates in Asian men modifying the effect of green tea (e.g. Kuriyama et al.,
2006), and/or phytoestrogens in green tea having a greater protective effect in women than
men (e.g. Cheng, 2007). Nevertheless, a potential oestrogen-related protective mechanism
against oesophageal and gastric cancer (or any other cancer) warrants further investigation
in Asian and other populations.
Various meta-analytic/systematic reviews of case-control and cohort studies suggest
that green tea consumption in Asian populations may protect against the development of
gastric (Kang, Rha, Oh, & Nam, 2010), oral (Wang, Yang, Zhang, & Wu, 2014) and liver
cancer (Fon Sing, Yang, S. Gao, J. Gao, & Xiang, 2011). Similarly, three meta-
130
analytic/systematic reviews suggest protective effects of green tea for ovarian and other
gynaecological malignancies across both Asian and Caucasian populations (Gao et al.,
2013; Trudel et al., 2012; Butler & Wu, 2011). In contrast, meta-analytic reviews of cohort
and/or case-control studies have found insufficient evidence to conclude that green tea
consumption may protect against breast (Wu, Zhang, & Kang, 2013) and colorectal cancer
in Asian populations (Wang et al., 2012; Wang, Gao, & Fang, 2012). Clearly, further large,
long-term epidemiological studies (especially cohort studies involving non-Asian
populations) are needed to provide more definitive and generalisable conclusions about the
chemopreventive effects of regular green tea intake (beverage or extract). Furthermore,
they must exert control over several confounding variables or limitations that have likely
compromised the outcomes of individual studies (e.g. adjustment for demographic and
lifestyle factors, such as sex, smoking, alcohol intake and body mass index; dose and
temperature of green tea beverage) and the ensuing meta-analytic/systematic reviews (e.g.
publication bias, study heterogeneity) performed thus far.
Finally, consistent with study 2, few adverse effects have been reported when green
tea has been used in moderate amounts orally (3-9 cups/day, ≤ 1200ml/day, minimum of
250mg/day catechins) or topically as appropriate (green tea extract containing 7% caffeine;
Ahn, 2003; Pisters et al., 2001; Katiyar, 2000; Boehm et al., 2009). Chronic excessive oral
consumption (5-6 litres/day or >250-300mg/day) has been associated with tachyarrhythmia
and sleep disturbance due to the caffeine content (IOM Institute of Medicine, 2001).
Additionally, in phase I trials involving cancer patients green tea extract has generally been
well-tolerated (Laurie, Miller, Grant, Chris, & Ng, 2005; Pisters et al., 2001). Mild side-
effects, partly due to caffeine content, included fatigue, pain and central nervous system
disturbances (nausea, insomnia, headaches, anxiety, restlessness) at lower doses (0.5-
1.0g/m2 per day), and gastrointestinal disturbances (dyspepsia, diarrhoea, polyuria) and
polydipsia (excessive thirst) at higher doses (1.0-3.0g/m2 per day). Grade 3/4 dose-limiting
toxicities attributed to caffeine content at high doses (> 3.0g/m2 per day) included
hypertension and gastrointestinal/central nervous system disturbances (diarrhoea, nausea,
insomnia, agitation), but improved with dose reduction of green tea extract (Laurie et al.,
2005; Pisters et al., 2001; Fritz et al., 2013).
131
3.5.2.6 Ginkgo (Ginkgo Biloba, EGb 761)
Three subsequent reviews (and two RCTs plus a crossover study) evaluating the
efficacy and/or safety of ginkgo in cancer prevention and care have been published. In the
largest double-blind RCT of ginkgo supplementation (EGb 761, 120mg twice daily)
conducted, involving dementia risk in 3069 elderly Americans (≥75 years, median follow-
up = 6.1 years), a secondary analysis revealed no support that regular use prevents cancer
(Biggs, Sorkin, Nahin, Kuller, & Fitzpatrick, 2010). Clearly, further large prospective
studies that are more representative of the general population and having longer follow-up
periods are required, given several limitations of the study (e.g. cancer cases not requiring
hospitalisation could not be identified, ginkgo dose may not have been optimal for cancer
prevention). In another double-blind RCT of ginkgo supplementation (EGb 761, 60mg
twice daily) involving 160 chemotherapy-naïve breast cancer patients, regular use during
adjuvant chemotherapy (and one month beyond) provided no subjective or objective
evidence for the prevention of chemotherapy-related cognitive dysfunction compared to
placebo at any time point up to 2 years post-treatment (Barton et al., 2013). Further large
RCTs are required to provide further confirmation of these outcomes.
Turning to safety, a prospective crossover trial involving 60 early-stage breast
cancer survivors receiving hormonal therapy (tamoxifen, anastrozole, letrozole; n = 20
each) reported that the majority of women experienced either no side-effects or mild
symptoms (most commonly, headache, flatulence, hot flushes, nausea and diarrhoea, some
of which would have been due to the hormonal treatment per se; Vardy et al., 2013).
Furthermore, recent systematic reviews (Shi & Klotz, 2012; Hermann & von Richter, 2012;
Li, Zeng, Yu, & Zhou, 2013) have indicated that recommended doses of ginkgo (up to
240mg/day) do not have significant or clinically-relevant effects on cytochrome P450
enzyme activity (CYP3A4, CYP1A2, CYP2C9, CYP2D6, CYP2B6, CYP2E1), with one
exception (CYP2C19). Modest induction of cytochrome P450 C219 enzyme activity has
been observed with higher doses of ginkgo (≥240mg/day) and may be CYP2C19 genotype-
dependent (i.e. induction is greater in poor metabolisers than extensive metabolisers; Lei et
al., 2009; Yin, Tomlinson, Waye, Chow, & Chow, 2004). While further studies are
required, ginkgo intake in the interim is either best avoided or should be monitored in
patients taking omeprazole (proton pump inhibitor for gastrointestinal disorders),
voriconazole (triazole antifungal for invasive fungal infections, such as candidiasis) or
other medications metabolised by the cytochrome P450 C219 enzyme.
132
3.5.3 Western Herbal Medicine
3.5.3.1 St. John’s Wort (Hypericum Perforatum, LI 160, Kira®, WS 5570/5572/5573,
Perika®, Hyperiplant®, Ze 117, Remotiv®)
Despite the large volume of clinical studies since the 1980s that have examined the
efficacy of St. John’s wort (SJW), very few clinical studies have investigated its potential
use in cancer treatment and care (Ernst, 2013). In fact, as far as can be ascertained, no RCT
examining the efficacy (and safety) of SJW among cancer patients exists in the scientific
literature, even in regard to depression which is its most popular therapeutic use.
Consequently, 13 subsequent published or newly-located reviews (and 13 other studies)
that have evaluated the safety and efficacy of SJW and are of relevance to cancer care will
be discussed.
A narrative review of 16 post-marketing surveillance studies of SJW extract
(standardised by hypericin and/or hyperforin content) as an antidepressant suggest that use
in recommended doses is associated with a low rate of adverse events (≤ 6%; Schulz,
2006). Adverse effects are generally mild-moderate or transient, with gastrointestinal
symptoms (e.g. constipation, nausea), allergic reactions (e.g. skin reddening/itching),
dizziness/confusion, restlessness, fatigue, tiredness, anxiety and dryness of mouth being
most common and largely attributed to hypericin/pseudohypericin content (Russo et al.,
2014; Schulz, 2006; International Journal of Toxicology, 2001; Greeson, Sanford, & Monti,
2001; Barnes, Anderson, & Phillipson, 2001). However, the safety of self-administered
SJW products without medical supervision is of concern and has been under-researched. A
small number of studies to that end have reported adverse effects including psychological
symptoms, allergic reactions and visual disturbances, which study participants attributed to
self-administered use of SJW products (International Journal of Toxicology, 2001; Ernst,
2013). Furthermore, SJW extracts or oil containing high hypericin content (0.5mg/kg of
body weight) may result in photodermatitis, based on reports of excessive cutaneous
phototoxicity observed in HIV patients with regular use (Gulick et al., 1999). Indeed,
clinical studies have shown that single oral doses of SJW (300-1800mg, 0.3% hypericin)
resulted in hypericin registering in blood plasma, with repeated doses leading to a steady-
state plasma concentration being achieved after only 14 days despite hypericin having an
elimination half-life of 24-27 hours (Staffeldt, 1994; International Journal of Toxicology,
2001; Ernst, 2013). Possible contraindications of SJW products therefore include
photosensitivity, known skin allergies, atopy or allergic hypersensitivity, pregnancy and
133
lactation.
Human studies have further suggested that SJW can have serious herb-drug
interactions with medicines (including anticancer agents), particularly those with narrow
therapeutic indices, by affecting drug metabolism (via induction of cytochrome P450
enzymes, particularly cytochrome P450 3A4 / 2C19, and P-glycoprotein) or levels of
neurotransmitters (primarily serotonin; Goey, Mooiman, Beijnen, Schellens, & Meijerman,
2013; Li et al., 2013; Posadski, Watson, & Ernst, 2012; Shi & Klotz, 2012). In addition to
imatinib and irinotecan, a recent probe study amongst cancer patients revealed that SJW
extract (300mg Hyperiplant®, three times daily over 14 days) significantly increased the
clearance of docetaxel (CYP 3A4 substrate) and thus is best avoided by metastatic breast
and other cancer patients to prevent potential undertreatment (Goey et al., 2014). In
contrast, probe studies have found no clinically-relevant effects of low-hyperforin-content
SJW preparations [e.g. Ze 117, 0.2% hypericin (1mg in the daily dose) and ≤0.2%
hyperforin (≤1mg in the daily dose), 250mg twice daily] when combined with various
drugs metabolised by cytochrome P450 or P-glycoprotein enzymes (midazolam,
alprazolam, caffeine, tolbutamide, digoxin, cyclosporine, oral contraceptives; Mueller et al.,
2006, 2009; Arold et al., 2005; Mai et al., 2004; Will-Shahab, Bauer, Kunter, Roots, &
Brattström, 2009). This evidence suggests that the potential for many herb-drug interactions
is associated with the hyperforin content of SJW and may be mitigated by using low-
hyperforin-content SJW extracts. The main problem therein, however, lies with the fact that
clinical trials suggest that the therapeutic effect exerted by SJW extracts on mild-moderate
depression is dependent on the hyperforin content (e.g. Laakmann, Schule, Baghai, &
Keiser, 1998). Recent narrative reviews evaluating the antidepressive effects of SJW
extracts of varying hyperforin content provide little evidence to the contrary (Kasper,
Caraci, Forti, Drago, & Aguglia, 2010; Russo et al., 2014), with only a few RCTs
purportedly examining low-hyperforin-content SJW extract (Ze 117, 0.2% hypericin,
unknown hyperforin content, 250mg twice daily) for mild-moderate depression in the short-
term (albeit with equivalent efficacy and compared to placebo/standard antidepressants, but
involving gender disproportionate samples, ≥ 2:1 females to males; Woelk, 2000; Schrader,
2000; Schrader, Meier, & Brattström, 1998). Clearly, further large high-quality RCTs with
longer follow-up periods extending beyond post-treatment are required to examine the
efficacy and safety of low-hyperforin-content SJW extracts for the treatment of both mild-
moderate and major depression (as well as other clinical problems, such as anxiety).
134
Ideally, these would be performed under close medical supervision amongst patients
screened for depressive symptoms (or other targeted symptoms) from
homogeneous/heterogeneous cancer populations and involve comparison to both placebo
and active control treatments (e.g. prescription antidepressants and/or psychological
therapy).
Finally, SJW may have interactions when used concomitantly with other herbal
supplements or foods. Specifically, reports suggest that it may potentiate the sedative
effects (and any adverse effects) when combined with herbs or foods possessing such
properties (e.g. valerian, lemon balm, kava, hops, catnip, Siberian ginseng, goldenseal,
California poppy, German chamomile, wild carrot/lettuce, celery, sage; Jellin, Gregory,
Batz, & Hitchen, 2004). Moreover, given the wide variety of SJW preparations that are
marketed, only some are of high quality (Ernst, 2013) and many online manufacturers,
pharmacies and health food stores fail to provide sufficient information concerning known
drug interactions, contraindications and adverse effects of SJW treatment (Thakor, Leach,
Gillham, & Esterman, 2011).
3.5.3.2 Garlic (Allium Sativum)
Eight subsequent reviews (and one large cohort study) evaluating the efficacy
and/or safety of garlic in cancer prevention and care have been published. A recent meta-
analysis based on 7 observational studies (3 cohort, 4 case-control;
retrospective/prospective) suggested that high garlic intake may reduce colorectal cancer
risk, although no association was found in cohort studies or for garlic supplementation per
se (Turati, Guercio, Pelucchi, La Vecchia, & Galeone, 2014). In contrast, the large
American Cancer Society CPS-II Nutrition Cohort study involving older American adults
(42,824 men, 56,876 women, 1,130 colorectal cancer diagnoses over 7 year follow-up)
found no significant association between current daily garlic consumption or
supplementation and colorectal cancer risk, but a possible increased risk in men who
formerly used garlic supplements (compared to those who have never used; McCullough,
Jacobs, Shah, Campbell, & Gapstur, 2012). Similarly, a more recent meta-analysis based on
5 prospective observational studies revealed that garlic supplementation possibly increased
the risk of colorectal cancer (Zhu, Zou, Qi, Zhong, & Miao, 2014). Clearly, further large
prospective cohort studies are required, preferably involving populations with higher garlic
intake and early lifetime exposure and focusing on the quantities and modality of intake
135
(i.e. preparation/cooking methods and supplemental garlic formulation) effective for cancer
prevention.
Consistent with study 2, a meta-analysis based on 12 observational studies (1
cohort, 11 case-control; Zhou et al., 2011) and a narrative review based on 14 case-control
studies (Guercio, Galeone, Turati, & La Vecchia, 2014) suggested that high garlic
consumption may reduce gastric cancer risk, but recommended further studies given
potential confounding factors (including garlic exposure misclassification of self-report
measures) and ambiguity in the dose-risk relationship. Finally, a meta-analysis based on 7
observational studies (2 prospective cohort, 5 case-control) suggested that garlic
consumption conferred protective effects for prostate cancer, but recommended further
well-designed prospective cohort or intervention studies given the relatively small number
of studies and study heterogeneity observed (Zhou, Ding & Liu, 2013).
Finally, subsequent reviews of herb-drug interactions have confirmed that garlic
appears to be generally safe, with two minor exceptions (Izzo, 2012; Shi & Klotz, 2012;
Hermann & von Richter, 2012). Human clinical trials have demonstrated that the efficacy
of chlorzoxazone (muscle relaxant) may be reduced by garlic oil or garlic oil extract due to
its atypical reliance on the cytochrome P450 C2E1 enzyme as a sole/predominant clearance
pathway (Gurley, Gardner, & Hubbard, 2005; Gurley et al., 2002; Loizou & Cocker, 2001).
Additionally, while garlic powder (600mg twice daily) modestly decreased the systemic
clearance of docetaxel in metastatic breast cancer patients, significantly reduced clearance
could not be ruled out in chemotherapy patients carrying a cytochrome P450 3A5*1A allele
(Cox et al., 2006).
3.5.3.3 Kava (Piper Methysticum, Kava-Kava, Kavain, WS1490)
Three subsequent reviews evaluating the efficacy and/or safety of kava that are of
relevance to cancer care have been published or newly-located. In contrast to study 2, a
more recent meta-analysis of 6 placebo-controlled RCTs performed in Germany suggested
that WS1490 acetone extracts (standardised kava extract; 150-300mg/day over 4-24 weeks)
had positive effects on self-reported anxiety in individuals diagnosed with non-psychotic
anxiety disorders, but statistical significance was not achieved for all outcomes (even when
one gender-biased study was excluded in sub-analysis; Witte, Loew, & Gaus, 2005). Larger
RCTs examining the anxiolytic effects of WS1490 (and other forms of kava) outside
Germany are required, preferably involving homogeneous/heterogeneous cancer
136
populations and active control treatments (e.g. benzodiazepines) with consideration given
to preparation methods (e.g. aqueous vs acetone/ethanol extracts), dose-response, treatment
duration (short- vs long-term) and safety.
Turning to safety, recent systematic/narrative reviews (Sarris, LaPorte, &
Schweitzer, 2011; Rychetnik & Madronio, 2011) have reinforced safety concerns about the
hepatotoxicity of kava, but suggest that the genetic polymorphism of the cytochrome P450
enzymes (e.g. CYP2D6 activity is deficient in approximately 79% of Caucasian
populations, but is negligible in Pacific/Asian/Aboriginal populations who have not
exhibited kava hepatotoxicity) and/or use of acetone/ethanol kava extracts (cf. aqueous
kava extracts) have been primarily responsible for serious occurrences (Poolsup, Li Wan
Po, & Knight, 2000; Wanwimolruk, Bhawan, Coville, & Chalcroft, 1998; Singh, 2005;
Russmann et al., 2003; Clough, Bailie, & Currie, 2003; Coulter, 2007). Similarly, chronic
use of aqueous kava extracts (average quantity of 118g/week over 1-18 years) have been
associated with dry scaly skin (dermopathy), elevated liver enzyme levels (gamma-
glutamyl transferase, alkaline phosphotase) and lower lymphocyte counts in Australian
Aboriginal populations (Clough et al., 2003). Furthermore, in a comprehensive systematic
review of predominantly controlled observational studies among Australian Aboriginal
populations, chronic and/or heavy ingestion of water-infused kava beverages for
recreational purposes (50 times more potent than the recommended therapeutic dosage of
140-250mg/day of kavalactones; LaPorte, Sarris, Stough, & Scholey, 2011) was found to
cause scaly skin rashes (dermopathy), weight loss, elevated gamma-glutamyl transferase
liver enzyme levels, nausea, appetite loss or indigestion (Rychetnik & Madronio, 2011).
Other associated adverse effects included conjunctivitis, impotence or loss of libido,
elevated cholesterol, low motivation and slowed/lazy activity, poor psychosocial outcomes
(financial, work/family) and self-reported poor overall health. Finally, a meta-
analytic/systematic review of 10 RCTs suggested that traditional- or commercially-
prepared kava does not produce cognitive impairment when acutely administered (single
doses), but that there was very limited evidence that chronic use (large doses) may reduce
visual attention accuracy on tasks during heavy cognitive demand (e.g. driving, operating
heavy machinery) and hence caution was advised (LaPorte et al., 2011). Clearly, large
high-quality RCTs examining the safety of kava are required as specified above.
137
3.5.3.4 Valerian (Valeriana Officinalis)
Two subsequent reviews (and one RCT) evaluating the efficacy and/or safety of
valerian in cancer care have been published. In the only controlled trial of valerian in the
cancer literature to the author’s knowledge, a double-blind placebo-controlled RCT
involving 202 cancer patients receiving treatment revealed no significant improvement in
self-reported sleep quality after 8 weeks of oral valerian (450mg capsules an hour before
bedtime each night; Barton et al., 2011). However, significant improvements were observed
in secondary sleep outcomes including sleep latency, amount of sleep per night, sleep
difficulties and drowsiness, as well as self-reported fatigue outcomes. Further RCTs are
recommended to examine the role valerian may play in the management of both sleep
disturbance and fatigue in cancer patients, and should include both objective and subjective
measures of primary and secondary endpoints. Finally, in terms of toxicity, no significant
differences in side-effects (nausea, headaches, trouble waking) between treatment arms
were reported by cancer patients in the RCT above (Barton et al., 2011). Additionally,
recent systematic and narrative reviews (Kelber, Nieber, & Kraft, 2014; Izzo, 2012) of
valerian found no plausible evidence for herb-drug interactions in case studies or probe
studies involving healthy individuals, nor any clinically-relevant effects on cytochtome
P450 3A4, 2D6, 2E1 and 1A2 pathways that could diminish the efficacy of associated
medications (Gurley et al., 2005).
3.5.3.5 Evening Primrose Oil (Oenothera Biennis)
No subsequent reviews or controlled trials evaluating the efficacy and/or safety of
evening primrose oil that are of relevance to the cancer field were located.
3.5.3.6 Black Cohosh (Actaea Racemosa, Cimicifuga Racemosa, Isopropanolic Black
Cohosh Extract, iCR, Remifemin®, Ethanolic Black Cohosh Extract, CR BNO 1055,
Ze 450, Cr 99)
Seven subsequent reviews (and one prospective observational study) evaluating the
efficacy and/or safety of black cohosh in breast cancer care and risk have been published or
newly-located. Consistent with study 2, recent meta-analytic/systematic reviews (including
a Cochrane review) of RCTs, cohort and/or prospective observational studies have found
insufficient evidence to support the use of black cohosh for hot flushes and other
menopausal symptoms (e.g. night sweats, vaginal dryness) in peri-/post-menopausal
138
women and breast cancer patients or survivors (Leach & Moore, 2012; Burbos & Morris,
2011; Fritz et al., 2014). Given significant limitations and heterogeneity in existing studies,
however, more rigorous RCTs of longer duration (> 6 months) are required, preferably
involving homogeneous/heterogeneous cancer populations (breast, prostate and other
gynaecological malignancies) and should include standardised doses/schedules, active
control treatments (e.g. fluoxetine), objective and subjective measures, and important
secondary outcomes (e.g. QoL, sexuality, sleep problems, musculoskeletal health, anxiety,
safety).
Black cohosh still appears to be generally safe, with no herb-drug interactions
reported and few (if any) serious adverse events concerning hepatotoxicity assigned
probable or certain causality (Beer & Neff, 2013; Teschke, Schwarzenboeck, Schmidt-
Taenzer, Wolff, & Hennermann, 2011; Mahady et al., 2008). Minor adverse effects include
nausea, vomiting, headaches, dizziness, mastalgia and weight gain (Rostock et al., 2011;
Wu, 2011; Huang, 2011; Zava, Dollbaum, & Blen, 1998). Regarding hepatotoxicity, a
meta-analysis of 5 double-blind, placebo-controlled RCTs involving healthy peri-/post-
menopausal women (40-60 years) revealed no evidence that isopropanolic black cohosh
extract (Remifenin®, 40-128mg daily for 3-6 months) adversely affects liver function tests
(alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltranspeptidase;
Naser et al., 2011). Similar outcomes were also reported in a more recent systematic review
of isopropanolic or ethanolic black cohosh extract use among peri-/post-menopausal
women with or without breast cancer, even at doses or treatment durations exceeding
European guidelines for use (based on 14 clinical studies including 9 RCTs; Beer & Neff,
2013).
In relation to other potential adverse effects, a systematic review suggested that
black cohosh does not exert significant oestrogenic effects on breast, endometrial or vaginal
tissues, or influence circulating hormone levels in breast cancer survivors and non-breast
cancer populations (based on 12 RCTs and 5 uncontrolled trials; Fritz et al., 2014). Similar
outcomes were also reported in another systematic review of isopropanolic or ethanolic
black cohosh extract use among peri-/post-menopausal women with or without breast
cancer (based on 19 clinical studies including 10 RCTs; Beer & Neff, 2013). Additionally,
preliminary evidence suggested black cohosh is not associated with increased breast cancer
risk or recurrence (based on 4 observational studies); however, as large prospective studies
of longer duration (> 6 months) are required for confirmation, thus women with oestrogen-
139
dependent tumours should avoid or use black cohosh with caution in the interim. Finally,
no serious adverse events or herb-drug interactions were observed in a systematic review
evaluating breast cancer survivors’ use of black cohosh while receiving hormonal therapy
(tamoxifen and/or raloxifene; based on 5 clinical trials and one cohort study; Fritz et al.,
2014; Rostock et al., 2011).
3.5.3.7 Echinacea (Echinacea Purpurea, Echinacin®, Echinacea Angustifolia,
Echinacea Pallida, Radix Echinaceae, Esberitox N®, Samital®)
Two subsequent reviews (and 5 clinical trials plus 1 case report) evaluating the
efficacy and/or safety of echinacea or echinacea-based botanical preparations in cancer
treatment and care have been published or newly-located. Preliminary data from a few
small case series/studies has revealed insufficient evidence that echinacea extract
(Echinacin®) confers increased survival or other benefits when used as an adjunct to
palliative chemotherapy in advanced cancer patients (Pilkington, 2012; Basch et al., 2005).
Similarly, preliminary evidence from a number of small randomised trials and case
series/observational studies is inconclusive for the use of echinacea-based herbal extracts
[Esberitox N®, ethanolic-aqueous extract comprising Radix echinaceae, thuja (Thujae
occidentalis) and wild indigo root (Radix baptisiae tinctoriae)] in the management of
radiation-induced leukopenia (Pilkington, 2012; Basch et al., 2005). Clearly, large RCTs
are required. Finally, preliminary evidence from two small clinical trials (single-blind,
placebo-controlled RCT involving head and neck cancer patients; observational study
involving haematology patients) suggest that a standardised echinacea-containing botanical
extract [Samital®, Vaccinium myrtillus (bilberry), Macleaya cordata fruits and Echinacea
angustifolia roots] may ameliorate oral and/or gastrointestinal mucositis (and related
outcomes, such as pain, eating difficulties and QoL) induced by chemotherapy ±
radiotherapy (Pawar et al., 2013; Bertoglio et al., 2013). Studies, however, are still very
much in their infancy. Clearly, large double-blind RCTs comparing Samital® to active
control treatments (e.g. antiemetics, analgesics, proton pump inhibitors) in different cancer
populations are needed.
Short-term use of echinacea is still generally safe. Echinacea and echinacea-based
or –containing extracts have been well-tolerated in preliminary cancer clinical trials (Pawar
et al., 2013; Bertoglio et al., 2013). Furthermore, no serious adverse events or clinically-
relevant herb-drug interactions have been reported in probe studies involving chemotherapy
140
patients receiving docetaxel (Goey et al., 2013) or HIV patients receiving antiretroviral
therapy (Moltó et al., 2011, 2012). However, caution or avoidance may be advised in
chemotherapy patients receiving etoposide ± cisplatin, given a recent case report of a non-
small cell lung cancer patient exhibiting profound thrombocytopenia that was attributed to
cytochrome P450 3A4 inhibition of etoposide (Bossaer & Odle, 2012).
3.5.3.8 Milk Thistle (Silybum Marianum, Carduus Marianum)
One subsequent review (and two clinical trials) evaluating the safety of milk thistle
in cancer care have been published or newly-located. Milk thistle still appears to be
generally safe. No adverse events or drug interactions were reported in a small crossover
trial of chemotherapy patients receiving irinotecan who were administered milk thistle
extract (80% silymarin; 200mg daily, three times daily over 12 days; van Erp et al., 2005),
thus indicating safety of concurrent use for many classes of chemotherapy agents (Frenkel
et al., 2013). Additionally, two clinical trials found that large to very large doses of milk
thistle (silybin-phytosome; 2.5-20g/day) were relatively safe in localised prostate cancer
patients preparing for surgery and advanced cancer patients also (Flaig et al., 2007, 2010).
All toxicities were mild (e.g. diarrhoea, hyperbilirubinaemia), with two exceptions (n = 2;
grade 4 postoperative thromboembolic event; grade 3 elevated liver toxicity, alanine
amintransferase). Nevertheless, further studies of milk thistle at higher doses in different
cancer populations are needed.
3.5.3.9 European Mistletoe (Viscum Album L., Viscum Fraxini-2, Iscador®, Eurixor®,
Helixor®, abnobaVISCUM, Isorel, Cephalektin, Lektin, PS76A, Lectin ML-1, INN:
Aviscumine, PS76A2, Lektinol™)
Eight subsequent reviews evaluating the efficacy and/or safety of mistletoe in
cancer treatment and care have been published or newly-located. A large systematic review
of anthroposophic medicine in Europe including 133 clinical trials of mistletoe product use
in cancer therapy (RCTs, prospective/retrospective non-RCTs and uncontrolled trials)
found predominantly favourable clinical outcomes, uncommon side-effects or other
harmful risks (usually mild/moderate), and high patient satisfaction regarding outcomes and
safety (Kienle, Glockmann, Grugel, Hamre, & Kiene, 2011). However, further high-quality
studies were advised given substantial heterogeneity in the methodological quality of the
clinical trials. Additionally, a meta-analysis of 4 retrolective, matched-pairs controlled
141
cohort studies (i.e. treatment consistent with patient preferences had already started prior to
study initiation) found a moderate effect size for survival advantage of mistletoe extract
used as an adjunct to conventional anticancer treatment, but observed several limitations to
retrolective study designs (e.g. possible inaccuracies in cancer diagnosis or screening
history, different starting points, inequalities in documentation and monitoring) in addition
to study heterogeneity (Ostermann & Büssing, 2012). Similarly, a comprehensive narrative
review of mistletoe extract use in breast cancer suggested that adjuvant mistletoe therapy
may enhance survival and QoL and reduce adverse effects of conventional treatments
(based on 20 clinical studies, including 10 randomised and/or controlled trials), but
recommended further high-quality clinical trials given study heterogeneity (Marvibaigi,
Supriyanto, Amini, Abdul Majid, & Jaganatha, 2014). Moreover, another 15 clinical studies
demonstrated that subcutaneous mistletoe extract was able to boost immune response in
breast and other cancer patients. This is consistent with an earlier review that found that
many clinical trials showed positive effects of mistletoe extract (Iscador®) on natural killer
cell activity, although the author in that instance recommended dedicated studies with
optimised treatment schedules and comparable doses be performed to confirm the
immunomodulatory effects of mistletoe (Braedel-Ruoff, 2010).
Several mistletoe extracts and products have been studied in cancer clinical trials,
most commonly Iscador® amongst others [e.g. Eurixor®, Helixor®, Lektin (PS76A),
Lektinol™ (PS76A2), Isorel, abnobaVISCUM and recombinant lectin ML-1 (INN:
Aviscumine)]. A meta-analysis of 22 controlled studies (41 data sets; 12 prospective; 5
RCTs, 10 matched-pairs design; all moderate/poor quality) indicated that Iscador® was
associated with significantly improved cancer survival when compared to no active
treatment (standard cancer care), but observed several limitations to these findings
(significance was observed in matched-pairs design studies, but not RCTs; all studies were
of moderate/poor methodological quality, including loose matched pairings in matched-
control design studies; publication bias; Ostermann, Raak, & Büssing, 2009). A more
recent systematic review suggested that Iscador® may enhance survival and reduce adverse
effects of conventional anticancer therapy as an adjuvant rather than as a standalone
treatment (based on 11 clinical studies, including 3 RCTs and 6 prospective/retrospective
cohort studies; National Cancer Institute, 2014). However, it was observed that some
studies had major methodological weaknesses (e.g. use of mean as opposed to the standard
less-biased median survival, unblinded treatment, historical controls and retrospective
142
designs). Similar positive outcomes and methological weaknesses were also witnessed in
the same review based on 11 clinical studies (8 RCTs, 3 non-RCTs) examining other
mistletoe preparations [Eurixor®, Helixor®, PS76A (Lektin), Isorel, abnobaVISCUM,
Viscum fraxini-2], and were mirrored for QoL-related outcomes in a meta-analysis of 13
prospective clinical trials (9 RCTs, 4 non-RCTs, all unblinded and poor quality) comparing
Iscador® to standard care in cancer patients (Büssing, Raak, & Ostermann, 2012).
Despite the wide range of mistletoe products used in human studies, serious adverse
events are still rare and reported side-effects have generally been minimal. A recent
systematic review based on 69 clinical studies (22 RCTs, 3 non-RCTs, 44 single-arm
studies, medical/healthy populations) revealed that higher doses of mistletoe extract (up to
1500mg) or isolated mistletoe lectins (up to 0.0064mg/kg or 6.4μg/kg body weight) exerted
no immunosuppressive effects (Kienle, Grugel, & Kiene, 2011). Reported adverse effects
were dose-dependent and mainly consisted of influenza-like symptoms, local reactions at
the injection site (e.g. erythema, induration, swelling, pain), fever and chills, headaches,
fatigue/dizziness and mild gastrointestinal symptoms. Adverse events (n = 7; anaphylaxis,
reversible grade 3 hepatotoxicity, hive-like angioedema/urticaria) were rare and occurred at
very high doses of recombinant lectin ML (0.0048-0.0064mg/kg body weight) and
mistletoe extract. Nevertheless, clinicians should monitor cancer patients using high-dose
mistletoe.
3.6 Manipulative and Body-Based Practices
3.6.1 Massage Therapy
Nine subsequent reviews (and 3 case studies) evaluating the efficacy and/or safety
of massage therapy in cancer treatment and care have been published or newly-located.
Consistent with study 2, a systematic review of 6 studies (3 RCTs, 1 quasi-experimental, 2
observational) suggested that partial/full-body massage provided acute relief of perceived
cancer pain and reduced dosage fluctuations of analgesic use in palliative care patients
(prognosis < 6 months), although no significant reduction in the frequency of analgesics
was observed (Falkensteiner, Mantovan, Müller, & Them, 2011). However, evidence of
benefit for pain (and concomitant anxiety and depression) should be considered
preliminary, at best, given the heterogeneity exhibited by the small number of studies
involved. More large high-quality RCTs evaluating different types of massage among
palliative cancer patients are required, and should involve standardised interventions (e.g.
143
massage technique, frequency and duration/length) and subjective/objective outcome
measures, as well as active control treatments (e.g. analgesics, exercise interventions).
Several massage therapy studies have been performed in breast cancer patients and
survivors. A meta-analytic/systematic review of 6 predominantly small RCTs revealed
insufficient evidence for the use of massage as supportive care for breast cancer patients
(pain, fatigue, general breast cancer symptoms, depression, anxiety, anger/hostility, QoL;
M. S. Lee, E. N. Lee, & Ernst, 2011). A more recent meta-analytic/systematic review of 18
RCTs, however, revealed limited evidence for the beneficial effect of massage therapy on
anger, fatigue and QoL among breast cancer patients/survivors (compared to standard care
or active control treatments, such as self-initiated social support), but no significant
improvements in depression, anxiety, pain, cortisol levels (stress) or upper limb
lymphoedema (Pan, Yang, Wang, Zhang, & Liang, 2013). Again, more large high-quality
RCTs as detailed above are recommended, involving assessment of both short- and long-
term effects of massage therapy among (breast) cancer patients or survivors.
Several aromatherapy studies, predominantly small, have been conducted amongst
cancer patients. A systematic review of 18 aromatherapy studies (± massage therapy; 9
RCTs, 2 non-RCTs, 7 uncontrolled) suggested limited evidence for short-term benefits on
anxiety (subjective/objective), depression and pain in cancer patients, but
insufficient/inconclusive evidence for other indices (sleep, cortisol levels,
psychological/overall well-being, subjective symptom relief, QoL; Boehm, Büssing, &
Ostermann, 2012).
Turning to surgical patients, a Cochrane meta-analytic/systematic review of 6 RCTs
and 3 case-controlled trials (mostly adult females, 1 paediatric study) revealed insufficient
evidence for the use of isopropyl alcohol or peppermint oil vapour inhalation aromatherapy
to reduce acute postoperative nausea (and vomiting; ≤ 1 hour) when compared to
conventional antiemetic treatment (ondanestron, promethazine; Hines, Steels, Chang, &
Gibbons, 2012). Isopropyl alcohol vapour inhalation was more effective than saline placebo
but not conventional antiemetics in reducing the proportion of patients requiring rescue
antiemetics, and patient satisfaction was no greater either compared to antiemetics.
Nevertheless, large high-quality RCTs are needed, preferably involving surgical cancer
patients and aromatherapy other than isopropyl alcohol, to investigate the acute and delayed
effects on postoperative nausea and vomiting, respectively, relative to standard antiemetics
and other active control treatments. Interestingly, a more recent narrative review examining
144
the effects of various aromatherapy essential oils in surgical patients suggested that
peppermint oil had positive effects on acute postoperative nausea, but appears overstated as
the only study that assessed nausea as an endpoint out of the three identified since the
Cochrane review did not achieve significance (Stea, Beraudi, & De Pasquale, 2014).
Similar conclusions based on 3 controlled trials were drawn regarding the inhalation effects
of lavender or orange essential oils on self-reported pre-surgical/procedural anxiety, but
arguably were more valid. Inconclusive/insufficient evidence, however, was indicated for
peri-operative pain, infection prophylaxis after oral surgery and post-surgical wound
healing, although topical tea tree oil warrants further investigation for wound healing given
recent favourable preliminary results (Chin & Cordell, 2013; Blackwood et al., 2013;
Edmondson et al., 2011; Stea et al., 2014).
Despite the wide variety of massage therapies, even within individual modalities
such as aromatherapy, serious adverse events are still uncommon; and more so when the
massage is of the less exotic variety, and administered and tailored to patients by trained
professionals (see Collinge, MacDonald, & Walton, 2012). The chief modifications for
oncology massage are in regard to use of pressure (reduced pressure and/or avoidance of
direct or deep tissue massage as appropriate; e.g. lymphoedema), joint movement (e.g. bone
metastases, osteoporosis), patient position for comfort, and extent/duration of massage (e.g.
palliative patients may require shorter partial- rather than full-body massages if they are in
poor general health; Collinge et al., 2012; Falkensteiner et al., 2011).
Massage lubricants and use of essential oils in aromatherapy may hold the most
potential for adverse effects due to allergic reactions. A safe dilution generally accepted by
practitioners for most non-toxic, unadulterated aromatherapy/essential oils used on the skin
is a maximum of 2.5% for adults, which equates to 2 drops of essential oil per 100 drops of
carrier oil (2% dilution: 10-12 drops of essential oil per ounce of carrier oil; Boehm et al.,
2012; Lis-Balchin, 1999). Alternatively, 5-10 drops of essential oil per bath is the usual
dosage for full-body baths. A recent systematic review yielded 71 cases of adverse effects
resulting from aromatherapy, most frequently involving the commonly-used essential oils
lavender, peppermint, tea tree oil and ylang-ylang (Posadzki, Alotaibi, & Ernst, 2012).
Adverse effects ranged from mild to severe (including one death), with contact dermatitis
most implicated with prolonged topical exposure. Oral ingestion of essential oils,
commonly practiced in Australia and France, holds much greater risk in large amounts and
is generally not advised (e.g. life-threatening phototoxic skin reactions after ingestion of
145
psoralen and exposure to artificial UV radiation; Kaddu, Kerl, & Wolf, 2001; coma induced
by chronic ingestion of cough drops containing menthol; Baibars, Eng, Shaheen, Alraiyes,
& Alraies, 2012). Additionally, repeated topical exposure to lavender and tea tree oils has
been associated with reversible prepubescent gynaecomastia due to oestrogenic and anti-
androgenic effects (Henley, Lipson, Korach, & Bloch, 2007), and may be best avoided by
cancer patients with oestrogen-dependent tumours. Finally, use of novel essential oils by
aromatherapists generally holds greater risk, given they are commonly derived from wild
plants with many cultivations of differing chemical compositions and sourced from
unregulated markets with unknown toxicity (Lis-Balchin, 1999).
3.6.2 Acupuncture
Twenty subsequent reviews evaluating the efficacy and/or safety of acupuncture in
cancer treatment and care have been published or newly-located. A systematic review of 7
systematic reviews (mostly good-quality reviews predominantly based on a small number
of poor-quality studies, often Chinese, with high risk of bias) suggested that acupuncture-
point stimulation (manual acupuncture, electroacupunture, self-/practitioner-administered
acupressure) combined with antiemetics was effective in the treatment of acute
chemotherapy-induced nausea and vomiting, but there was insufficient evidence for other
symptoms encountered in supportive and palliative cancer care (general treatment-related
toxicities, hot flushes, pain, leukopenia, xerostomia; Ernst & Lee, 2010). Further large
rigorous RCTs are required, however, comparing acupuncture-point stimulation (or any of
its individual modalities) to sham variants (if suitable), standard antiemetics and other
treatments for chemotherapy-induced nausea and vomiting. Similarly, a more recent
systematic review of 17 systematic/non-systematic reviews found a consensus for the use of
acupuncture-point stimulation for chemotherapy-induced nausea and vomiting based on 9
of the reviews; however, significant heterogeneity witnessed by the authors in quality,
interventions, control groups and outcome measures rendered studies unviable for meta-
analysis and needed to be addressed in future RCTs (Towler, Molassiotis, & Brearley,
2013). Positive effects were also indicated for hot flushes, xerostomia, cancer-related
fatigue, cancer pain (including arthralgia and neuropathic pain), dyspnoea and anxiety, but
were predominantly from lower-quality non-systematic reviews. Finally, in one of the most
recent systematic reviews of acupuncture RCTs in cancer care (n = 41), acupuncture-point
stimulation was deemed an appropriate adjunctive treatment for uncontrolled
146
chemotherapy-induced nausea and vomiting based on 11 RCTs, but additional studies were
advised to further consolidate this finding (Garcia et al., 2013). Yet again, the efficacy of
acupuncture was inconclusive/insufficient for other symptoms (pain, hot flushes,
xerostomia, anxiety, fatigue) due to a high risk of bias among studies (e.g. inadequate
blinding of patients and outcome assessors; use of single unblinded acupuncturists across
all patients in sham-controlled trials; small samples).
Despite the outcomes of these systematic review overviews in cancer care, the
effects of acupuncture on symptoms other than chemotherapy-induced nausea and vomiting
bears closer examination, especially where meta-analytic reviews have been performed or
more recent systematic reviews have been published. In relation to cancer pain, a meta-
analytic/systematic review of 15 RCTs suggested that acupuncture is not more effective
than pharmacotherapy (n = 8), but may enhance the effects of conventional
pharmacotherapy in reducing pain compared to pharmacotherapy alone (n = 7; Choi, Lee,
Kim, Zaslawski, & Ernst, 2012). Nevertheless, poor methodological quality of the trials
precluded any firm conclusions and large rigorous RCTs examining both efficacy and
safety of acupuncture in cancer pain were recommended, using validated outcome measures
and controlling for potential confounding variables (e.g. use of over-the-counter pain
analgesics or other treatments, comorbid pain conditions, physiological effects of sham
acupuncture, non-specific placebo effects related to patient expectations or patient-
practitioner interactions). Additionally, a systematic review of 7 clinical trials (3 RCTs, 1
retrospective non-RCT, 3 case series/reports) suggested that acupuncture may be effective
in ameliorating chemotherapy-induced neuropathic pain (common toxicity of the vinca
alkaloids, platinum derivatives and taxanes, as well as newer agents such as bortezomib and
thalidomide), but the current evidence is quite limited due to the poor methodological
quality and heterogeneity of the studies (Franconi, Manni, Schröder, Marchetti, Robinson,
2013). Large high-quality RCTs as detailed above are required.
Turning to menopausal hot flushes, a Cochrane meta-analytic review of 16 RCTs
(including 7 cancer studies) suggested that acupuncture compared to sham treatment had
beneficial effects for severity but not frequency of hot flushes in peri-/post-menopausal
women. Subgroup analysis rendered both effects negligible, however, when breast cancer
studies were removed, indicating that the effect of acupuncture on hot flushes may differ
for peri-/post-menopausal breast cancer survivors (Dodin et al., 2013). Indeed, a more
recent systematic review of 6 acceptable-quality (RCTs: 5 breast, 1 prostate cancer) and 10
147
low-quality studies (9 uncontrolled; 6 breast, 4 prostate) found a significant reduction in hot
flushes at the end of acupuncture treatment (up to 43% in higher-quality RCTs compared to
pretreatment) in breast/prostate cancer patients and survivors, which was maintained at
post-treatment follow-up (range: 3-12 months; Frisk, Hammar, Ingvar, & Spetz Holm,
2014). Nonetheless, the evidence is limited by the general small nature, heterogeneity (e.g.
acupuncture types included traditional, auricular and electroacupuncture; hormonal vs non-
hormonal therapy status of participants) and poor methodological quality of the studies.
Consequently, larger high-quality RCTs with longer follow-up periods (particularly among
prostate cancer patients/survivors) are required to confirm these encouraging outcomes, and
should compare traditional acupuncture to sham acupuncture and other types of
acupuncture and interventions for hot flushes (e.g. venlafaxine).
In relation to cancer-related fatigue, a meta-analysis of 7 RCTs suggested that
acupuncture was no more effective than sham acupuncture (n = 3), no treatment / wait-list
control (n = 2) or active control treatments (n = 2; acupressure or self-acupuncture) in
cancer patients/survivors (Zeng, Luo, Finnegan-John, & Cheng, 2013). General QoL and
functioning status was not significantly impacted upon either (n = 3). The authors,
however, found that acupuncture combined with passive and/or active education
interventions was significantly better in managing cancer-related fatigue in the short-term
than usual care (n = 2; up to 10 weeks post-treatment), but rendered this finding invalid by
statistically pooling studies that were not sufficiently similar in their definition of usual care
(i.e. one study combined passive education and physician usual care for enhanced usual
care, while the other simply employed physician usual care). More equivocally, a
systematic review of 7 RCTs demonstrated inconclusive evidence for the use of
acupuncture/electroacupuncture in cancer-related fatigue management for cancer
patients/survivors (Posadzki et al., 2013). Notably, the authors observed significant
methodological, statistical and clinical heterogeneity across studies, which precluded meta-
analysis. Clearly, large rigorous RCTs with longer follow-up periods are required to
determine whether acupuncture has any specific beneficial effect on cancer-related fatigue
beyond non-specific placebo effects.
In regard to immune system function, a meta-analytic/systematic review of 31
controlled trials (predominantly Chinese with at least moderate heterogeneity; Chen, Li,
Cho, & Zhang, 2013) among lung cancer patients evaluated the use of acupuncture-point
stimulation [acupuncture needle insertion, acupuncture injection with herbs, acupoint
148
plaster application, moxibustion (thermal skin stimulation by burning dried mugwort and/or
other herbs compressed into a moxa stick at acupuncture/moxibustion points)]. Consistent
with study 2, limited evidence suggested that acupuncture-point stimulation as an adjunct to
conventional anticancer treatment or as a standalone intervention may be associated with
enhanced immunomodulatory effects (by increasing interleukin-2, various T-cell/T-helper
cell and natural killer cell activity), haemoglobin and platelet levels, as well as reduced
bone marrow suppression secondary to conventional treatment in lung cancer patients.
Positive effects were also shown for grade 2-4 chemotherapy-induced nausea and vomiting,
performance status and QoL. Nevertheless, the authors advised large well-designed RCTs
among lung cancer patients to confirm these results, given heterogeneity (e.g.
frequency/duration of acupoint stimulation, diverse control interventions), high risk of
study bias (e.g. inadequate blinding and randomisation procedures) and the unknown
effects exerted by herbs used in some acupuncture-point stimulation procedures (acupoint
injection, plaster application, moxibustion). Unsurprisingly, similar outcomes and
conclusions were also observed in a Cochrane systematic review of non-pharmacological
interventions for dyspnoea regarding the use of acupuncture/acupressure amongst lung
cancer and chronic obstructive pulmonary disease patients (n = 5; Bausewein, Booth,
Gysels, & Higginson, 2008).
Finally, additional RCTs evaluating the efficacy and safety of acupuncture in
ameliorating radiation-induced xerostomia have been performed since study 2. Two
systematic reviews of 3-4 small RCTs demonstrated that acupuncture provided subjective
symptom relief of radiation-induced xerostomia among head and neck cancer patients, but
no objective symptom relief compared to sham acupuncture or usual care (Zhuang et al.,
2013; O’Sullivan & Higginson, 2010). Consequently, insufficient evidence was
demonstrated to support acupuncture as an effective and safe treatment or propyhlaxis for
radiation-induced xerostomia, but there was sufficient merit to warrant large well-designed
RCTs with long follow-up periods. Specifically, the design of these trials must employ
standardised treatments (e.g. number and type of included acupoints, intervention
type/frequency/intensity/duration, non-specific placebo effects), appropriate placebo (i.e.
inert sham acupuncture that induces neither activation nor deactivation) and active
treatment control groups (e.g. saliva-inducing mouthwashes), and standardised outcome
measures (e.g. subjective: saliva quality, appetite, nausea, daily fluid intake and sleep
diaries; objective: magnetic resonance sialography of salivary gland function; Zhuang et al.,
149
2013; O’Sullivan & Higginson, 2010). Interestingly, comparable insufficient evidence
(albeit promising) and conclusions for rigorous RCTs were offered regarding manual
acupuncture/electroacupuncture when compared to pharmacotherapy (oral or intramuscular
injections) for hiccup relief in cancer patients, in a meta-analytic/systematic review of 5
RCTs (all small Chinese RCTs with high risk of bias, but no significant heterogeneity;
Choi, Lee, & Ernst, 2012).
Despite the wide variety of acupuncture techniques, serious adverse effects are still
rare; particularly when administered by trained licensed professionals and sterile
procedures are observed (He, Zhao, Li, Xi, & Guo, 2012; Zhang, Shang, Gao, & Ernst,
2010; Ernst, 2010). The most frequent adverse events are fainting, pneumothorax,
subarachnoid haemorrhage and infection (due to insufficient knowledge and inadequate
sterile practices by acupuncturists), while the most serious ones are cardiovascular injuries,
subarachnoid haemorrhage, pneumothorax, recurrent cerebral haemorrhage and death
related to these (He et al., 2012; Zhang et al., 2010; Ernst, 2010). Possible contraindications
include bleeding abnormalities (e.g. severe clotting disorders, such as haemophilia), needle
phobia, cardiac conditions necessitating pacemakers or defibrillators (electroacupuncture
only), seizure disorders, infection or immunosuppression, cachexia, oedema, cancer-
induced bone pain, hyperalgesia or allodynia and pregnancy (Fønnebø, 2013; Paley,
Johnson, & Bennett, 2011; Filshie & Hester, 2006).
3.6.3 Exercise Interventions
Seventeen subsequent reviews evaluating the efficacy and/or safety of exercise
interventions in cancer treatment and care have been published. In an update to a Cochrane
meta-analytic/systematic review reported in study 2, evaluation of 56 RCTs (including 28
breast cancer studies) indicated once again that various exercise-based interventions
collectively had a small beneficial short-term effect in reducing cancer-related fatigue
during treatment or survivorship at post-intervention relative to control group comparisons
(predominantly no intervention, wait-list control or usual care; Cramp & Byron-Daniel,
2012). Subgroup analyses revealed small beneficial short-term effects for breast and
moderate effects for prostate cancer patients/survivors (i.e. solid tumours), but none for
those with haematological malignancies. Similar outcomes were also observed for aerobic
exercise, but not resistance exercise in comparison to control group arms. Furthermore,
improvements in cancer-related fatigue were not maintained at follow-up in the few studies
150
available (n = 5; range: 1-12 months) and results were mixed as to whether exercise-based
interventions had a positive impact on QoL (n = 33). Similarly, a more recent meta-
analytic/systematic review of 72 RCTs found a moderate beneficial short-term effect for
exercise interventions reducing cancer-related fatigue during treatment or survivorship at
post-intervention compared to control group arms (usual care or non-exercise
interventions), with more recent RCTs contributing larger effects (Tomlinson, Diorio,
Beyene, & Sung, 2014). Stronger effects were exhibited for solid tumours than
haematological or mixed malignancies, but did not differ by type of exercise intervention.
Furthermore, medium and small short-term improvements in depression (n = 20) and sleep
disturbance (n = 17), respectively, were demonstrated also. Nevertheless, as recommended
previously, further large RCTs comparing different forms of exercise interventions
(aerobic, resistance, combined) across settings in homogeneous/heterogeneous cancer
populations with cancer-related fatigue are required. Specifically, they should involve
cancer patients/survivors screened for cancer-related fatigue (via self-report and clinical
measures), standalone exercise interventions (i.e. not exercise-based interventions including
components such as relaxation/meditation or nutritional counselling), standardised
interventions tailored to target populations (e.g. exercise type, frequency/intensity and
duration/length), comparison of different exercise settings (e.g. unsupervised home-based
vs supervised institution-based, individual vs group programmes), active non-exercise
control interventions (e.g. nutritional counselling), subjective/objective outcome measures
(including related secondary outcomes, such as sleep disturbance) and longer follow-up
periods post-intervention. Adjustment for potential confounding factors should also be
performed (e.g. baseline characteristics such as sex, age, and disease/treatment status;
dietary changes or use of other fatigue relief strategies while on-study).
Looking beyond cancer-related fatigue, a Cochrane meta-analytic/systematic review
of 56 controlled trials (54 RCTs, 30 breast cancer studies) found that exercise interventions
had small/medium short-term positive effects on overall QoL (and fatigue; up to 12 weeks
post-intervention compared to usual care or non-exercise interventions), but negligible
longer-term effects (up to 6 months post-intervention) in planned or actively treated
patients and cancer survivors (Mishra et al., 2012). Small/medium improvements in the
short- and longer-term were also demonstrated for physical, role and social functioning, but
benefits were negligible or inconsistent for a number of other QoL/psychosocial outcomes
(anxiety, depression, emotional well-being, body image, pain, sleep disturbance, cognitive
151
functioning). Subgroup analyses further revealed that exercise had more positive effects on
several QoL outcomes in non-breast cancer survivors (overall QoL, physical and role
functioning, depression, fatigue, sleep disturbance and emotional well-being), or when it
was of moderate/vigorous intensity (overall QoL, physical functioning, anxiety, fatigue,
sleep disturbance). Breast cancer survivors fared better than other cancer survivors,
however, with respect to anxiety. Nonetheless, the authors advised caution in interpreting
these results given heterogeneity (interventions, outcome measures) and high risk of bias
among studies. Additionally, they recommended further rigorous RCTs (as prescribed
above for cancer-related fatigue) examining whether any beneficial effects of exercise
interventions can be maintained much beyond the end of active programmes and, to this
end, the collection of qualitative data in such trials to gain insight into how to sustain
changes in exercise behaviours among cancer patients/survivors. Interestingly, in another
meta-analytic/systematic review of 15 controlled studies focusing on resistance exercise
among actively treated patients and cancer survivors, similar short-term improvements
(physical functioning, muscular strength/endurance, body composition, QoL) and
observations regarding sustained benefit were also offered (Focht et al., 2013).
Judging from the recent proliferation of reviews, there is growing interest in the
prescription of exercise interventions to improve clinical outcomes for cancer patients pre-
and post-surgically. A systematic review of 18 clinical trials (mostly small and involving
aerobic exercise and lung cancer patients; 10 RCTs, 3 non-RCTs, 6 pilot studies) showed
preliminary evidence suggesting that exercise undertaken pre-surgically by cancer patients
may improve physical and functional recovery outcomes (cardiorespiratory fitness,
functional walking capacity, rate of incontinence), but insufficient evidence for other
outcomes (QoL, post-surgical length of hospital stay; Singh, Newton, Galvão, Spry, &
Baker, 2013). Additionally, a systematic review of 20 clinical trials (mostly small involving
supervised aerobic exercise; 8 RCTs; 9 pre-surgical, 9 post-surgical, 2 pre/post-surgical)
also suggested that exercise-based interventions undertaken by non-small cell lung cancer
patients was associated with improvement in some clinical outcomes (cardiopulmonary
exercise capacity, muscle strength, fatigue, postoperative complications, post-surgical
length of hospital stay), but that there was insufficient/inconclusive evidence for other
outcomes (patient acceptability, QoL, pulmonary function, blood gas indicators; Crandall,
Maguire, Campbell, & Kearney, 2014). Clearly, large high-quality studies (not unlike those
prescribed above) are required to confirm these encouraging outcomes among surgical
152
cancer patients, with special focus on intervention design and feasibility perceptions of
surgeons and other health professionals, patient acceptability and intervention adherence
and adverse effects.
In the same manner as pre/post-surgical cancer patients, there has been a recent
proliferation of reviews examining the effects of exercise interventions on symptom
management in prostate cancer patients. In a systematic review of 8 RCTs and 4 non RCTs,
various exercise-based interventions (≥2 sessions weekly for 4-26 weeks) were associated
with improvements in muscle mass/thickness/strength/endurance, proportion of body fat,
functional capacity, fatigue, physical/social functioning and overall QoL (group-based
interventions only, mostly resistance exercise) and aerobic endurance (group-based
interventions, home-based interventions, mostly aerobic exercise plus group counselling) in
older prostate cancer patients receiving active or inactive treatment (generally 66-72 years
old and 2-4 years post-diagnosis on average, with at least one other comorbid condition;
Keogh & MacLeod, 2012). Similarly, a systematic review of 25 RCTs suggested that
varied exercise interventions were associated with benefits for physical fitness, body
composition, incontinence (home-based pelvic floor/sphincter exercise only), fatigue and
QoL in prostate cancer patients receiving active medical treatment (radiotherapy, androgen-
deprivation therapy, pre/post-surgical care) or subsequent aftercare (Baumann, Zopf, &
Bloch, 2012). Other systematic reviews (Gardner, Livingston, & Fraser, 2014;
Chipperfield, Brooker, Fletcher, & Burney, 2013) have focused on varied exercise
interventions among prostate cancer patients undergoing androgen-deprivation therapy per
se. Based on a limited number of small RCTs and uncontrolled or pre/post-intervention
studies, the reviews suggested preliminary evidence for beneficial effects on muscle
strength/endurance and lean body mass (resistance exercise more than aerobic),
cardiorespiratory fitness, functional capacity and prostate-specific antigen or testosterone
levels, but insufficient/inconclusive evidence for other outcomes (QoL, depression, anxiety,
fatigue, body fat content, cardiometabolic risk markers, bone health). Again, large high-
quality RCTs are clearly needed as detailed previously to identify optimal dose-response
effects of exercise interventions and the minimum dose required for benefit in prostate
cancer patients.
The greatest proliferation of reviews evaluating exercise interventions in cancer care
recently has focused on cancer survivors. Two meta-analytic/systematic reviews of high-
quality RCTs (n1 = 37, n2 = 15) demonstrated that varied exercise interventions (3 sessions
153
for several weeks on average) compared to usual care ± written/telephone educational
support had a small overall positive effect on depressive symptoms experienced by cancer
survivors and patients starting/receiving adjuvant treatment (generally white American
women, average age 51 years and diagnosed with curable breast cancer; Brown et al., 2012;
Craft, Vaniterson, Helenowski, Rademaker, Courneya, 2012). Subgroup and moderator
analyses revealed the greatest improvement in depressive symptoms were observed in
cancer patients/survivors aged 47-62 years or breast cancer patients/survivors per se,
fully/partially-supervised group-based interventions, higher intensity/frequency aerobic
exercise interventions and exercise interventions with longer sessions (>30 minutes).
Similarly, a meta-analysis of 78 RCTs and pre/post-intervention studies found that exercise
interventions (23 sessions, 50 minutes long over 13 weeks on average) enhanced QoL
outcomes in both the short- and longer-term (up to months post-intervention) amongst
cancer survivors (mostly breast cancer patients), although they were more effective when
they involved women or moderate intensity aerobic exercise interventions (Ferrer, Huedo-
Medina, Johnson, Ryan, & Pescatello, 2011). Number of intervention sessions, higher
intensity resistance exercise interventions and training of intervention facilitators did not
significantly influence QoL outcomes.
Turning to clinical outcomes, a systematic review of 21 small clinical trials (10
RCTs, 6 non-RCTs, 5 pre/post-intervention studies; 18 adult studies) found preliminary
evidence suggesting that varied exercise interventions (chronic and/or acute; acute = 1
session) were associated with increased natural killer cell activity, lymphocyte proliferation
and granulocyte levels, as well as maintenance of other immune function indicators
(leukocyte, lymphocyte, natural killer cell, T-cell/T-helper cell, C-reactive protein and
pro/anti-inflammatory mediator levels) in cancer survivors and patients starting/receiving
treatment (Kruijsen-Jaarsma, Révész, Bierings, Buffart, & Takken, 2013). Additionally, a
meta-analytic/systematic review of 11 RCTs focusing on resistance exercise interventions
(generally 2-3 sessions for 12-52 weeks, average intensity: 50-80% one-repetition
maximum, 6 sets for each muscle group per week) showed large positive effects on
lower/upper-limb muscle strength, moderate effects on lean body mass and proportion of
body fat and small effects on fatigue and QoL, in cancer survivors and patients undergoing
treatment (mostly women diagnosed with breast cancer) compared to control conditions (no
exercise, usual care or alternative intervention or exercise type; Strasser, Steindorf,
Wiskemann, & Ulrich, 2013). Clearly, further large high-quality RCTs are needed as
154
detailed previously to identify optimal dose-response effects of exercise interventions and
the minimum dose required for benefit in cancer survivors, particularly in non-breast cancer
populations.
Finally, aerobic and resistance exercise interventions still appear to be relatively
safe in cancer survivors and patients. Controversy, however, still surrounds whether
lymphoedema in breast cancer patiens is a necessary contraindication of exercise
interventions, particularly those involving resistance exercise. Two recent meta-
analytic/systematic reviews of clinical studies published after 2001 (n1 = 11 RCTs; n2 = 19,
7 RCTs, 4 narrative/systematic reviews) have suggested that varied resistance and/or
aerobic exercise interventions or weight training regimes are not associated with the
development or exacerbation of breast cancer-related lymphoedema in women with or at-
risk of it post-surgery during adjuvant treatment or survivorship, and may have beneficial
effects on limb strength and physical QOL outcomes (Paramanandam & Roberts, 2014;
Kwan, Cohn, Armer, Stewart, & Cormier, 2011). Nevertheless, the moderating effects of
pressure garment use during exercise, as well as the supervision and intensity of such
interventions require clarification in further research.
3.7 Energy Therapies
3.7.1 Biofield Therapies
3.7.1.1 Qigong
Three subsequent reviews evaluating the efficacy and safety of Qigong in cancer
treatment and care have been published. A narrative review examining the effects of varied
medical Qigong interventions among cancer patients receiving treatment (5 RCTs, 5
pre/post-intervention studies; mostly small, poor-quality studies with high risk of bias)
found inconclusive evidence for benefit on QoL outcomes (e.g. overall QoL, cancer-related
fatigue) and psychological distress, but limited preliminary evidence for positive effects on
clinical outcomes such as immune function, leukopenia and long-term survival (Oh et al.,
2012). In contrast, a systematic review of 23 controlled trials (8 RCTs, 15 non-RCTs;
predominantly small, poor-quality studies with high risk of bias) found that poor-quality
non-RCTs showed favourable effects of varied Qigong interventions on QoL and clinical
outcomes (notably, overall QoL, cancer-related fatigue and immune function) among
cancer patients receiving treatment, while moderately better-quality RCTs produced mixed
results at best (Chan et al., 2012). Consequently, the authors concluded that the poor quality
155
and high risk of bias of the studies precluded any firm conclusions about whether Qigong
interventions should be adopted in supportive cancer care. More equivocally, a recent meta-
analytic/systematic review of Qigong and tai chi interventions revealed limited benefit of
Guolin/medical Qigong on overall QoL in the short-term among cancer patients receiving
treatment compared to usual care (based on 5 small RCTs), but insufficient/inconclusive
evidence for other health outcomes (depression, anxiety, cancer-related fatigue,
inflammation and immune function; Zeng et al., 2014). Consistent with study 2, larger
high-quality RCTs are recommended (particularly given the very good safety profile
demonstrated in recent cancer studies; Zeng et al., 2014; Oh et al., 2012), and they should
examine the short- and long-term efficacy of different forms of Qigong interventions in
homogeneous/heterogeneous cancer populations. Specifically, they should involve both
cancer patients and survivors, standardised interventions tailored to target populations (e.g.
form of Qigong, frequency/intensity and duration/length), comparison of different formats
(e.g. individual vs group), active control interventions (e.g. aerobic and/or resistance
exercise, acupuncture), subjective/objective outcome measures as appropriate (e.g. cancer-
related fatigue) and use of a suitable placebo control group to account for non-specific
effects of Qigong practitioner-patient interactions (e.g. usual cancer care + telephone
support).
3.7.2 Bioelectromagnetic-Based Therapies
3.7.2.1 Microwave (UHF Radiowave)/Tronado Therapy
No subsequent reviews or controlled trials evaluating the efficacy and/or
safety of microwave or ultra high frequency (UHF) therapy that are of relevance to the
cancer field were located.
156
References
Ahn, W. S., Yoo, J., Huh, S. W., Kim, C. K., Lee, J. M., Namkoong, S. E, . . . Lee, I. P.
(2003). Protective effects of green tea extracts (polyphenon E and EGCG) on
human cervical lesions. European Journal of Cancer Prevention, 12(5), 383-390.
Albers, J. W., Chaudhry, V., Cavaletti, G., & Donehower, R. C. (2014). Interventions for
preventing neuropathy caused by cisplatin and related compounds. Cochrane
Database of Systematic Reviews, 3, CD005228.
Ang-Lee, M. K., Moss, J., & Yuan, C. S. (2001). Herbal medicines and perioperative care.
Journal of the American Medical Association, 286(2), 208-216.
Archie, P., Bruera, E., & Cohen, L. (2013). Music-based interventions in palliative cancer
care: A review of quantitative studies and neurobiological literature. Supportive
Care in Cancer, 21(9), 2609-2624.
Arfeen, Z., Owen, H., Plummer, J. L., Ilsley, A. H., Sorby-Adams, R. A., & Doecke, C. J.
(1995). A double-blind randomized controlled trial of ginger for the prevention of
postoperative nausea and vomiting. Anaesthesia and Intensive Care, 23(4), 449-
452.
Arias, A. J., Steinberg, K., Banga, A., & Trestman, R. L. (2006). Systematic review of the
efficacy of meditation techniques as treatments for medical illness. Journal of
Alternative and Complementary Medicine, 12(8), 817-832.
Arold, G., Donath, F., Maurer, A., Diefenbach, K., Bauer, S., Henneicke-von Zepelin, H.
H., . . . Roots, I. (2005). No relevant interaction with alprazolam, caffeine,
tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract.
Planta Medica, 71(4), 331-337.
Baibars, M., Eng, S., Shaheen, K., Alraiyes, A. H., & Alraies, M. C. (2012). Menthol
toxicity: An unusual cause of coma. Case Reports in Medicine, 2012, 187039.
Barnes, J., Anderson, L. A., & Phillipson, J. D. (2001). St. John's wort
(Hypericumperforatum L.): A review of its chemistry, pharmacology, and clinical
properties. Journal of Pharmacy and Pharmacology, 53, 583-600.
Barton, D. L., Soori, G. S., Bauer, B. A., Sloan, J. A., Johnson, P. A., Figueras, C., . . .
Loprinzi, C. L. (2010). Pilot study of Panax quinquefolius (American ginseng) to
improve cancer-related fatigue: A randomized, double-blind, dose-finding
evaluation: NCCTG trial N03CA. Supportive Care in Cancer, 18(2), 179-187.
157
Barton, D. L., Atherton, P. J., Bauer, B. A., Moore, D. F. Jr, Mattar, B. I., Lavasseur, B. I., .
. . Loprinzi, C. L. (2011). The use of Valeriana officinalis (Valerian) in improving
sleep in patients who are undergoing treatment for cancer: A phase III randomized,
placebo-controlled, double-blind study (NCCTG Trial, N01C5). Journal of
Supportive Oncology, 9(1), 24-31.
Barton, D. L., Burger, K., Novotny, P. J., Fitch, T. R., Kohli, S., Soori, G., . . . Loprinzi, C.
L. (2013). The use of Ginkgo biloba for the prevention of chemotherapy-related
cognitive dysfunction in women receiving adjuvant treatment for breast cancer,
N00C9. Supportive Care in Cancer, 21(4), 1185-1192.
Barton, D. L., Liu, H., Dakhil, S. R., Linquist, B., Sloan, J. A., Nichols, C. R., . . . Loprinzi,
C. L. (2013). Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related
fatigue: A randomized, double-blind trial, N07C2. Journal of the National Cancer
Institute, 105(16), 1230-1238.
Basch, E., Ulbricht, C., Basch, S., Dalton, S., Ernst, E., Foppa, I. . . . Vora, M. (2005). An
evidence-based systemic review Echinacea E. angustifolia DC, E. pallida, E.
purpurea by the Natural Standard Research Collaboration. Journal of Herbal
Pharmacotherapy, 5(2), 57-88.
Baumann, F. T., Zopf, E. M., & Bloch, W. (2012). Clinical exercise interventions in
prostate cancer patients – A systematic review of randomized controlled trials.
Supportive Care in Cancer, 20(2), 221-233.
Bausewein, C., Booth, S., Gysels, M., & Higginson, I. (2008). Non-pharmacological
interventions for breathlessness in advanced stages of malignant and non-malignant
diseases. Cochrane Database of Systematic Reviews, 2, CD005623.
Bechtold, M. L., Puli, S. R., Othman, M. O., Bartalos, C. R., Marshall, J. B., & Roy, P. K.
(2009). Effect of music on patients undergoing colonoscopy: A meta-analysis of
randomized controlled trials. Digestive Diseases and Sciences, 54(1), 19-24.
Beer, A. M., & Neff, A. (2013). Differentiated evaluation of extract-specific evidence on
Cimicifuga racemosa’s efficacy and safety for climacteric complaints. Evidence-
Based Complementary and Alternative Medicine, 2013, 860602.
Bertoglio, J. C., Calderón, Lesina, B., Pilleux, L., Morazzoni, P., Riva, A., . . . Petrangolini,
G. (2013). Effect of SAMITAL® in the treatment of chemotherapy-induced
mucositis in adult oncohematological patients. Future Oncology, 9(11), 1727-1732.
158
Biggs, M. L., Sorkin, B. C., Nahin, R. L., Kuller, L. H., & Fitzpatrick, A. L. (2010). Ginkgo
biloba and risk of cancer: Secondary analysis of the Ginkgo Evaluation of Memory
(GEM) Study. Pharmacoepidemiology and Drug Safety, 19(7), 694-698.
Bilgi, N., Bell, K., Ananthakrishnan, A. N., & Atallah, E. (2010). Imatinib and Panax
ginseng: A potential interaction resulting in liver toxicity. Annals of
Pharmacotherapy, 44(5), 926-928.
Blackwood, B., Thompson, G., McMullan, R., Stevenson, M., Riley, T. V., Alderdice, F.
A., . . . McAuley, D. F. (2013). Tea tree oil (5%) body wash versus standard care
(Johnson's Baby Softwash) to prevent colonization with methicillin-resistant
Staphylococcus aureus in critically ill adults: A randomized controlled trial. Journal
of Antimicrobial Chemotherapy, 68(5), 1193-1199.
Boehm, K., Borrelli, F., Ernst, E., Habacher, G., Hung, S. K., Milazzo, S., & Horneber, M.
(2009). Green tea (Camellia sinensis) for the prevention of cancer. Cochrane
Database of Systematic Reviews, 3, CD005004.
Boehm, K., Büssing, A., & Ostermann, T. (2012). Aromatherapy as an adjuvant treatment
in cancer care – A descriptive systematic review. African Journal of Traditional
Complementary and Alternative Medicine, 9(4), 503-518.
Boehm, K., Ostermann, T., Milazzo, S., & Büssing, A. (2012). Effects of yoga
interventions on fatigue: A meta-analysis. Evidence-Based Complementary and
Alternative Medicine, 2012, 124703.
Bossaer, J.B., & Odle, B. L. (2012). Probable etoposide interaction with Echinacea. Journal
of Dietary Supplements, 9(2), 90-95.
Bourhis, J., Blanchard, P., Maillard, E., Brizel, D. M., Movsas, B., Buentzel, J., . . . Pignon,
J. P. (2011). Effect of amifostine on survival among patients treated with
radiotherapy: A meta-analysis of individual patient data. Journal of Clinical
Oncology, 29(18), 2590-2597.
Bradt, J., Dileo, C., Grocke, D., & Magill, L. (2011). Music interventions for improving
psychological and physical outcomes in cancer patients. Cochrane Database of
Systematic Reviews, 10, CD006911.
Bradt, J., Dileo, C., & Shim, M. (2013). Music interventions for preoperative anxiety.
Cochrane Database of Systematic Reviews, 6, CD006908.
159
Braedel-Ruoff, S. (2010). Immunomodulatory effects of Viscum album extracts on natural
killer cells: Review of clinical trials. Forschende Komplementarmedizin, 17(2), 63-
73.
Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Ryan, S. M., Pescatello, S. M.,
Moker, E., . . . Johnson, B. T. (2012). The efficacy of exercise in reducing
depressive symptoms among cancer survivors: A meta-analysis. PLoS One, 7(1),
e30955.
Buffart, L. M., van Uffelen, J. G., Riphagen, I. I., Brug, J., van Mechelen, W., Brown, W.
J., & Chinapaw, M. J. (2012). Physical and psychosocial benefits of yoga in cancer
patients and survivors, a systematic review and meta-analysis of randomized
controlled trials. BMC Cancer, 12, 559.
Burbos, N., & Morris, E. P. (2011). Menopausal symptoms. Clinical Evidence, 06, 0804.
Büssing, A., Raak, C., & Ostermann, T. (2012). Quality of life and related dimensions in
cancer patients treated with mistletoe extract (iscador): A meta-analysis. Evidence-
Based Complementary and Alternative Medicine, 2012, 219402.
Butler, L. M., & Wu, A. H. (2011). Green and black tea in relation to gynecologic cancers.
Molecular Nutrition & Food Research, 55(6), 931-940.
Campbell, A., & Jack, T. (1979). Acute reactions to mega ascorbic acid therapy in
malignant disease. Scottish Medical Journal, 24, 151-153.
Casellas-Grau, A., Font, A., & Vives, J. (2014). Positive psychology interventions in breast
cancer. A systematic review. Psychooncology, 23(1), 9-19.
Cepeda, M. S., Carr, D. B., Lau, J., & Alvarez, H. (2006). Music for pain relief. Cochrane
Database of Systematic Reviews, 19(2), CD004843.
Chan, C. L., Wang, C. W., Ho, R. T., Ng, S. M., Chan, J. S., Ziea, E. T., & Wong, V. C.
(2012). A systematic review of the effectiveness of qigong exercise in supportive
cancer care. Supportive Care in Cancer, 20(6), 1121-1133.
Chan, T. Y. (2006). A probable case of amygdalin-induced peripheral neuropathy in a
vegetarian with vitamin B12 deficiency. Therapeutic Drug Monitoring, 28(1), 140-
141.
Chen, H. Y., Li, S. G., Cho, W. C., & Zhang, Z. J. (2013). The role of acupoint stimulation
as an adjunct therapy for lung cancer: A systematic review and meta-analysis. BMC
Complementary and Alternative Medicine, 13, 362.
160
Chen, J., Song, Y., & Zhang, L. (2013). Lycopene/tomato consumption and the risk of
prostate cancer: A systematic review and meta-analysis of prospective studies.
Journal of Nutritional Science and Vitaminology (Tokyo), 59(3), 213-223.
Chen, S., Wang, Z., Huang, Y., O'Barr, S. A., Wong, R. A., Yeung, S., & Chow, M. S.
(2014). Ginseng and anticancer drug combination to improve cancer chemotherapy:
A critical review. Evidence-Based Complementary and Alternative Medicine, 2014,
168940.
Cheng, T. O. (2007). Why is green tea more cardioprotective in women than in men?
International Journal of Cardiology, 122, 244.
Chin, K. B., & Cordell, B. (2013). The effect of tea tree oil (Melaleuca alternifolia) on
wound healing using a dressing model. Journal of Alternative and Complementary
Medicine, 19(12), 942-945.
Chipperfield, K., Brooker, J., Fletcher, J., & Burney, S. (2013). The impact of physical
activity on psychosocial outcomes in men receiving androgen deprivation therapy
for prostate cancer: A systematic review. Health Psychology. Advance online
publication. Retrieved from http://dx.doi.org/10.1037/hea0000006
Choi, J., Kim, T. H., Choi, T. Y., & Lee, M. S. (2013). Ginseng for health care: A
systematic review of randomized controlled trials in Korean literature. PLoS One,
8(4), e59978.
Choi, T. Y., Lee, M. S., & Ernst, E. (2012). Acupuncture for cancer patients suffering from
hiccups: A systematic review and meta-analysis. Complementary Therapy in
Medicine, 20(6), 447-455.
Choi, T. Y., Lee, M. S., Kim, T. H., Zaslawski, C., & Ernst, E. (2012). Acupuncture for the
treatment of cancer pain: A systematic review of randomised clinical trials.
Supportive Care in Cancer, 20(6), 1147-1158.
Chua, M. E., Sio, M. C., Sorongon, M. C., & Dy, J. S. (2012). Relationship of dietary
intake of omega-3 and omega-6 Fatty acids with risk of prostate cancer
development: A meta-analysis of prospective studies and review of literature.
Prostate Cancer, 2012, 826254.
Clough, A. R., Bailie, R. S., & Currie, B. (2003). Liver function test abnormalities in users
of aqueous kava extracts. Journal of Toxicology-Clinical Toxicology, 41(6), 821-
829.
161
Cole, L. C., & LoBiondo-Wood, G. (2014). Music as an adjuvant therapy in control of pain
and symptoms in hospitalized adults: A systematic review. Pain Management
Nursing, 15(1), 406-425.
Collinge, W., MacDonald, G., & Walton, T. (2012). Massage in supportive cancer care.
Seminars in Oncology Nursing, 28(1), 45-54.
Coulter, D. (2007). Assessment of the risk of hepatotoxicity with kava products. Geneva:
World Health Organization.
Cox, M. C., Low, J., Lee, J., Walshe, J., Denduluri, N., Berman, A, . . . Swain, S. M.
(2006). Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel.
Clinical Cancer Research, 12(15), 4636-4640.
Craft, L. L., Vaniterson, E. H., Helenowski, I. B., Rademaker, A. W., & Courneya, K. S.
(2012). Exercise effects on depressive symptoms in cancer survivors: A systematic
review and meta-analysis. Cancer and Epidemiology Biomarkers & Prevention,
21(1), 3-19.
Cramer, H., Lange, S., Klose, P., Paul, A., & Dobos, G. (2012a). Yoga for breast cancer
patients and survivors: A systematic review and meta-analysis. BMC Cancer, 12,
412.
Cramer, H., Lange, S., Klose, P., Paul, A., & Dobos, G. (2012b). Can yoga improve fatigue
in breast cancer patients? A systematic review. Acta Oncologica, 51(4), 559-560.
Cramer, H., Lauche, R., Paul, A., & Dobos, G. (2012). Mindfulness-based stress reduction
for breast cancer-a systematic review and meta-analysis. Current Oncology, 19(5),
e343-e352.
Cramp, F., & Byron-Daniel, J. (2012). Exercise for the management of cancer-related
fatigue in adults. Cochrane Database of Systematic Reviews, 11, CD006145.
Crandall K, Maguire R, Campbell A, Kearney N. Exercise intervention for patients
surgically treated for Non-Small Cell Lung Cancer (NSCLC): A systematic review.
Surgical Oncology, 23(1), 17-30.
Culos-Reed, S. N., Mackenzie, M. J., Sohl, S. J., Jesse, M. T., Zahavich, A. N., &
Danhauer, S. C. (2012). Yoga & cancer interventions: A review of the clinical
significance of patient reported outcomes for cancer survivors. Evidence-Based
Complementary and Alternative Medicine, 2012, 642576.
162
de Jager Meezenbroek, E., Garssen, B., van den Berg, M., van Dierendonck, D., Visser, A.,
& Schaufeli, W. B. (2012). Measuring spirituality as a universal human experience:
A review of spirituality questionnaires. Journal of Religion and Health, 51(2), 336-
354.
Dodin, S., Blanchet, C., Marc, I., Ernst, E., Wu, T., Vaillancourt, C., . . . Maunsell, E.
(2013). Acupuncture for menopausal hot flushes. Cochrane Database of Systematic
Reviews, 7, CD007410.
Dugoua, J. J., Wu, P., Seely, D., Eyawo, O., & Mills, E. (2010). Astragalus-containing
Chinese herbal combinations for advanced non-small-cell lung cancer: A meta-
analysis of 65 clinical trials enrolling 4751 patients. Lung Cancer: Targets and
Therapy, 1, 85-100.
Duval, M., & Daniel, S. J. (2012). Meta-analysis of the efficacy of amifostine in the
prevention of cisplatin ototoxicity. Journal of Otolaryngology Head & Neck
Surgery, 41(5), 309-315.
Edmondson, M., Newall, N., Carville, K., Smith, J., Riley, T. V., & Carson, CF. (2011).
Uncontrolled, open-label, pilot study of tea tree (Melaleuca alternifolia) oil solution
in the decolonisation of methicillin-resistant Staphylococcus aureus positive
wounds and its influence on wound healing. International Wound Journal, 8(4),
375-384.
Elam, J. L., Carpenter, J. S., Shu, X. O., Boyapati, S., & Friedmann-Gilchrist, J. (2006).
Methodological issues in the investigation of ginseng as an intervention for fatigue.
Clinical Nurse Specialist, 20(4), 183-189.
Engwall, M., & Duppils, G. S. (2009). Music as a nursing intervention for postoperative
pain: A systematic review. Journal of PeriAnesthesia Nursing, 24(6), 370-383.
Ernst, E. (2010). Deaths after acupuncture: A systematic review. International Journal of
Risk & Safety in Medicine, 22, 131-136.
Ernst, E.; CAM-Cancer Consortium. (2013). St. John's wort (Hypericum perforatum)
[online document]. Retrieved from http://www.cam-cancer.org/CAM-
Summaries/Herbal-products/St.-John-s-wort-Hypericum-perforatum
Ernst, E., & Lee, M. S. (2010). Acupuncture for palliative and supportive cancer care: A
systematic review of systematic reviews. Journal Pain and Symptom Management,
40(1), e3-e5.
163
Falkensteiner, M., Mantovan, F., Müller, I., & Them, C. (2011). The use of massage
therapy for reducing pain, anxiety, and depression in oncological palliative care
patients: A narrative review of the literature. ISRN Nursing, 2011, 929868.
Faller, H., Schuler, M., Richard, M., Heckl, U., Weis, J., & Küffner, R. (2013). Effects of
psycho-oncologic interventions on emotional distress and quality of life in adult
patients with cancer: Systematic review and meta-analysis. Journal of Clinical
Oncology, 31(6), 782-793.
Felbel, S., Meerpohl, J. J., Monsef, I., Engert, A., & Skoetz, N. (2014). Yoga in addition to
standard care for patients with haematological malignancies. Cochrane Database of
Systematic Reviews, 6, CD010146.
Ferrer, R. A., Huedo-Medina, T. B., Johnson, B. T., Ryan, S., & Pescatello, L. S. (2011).
Exercise interventions for cancer survivors: A meta-analysis of quality of life
outcomes. Annals of Behavioral Medicine, 41(1), 32-47.
Filshie, J., & Hester, J. (2006). Guidelines for providing acupuncture treatment for cancer
patients: A peer-reviewed sample policy document. Acupuncture in Medicine, 24,
172-182.
Flaig, T. W., Gustafson, D. L., Su, L. J., Zirrolli, J. A., Crighton, F., Harrison, G. S., . . .
Glodé, L. M. (2007). A phase I and pharmacokinetic study of silybin-phytosome in
prostate cancer patients. Investigational New Drugs, 25(2), 139-146.
Flaig, T. W., Glodé, M., Gustafson, D., van Bokhoven, A., Tao, Y., Wilson, S., . . . Pollak,
M. (2010). A study of high-dose oral silybin-phytosome followed by prostatectomy
in patients with localized prostate cancer. Prostate, 70(8), 848-855.
Focht, B. C., Clinton, S. K., Devor, S. T., Garver, M. J., Lucas, A. R., Thomas-Ahner, J.
M., & Grainger, E. (2013). Resistance exercise interventions during and following
cancer treatment: A systematic review. Journal of Supportive Oncology, 11(2), 45-
60.
Fon Sing, M., Yang, W. S., Gao, S., Gao, J., & Xiang, Y. B. (2011). Epidemiological
studies of the association between tea drinking and primary liver cancer: A meta-
analysis. European Journal of Cancer Prevention, 20(3), 157-165.
164
Fønnebø V.; CAM-Cancer Consortium. (2013). Acupuncture and acupressure for
chemotherapy-associated nausea and vomiting [online document]. Retrieved from
http://www.cam-cancer.org/CAM-Summaries/Mind-body-
interventions/Acupuncture-and-acupressure-for-chemotherapy-associated-nausea-
and-vomiting
Franconi, G., Manni, L., Schröder, S., Marchetti, P., & Robinson, N. (2013). A systematic
review of experimental and clinical acupuncture in chemotherapy-induced
peripheral neuropathy. Evidence-Based Complementary and Alternative Medicine,
2013, 516916.
Frenkel, M. (2010). Homeopathy in cancer care. Alternative Therapies in Health and
Medicine, 16(3), 12-16.
Frenkel, M., Abrams, D. I., Ladas, E. J., Deng, G., Hardy, M., Capodice, J. L., . . . Block,
K. I. (2013). Integrating dietary supplements into cancer care. Integrative Cancer
Therapies, 12(5), 369-384.
Frisk, J. W., Hammar, M. L., Ingvar, M., & Spetz Holm, A. C. (2014). How long do the
effects of acupuncture on hot flashes persist in cancer patients? Supportive Care in
Cancer, 22(5), 1409-1415.
Fritz, H., Flower, G., Weeks, L., Cooley, K., Callachan, M., McGowan, J., . . . Seely, D.
(2014). Intravenous Vitamin C and cancer: A systematic review. Integrative Cancer
Therapies, 13(4), 280-300.
Fritz, H., Seely, D., McGowan, J., Skidmore, B., Fernandes, R., Kennedy, D. A., . . .
Fergusson, D. (2014). Black cohosh and breast cancer: A systematic review.
Integrative Cancer Therapies, 13(1), 12-29.
Fritz, H., Kennedy, D., Fergusson, D., Fernandes, R., Doucette, S., Cooley, K., … Seely, D.
(2011a). Vitamin A and retinoid derivatives for lung cancer: A systematic review
and meta analysis. PLoS One, 6(6), e21107.
Fritz, H., Kennedy, D., Fergusson, D., Fernandes, R., Doucette, S., Cooley, K., … Seely, D.
(2011b). Selenium and lung cancer: A systematic review and meta analysis. PLoS
One, 6(11), e26259.
Fritz, H., Seely, D., Kennedy, D. A., Fernandes, R., Cooley, K., & Fergusson, D. (2013).
Green tea and lung cancer: A systematic review. Integrative Cancer Therapies,
12(1), 7-24.
165
Fulan, H., Changxing, J., Baina, W. Y., Wencui, Z., Chunqing, L., Fan, W., . . . Yashuang
Z. (2011). Retinol, vitamins A, C, and E and breast cancer risk: A meta-analysis and
meta-regression. Cancer Causes and Control, 22(10), 1383-1396.
Galaal, K., Bryant, A., Deane, K. H., Al-Khaduri, M., & Lopes, A. D. (2011).
Interventions for reducing anxiety in women undergoing colposcopy. Cochrane
Database of Systematic Reviews, 12, CD006013.
Gao, M., Ma, W., Chen, X. B., Chang, Z. W., Zhang, X. D., & Zhang, M. Z. (2013). Meta-
analysis of green tea drinking and the prevalence of gynecological tumors in
women. Asia Pacific Journal of Public Health, 25(4 Suppl), 43S-48S.
Garcia, M. K., McQuade, J., Haddad, R., Patel, S., Lee, R., Yang, P., . . . Cohen, L. (2013).
Systematic review of acupuncture in cancer care: A synthesis of the evidence.
Journal of Clinical Oncology, 31(7), 952-960.
Gardner, J. R., Livingston, P. M., & Fraser, S. F. (2014). Effects of exercise on treatment-
related adverse effects for patients with prostate cancer receiving androgen-
deprivation therapy: A systematic review. Journal of Clinical Oncology, 32(4), 335-
346.
Goey, A. K., Meijerman, I., Rosing, H., Marchetti, S., Mergui-Roelvink, M., Keessen, M., .
. . Schellens, J. H. (2014). The effect of St John's wort on the pharmacokinetics of
docetaxel. Clinical Pharmacokinetics, 53(1), 103-110.
Goey, A. K., Meijerman, I., Rosing, H., Burgers, J. A., Mergui-Roelvnik, M., Keessen, M.,
. . . Schellens, J. H. (2013). The effect of Echinacea purpurea on the
pharmacokinetics of docetaxel. British Journal of Clinical Pharmacology, 76(3),
467-474.
Goey, A. K., Mooiman, K. D., Beijnen, J. H., Schellens, J. H., & Meijerman I. (2013).
Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb-drug
interactions in cancer patients. Cancer Treatment Reviews, 39(7), 773-783.
Gooding, L., Swezey, S., & Zwischenberger, J. B. (2012). Using music interventions in
perioperative care. Southern Medical Journal, 105(9), 486-490.
Greeson, J. M., Sanford, B., & Monti, D. A. (2001). St. John's wort (Hypericum
perforatum): A review of the current pharmacological, toxicological, and clinical
literature. Psychopharmacology, 153, 402-414.
166
Griffiths, K. M., Calear, A. L., & Banfield, M. (2009). Systematic review on internet
support groups (ISGs) and depression (1): Do ISGs reduce depressive symptoms?
Journal of Medical Internet Research, 11(3), e40. Retrieved from
http://dx.doi.org/10.2196/jmir.1270
Gu, J., Zhu, S., Li, X., Wu, H., Li, Y., & Hua, F. (2014). Effect of amifostine in head and
neck cancer patients treated with radiotherapy: A systematic review and meta-
analysis based on randomized controlled trials. PLoS One, 9(5), e95968.
Guercio, V., Galeone, C., Turati, F., & La Vecchia, C. (2014). Gastric cancer and allium
vegetable intake: A critical review of the experimental and epidemiologic evidence.
Nutrition and Cancer, 66(5), 757-773.
Gulick, R. M., McAuliffe, V., Holden-Wiltse, J., Crumpacker, C., Liebes, L., Stein, D. S., .
. . Valentine, F. T. (1999). Phase I studies of hypericin, the active compound in St.
John's wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials
Group Protocols 150 and 258. Annals of Internal Medicine, 130, 510-514.
Gurley, B. J., Gardner, S. F., Hubbard, M. A., Williams, D. K., Gentry, W. B., Cui, Y., &
Ang, C. Y. (2002). Cytochrome P450 phenotypic ratios for predicting herb-drug
interactions in humans. Clinical Pharmacology & Therapeutics, 72(3), 276-287.
Gurley, B., Gardner, S., & Hubbard, M. (2005). Clinical assessment of botanical
supplementation on cytochrome P450 phenotypes in the elderly: St. John’s
wort, garlic oil, Panax ginseng, and Ginkgo biloba. Drugs & Aging, 22, 525-539.
Haniadka, R., Rajeev, A. G., Palatty, P. L., Arora, R., & Baliga, M, S. (2012). Zingiber
officinale (ginger) as an anti-emetic in cancer chemotherapy: A review. Journal of
Alternative and Complementary Medicine, 18(5), 440-444.
Harder, H., Parlour, L., & Jenkins, V. (2012). Randomised controlled trials of yoga
interventions for women with breast cancer: A systematic literature review.
Supportive Care in Cancer, 20(12), 3055-3064.
Harris, H. R., Orsini, N., & Wolk, A. (2014). Vitamin C and survival among women with
breast cancer: A meta-analysis. European Journal of Cancer, 50(7), 1223-1231.
He, B. C., Gao, J. L., Luo, X., Luo, J., Shen, J., Wang, L., . . . Zhang, B. Q. (2011).
Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of
Wnt/ß-catenin signaling. International Journal of Oncology, 38(2), 437-445.
167
He, H., Zhou, X., Wang, Q., & Zhao, Y. (2013). Does the couse of astragalus-containing
Chinese herbal prescriptions and radiotherapy benefit to non-small-cell lung cancer
treatment: A meta-analysis of randomized trials. Evidence-Based Complementary
and Alternative Medicine, 2013, 426207.
He, W., Zhao, X., Li, Y., Xi, Q., & Guo, Y. (2012). Adverse events following acupuncture:
A systematic review of the Chinese literature for the years 1956-2010. Journal of
Alternative and Complementary Medicine, 18(10), 892-901.
Henley, D. V., Lipson, N., Korach, K. S., & Bloch, C. A. (2007). Prepubertal gynecomastia
linked to lavender and tea tree oils. New England Journal of Medicine, 356(5), 479-
485.
Hensley, M. L., Hagerty, K. L., Kewalramani, T., Green, D. M., Meropol, N. J.,
Wasserman, T. H., . . . Schuchter, L. M. (2009). American Society of Clinical
Oncology 2008 clinical practice guideline update: Use of chemotherapy and
radiation therapy protectants. Journal of Clinical Oncology, 27(1), 127-145.
Hermann, R., & von Richter, O. (2012). Clinical evidence of herbal drugs as perpetrators of
pharmacokinetic drug interactions. Planta Medica, 78(13), 1458-1477.
Hines, S., Steels, E., Chang, A., & Gibbons, K. (2012). Aromatherapy for treatment of
postoperative nausea and vomiting. Cochrane Database of Systematic Reviews, 4,
CD007598.
Hofmann, S. G., Sawyer, A. T., Witt, A. A., & Oh, D. (2010). The effect of mindfulness-
based therapy on anxiety and depression: A meta-analytic review. Journal of
Consulting and Clinical Psychology, 78(2), 169-183.
Hong, Y., Peña-Purcell, N. C., & Ory, M. G. (2012). Outcomes of online support and
resources for cancer survivors: A systematic literature review. Patient Education
and Counseling, 86(3), 288-296.
Hu, F., Wang Yi, B. W., Zhang, W., Liang, J., Lin, C., Li, D., . . . Zhao, Y. (2012).
Carotenoids and breast cancer risk: A meta-analysis and meta-regeression. Breast
Cancer Research and Treatment, 131(1), 239-253.
Huang, X. F. (2011). The clinical research of black cohosh extract in breast cancer
patients with climacteric complaints. (Unpublished masters dissertation). Nanjing
University of Chinese Medicine, Nanjing.
Im, E. O., & Chee, W. (2009). The use of Internet cancer support groups by ethnic
minorities. Journal of Transcultural Nursing, 19(1), 74-82.
168
Ilic, D., Forbes, K. M., & Hassed, C. (2011). Lycopene for the prevention of prostate
cancer. Cochrane Database of Systematic Reviews, 11, CD008007.
IOM Institute of Medicine. (2001). Caffeine for the sustainment of mental task
performance: Formulations for military operations. Washington, DC: National
Academy Press.
International Journal of Toxicology. (2001). Final report on the safety assessment of
Hypericum perforatum extract and Hypericum perforatum oil. International Journal
of Toxicology, 20(Suppl2), 31-39.
Izzo, A. A. (2012). Interactions between herbs and conventional drugs: Overview of the
clinical data. Medical Principles and Practice, 21(5), 404-428.
Jellin, J. M., Gregory, P. J., Batz, F., & Hitchen, K. (2002). Pharmacist's
Letter/Prescriber's Letter Natural Medicines Comprehensive Database (4th ed.).
Stockton, California: Therapeutic Research Faculty.
Jeon, Y. J.., Myung, S. K., Lee, E. H., Kim, Y., Chang, Y. J., Cho, H. J. , . . . Huh, B. Y.
(2011). Effects of beta-carotene supplements on cancer prevention: Meta-analysis of
randomized controlled trials. Nutrition and Cancer, 63(8), 1196-1207.
Jeong, A., Lee, H. J., Jeong, S. J., Lee, H. J., Lee, E. O., Bae, H., & Kim, S. H. (2010).
Compound K inhibits basic fibroblast growth factor-induced angiogenesis via
regulation of p38 mitogen activated protein kinase and AKT in human umbilical
vein endothelial cells. Biological & Pharmaceutical Bulletin, 33(6), 945-950.
Jensen, S. B., Pedersen, A. M., Vissink, A., Andersen, E., Brown, C. G., Davies, A. N, . . .
Brennan, M. T.; Salivary Gland Hypofunction/Xerostomia Section; Oral Care Study
Group; Multinational Association of Supportive Care in Cancer
(MASCC)/International Society of Oral Oncology (ISOO). (2010). A systematic
review of salivary gland hypofunction and xerostomia induced by cancer therapies:
Management strategies and economic impact. Supportive Care in Cancer, 18(8),
1061-1079.
Jin, H., Leng, Q., & Li, C. (2012). Dietary flavonoid for preventing colorectal neoplasms.
Cochrane Database of Systematic Reviews, 8, CD009350.
Jin, X., Ruiz Beguerie, J., Sze, D. M., & Chan, G. C. (2012). Ganoderma lucidum (Reishi
mushroom) for cancer treatment. Cochrane Database of Systematic Reviews, 6,
CD007731.
169
Kaddu, S., Kerl, H., & Wolf, P. (2001). Accidental bullous phototoxic reactions to
bergamot aromatherapy oil. Journal of the American Academy of Dermatology,
45(3), 458-461.
Kang, H., Rha, S. Y., Oh, K. W., & Nam, C. M. (2010). Green tea consumption and
stomach cancer risk: A meta-analysis. Epidemiology and Health, 32, e2010001.
Kasper, S., Caraci, F., Forti, B., Drago, F., & Aguglia, E. (2010). Efficacy and tolerability
of Hypericum extract for the treatment of mild to moderate depression. European
Neuropsychopharmacology, 20(11), 747-765.
Katiyar, S. K., Ahmad, M., & Mukhtar, M. (2000). Green tea and skin. Archives of
Dermatology, 136, 989-994.
Kelber, O., Nieber, K., & Kraft, K. (2014). Valerian: No evidence for clinically relevant
interactions. Evidence-Based Complementary and Alternative Medicine, 2014,
879396.
Keogh, J. W., & MacLeod, R. D. (2012). Body composition, physical fitness, functional
performance, quality of life, and fatigue benefits of exercise for prostate cancer
patients: A systematic review. Journal of Pain and Symptom Management, 43(1),
96-110.
Khaw, K. T. (2013). Dietary fats and breast cancer risk. British Medical Journal, 347,
f4518.
Kienle, G. S., Grugel, R., & Kiene, H. (2011). Safety of higher dosages of Viscum album
L. in animals and humans – Systematic review of immune changes and safety
parameters. BMC Complementary and Alternative Medicine, 11, 72.
Kienle, G. S., Glockmann, A., Grugel, R., Hamre, H. J., & Kiene, H. (2011). Clinical
research on anthroposophic medicine: Update of a health technology assessment
report and status quo. Forschende Komplementarmedizin, 18(5), 269-282.
Koenig, H. G. (2012). Religion, spirituality, and health: The research and clinical
implications. ISRN Psychiatry, 2012, 278730. Retrieved from
http://dx.doi.org/10.5402/2012/278730
Kruijsen-Jaarsma, M., Révész, D., Bierings, M. B., Buffart, L. M., & Takken, T. (2013).
Effects of exercise on immune function in patients with cancer: A systematic
review. Exercise Immunology Review, 19, 120-143.
170
Kuriyama, S., Shimazu, T., Ohmori, K., Kikuchi, N., Nakaya, N., Nishino, Y., . . . Tsuji, I.
(2006). Green tea consumption and mortality due to cardiovascular disease, cancer,
and all causes in Japan: The Ohsaki study. Journal of the American Medical
Association, 296(10), 1255-1265.
Kwan, M. L., Cohn, J. C., Armer, J. M., Stewart, B. R., & Cormier, J. N. (2011). Exercise
in patients with lymphedema: A systematic review of the contemporary literature.
Journal of Cancer Survival, 5(4), 320-336.
Laakmann, G., Schule, C., Baghai, T., & Keiser, M. (1998). St. John's wort in mild to
moderate depression: The relevance of hyperforin for the clinical efficacy.
Pharmacopsychiatry, 31, 54-59.
LaPorte, E., Sarris, J., Stough, C., & Scholey, A. (2011). Neurocognitive effects of kava
(Piper methysticum): A systematic review. Human Psychopharmacology,
26(2),102-111.
Laurie, S. A., Miller, V. A., Grant, S. C., Kris, M. G., & Ng, K. K. (2005). Phase I study of
green tea extract in patients with advanced lung cancer. Cancer Chemotherapy and
Pharmacology, 55, 33-38.
Leach, M. J., & Moore, V. (2012). Black cohosh (Cimicifuga spp.) for menopausal
symptoms. Cochrane Database of Systematic Reviews, 9, CD007244.
Lee, E. H., Myung, S. K., Jeon, Y. J., Kim, Y., Chang, Y. J., Ju, W., . . . Huh BY. (2011).
Effects of selenium supplements on cancer prevention: Meta-analysis of
randomized controlled trials. Nutrition and Cancer, 63(8), 1185-1195.
Lee, J., & Oh, H. (2013). Ginger as an antiemetic modality for chemotherapy-induced
nausea and vomiting: A systematic review and meta-analysis. Oncology Nursing
Forum, 40(2), 163-170.
Lee, J. G., Lee, Y. Y., Kim, S. Y., Pyo, J. S., Yun-Choi, H. S., & Park, J. H. (2009).
Platelet antiaggregating activity of ginsenosides isolated from processed ginseng.
Pharmazie, 64(9), 602-604.
Lee, J. G., Lee, Y. Y., Kim, S. Y., Pyo, J. S., Yun-Choi, H. S., & Park, J. H. (2010).
Inhibitory activity of ginsenosides isolated from processed ginseng on platelet
aggregation. Pharmazie, 65(7), 520-522.
Lee, M. S., Lee, E. N., Ernst, E. (2011). Massage therapy for breast cancer patients: A
systematic review. Annals of Oncology, 22(6), 1459-1461.
171
Lee, S. H., Ahn, Y. M., Ahn, S. Y., Doo, H. K., & Lee, B. C. (2008). Interaction between
warfarin and Panax ginseng in ischemic stroke patients. Journal of Alternative and
Complementary Medicine, 14(6), 715-721.
Lee, T. K., Johnke, R. M., Allison, R. R., O'Brien, K. F., & Dobbs, L. J. Jr. (2005).
Radioprotective potential of ginseng. Mutagenesis, 20, 237-243.
Lee, Y. H., Lee, B. K., Choi, Y. J., Yoon, I. K., Chang, B. C., & Gwak, H. S. (2010).
Interaction between warfarin and Korean red ginseng in patients with cardiac valve
replacement. International Journal of Cardiology, 145(2), 275-276.
Lei, H. P., Wang, G., Wang, L. S., Ou-yang, D. S., Chen, H., Li, Q., . . . Zhou, H. H.
(2009). Lack of effect of Ginkgo biloba on voriconazole pharmacokinetics in
Chinese volunteers identified as CYP2C19 poor and extensive metabolizers. Annals
of Pharmacotherapy, 43, 726-731.
Levine, A. S., & Balk, J. L. (2012). Yoga and quality-of-life improvement in patients with
breast cancer: A literature review. International Journal of Yoga Therapy, 22, 95-
99.
Li, W., Zeng, S., Yu, L. S., & Zhou, Q. (2013). Pharmacokinetic drug interaction profile of
omeprazole with adverse consequences and clinical risk management. Therapeutics
and Clinical Risk Management, 9, 259-271.
Li, X., Yang, G., Li, X., Zhang, Y., Yang, J., Chang, J., . . . Bensoussan, A. (2013).
Traditional Chinese medicine in cancer care: A review of controlled clinical studies
published in Chinese. PLoS One, 8(4), e60338.
Lin, K. Y., Hu, Y. T., Chang, K. J., Lin, H. F., & Tsauo, J. Y. (2011). Effects of yoga on
psychological health, quality of life, and physical health of patients with cancer: A
meta-analysis. Evidence-Based Complementary and Alternative Medicine, 2011,
659876.
Lin, Y. W., Hu, Z. H., Wang, X., Mao, Q. Q., Qin, J., Zheng, X. Y., & Xie, L. P. (2014).
Tea consumption and prostate cancer: An updated meta-analysis. World Journal of
Surgical Oncology, 12, 38.
Lis-Balchin, M. (1999). Possible health and safety problems in the use of novel plant
essential oils and extracts in aromatherapy. The Journal of the Royal Society for the
Promotion of Health, 119(4), 240-243.
172
Liu, J., Li, X., Liu, J., Ma, L., Li, X., & Fønnebø, V. (2011). Traditional Chinese medicine
in cancer care: A review of case reports published in Chinese literature. Forschende
Komplementärmedizin, 18(5), 257-263.
Loizou, G. D., & Cocker, J. (2001). The effects of alcohol and diallyl sulphide on CYP2E1
activity in humans: A phenotyping study using chlorzoxazone. Human &
Experimental Toxicology, 20, 321-327.
Mahady, G. B., Low Dog, T., Barrett, M. L., Chavez, M. L., Gardiner, P., Ko, R., . . .
Sarma DN. (2008). United States Pharmacopeia review of the black cohosh case
reports of hepatotoxicity. Menopause, 15(4 Pt 1), 628-638.
Mai, I., Bauer, S., Perloff, E., Johne, A., Uehleke, B., Frank, B., . . . Roots, I. (2004).
Hyperforin content determines the magnitude of the St. John’s wort-cyclosporine
drug interaction. Clinical Pharmacology & Therapeutics, 76(4), 330-340.
Manusirivithaya, S., Sripramote, M., Tangjitgamol, S., Sheanakul, C., Leelahakorn, S.,
Thavaramara, T., & Tangcharoenpanich, K. (2004). Antiemetic effect of ginger in
gynecologic oncology patients receiving cisplatin. International Journal of
Gynecological Cancer, 14, 1063-1069.
Marx, W. M., Teleni, L., McCarthy, A. L., Vitetta, L., McKavanagh, D., Thomson, D., &
Isenring, E. (2013). Ginger (Zingiber officinale) and chemotherapy-induced nausea
and vomiting: A systematic literature review. Nutrition Reviews, 71(4), 245-254.
Marvibaigi, M., Supriyanto, E., Amini, N., Abdul Majid, F. A., & Jaganathan, S. K. (2014).
Preclinical and clinical effects of mistletoe against breast cancer. BioMed Research
International, 2014, 785479.
Masters, K. S., & Hooker, S. A. (2013). Religiousness/spirituality, cardiovascular disease,
and cancer: Cultural integration for health research and intervention. Journal of
Consulting and Clinical Psychology, 81(2), 206-216.
Matchim, Y., Armer, J. M., & Stewart B. R. (2011). Mindfulness-based stress reduction
among breast cancer survivors: A literature review and discussion. Oncology
Nursing Forum, 38(2), E61-E71.
Mateo-Carrasco, H., Gálvez-Contreras, M. C., Fernández-Ginés, F. D., & Nguyen, T. V.
(2012). Elevated liver enzymes resulting from an interaction between Raltegravir
and Panax ginseng: A case report and brief review. Drug Metabolism and Drug
Interactions, 27(3), 171-175.
173
McCullough, M. L., Jacobs, E. J., Shah, R., Campbell, P. T., & Gapstur, S. M. (2012).
Garlic consumption and colorectal cancer risk in the CPS-II Nutrition Cohort.
Cancer Causes and Control, 23(10), 1643-1651.
Milazzo, S., Ernst, E., Lejeune, S., Boehm, K., & Horneber, M. (2011). Laetrile treatment
for cancer. Cochrane Database of Systematic Reviews, 11, CD005476.
Ming, Y., Chen, Z., Chen, L., Lin, D., Tong, Q., Zheng, Z., & Song, G. (2011).
Ginsenoside compound K attenuates metastatic growth of hepatocellular carcinoma,
which is associated with the translocation of nuclear factor-κB p65 and reduction of
matrix metalloproteinase-2/9. Planta Medica, 77(5), 428-433.
Mishra, S. I., Scherer, R. W., Snyder, C., Geigle, P. M., Berlanstein, D. R., & Topaloglu, O.
(2012). Exercise interventions on health-related quality of life for people with
cancer during active treatment. Cochrane Database of Systematic Reviews, 8,
CD008465.
Moltó, J., Valle, M., Miranda, C., Cedeño, S., Negredo, E., Barbanoj, M. J., & Clotet, B.
(2011). Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir
in HIV-infected patients. Antimicrobial Agents and Chemotherapy, 55(1), 326-330.
Moltó, J., Valle, M., Miranda, C., Cedeño, S., Negredo, E., & Clotet, B. (2012). Herb-drug
interaction between Echinacea purpurea and etravirine in HIV-infected patients.
Antimicrobial Agents and Chemotherapy, 56(10), 5328-5331.
Montgomery, G. H., Schnur, J. B., & Kravits, K. (2013). Hypnosis for cancer care: Over
200 years young. CA: A Cancer Journal for Clinicians, 63(1), 31-44.
Monti, D. A., Mitchell, E., Bazzan, A. J., Littman, S., Zabrecky, G., Yeo, C. J., . . . Levine,
M. (2012). Phase I evaluation of intravenous ascorbic acid in combination with
gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One,
7(1), e29794.
Morrow, P. K., Mattair, D. N., & Hortobagyi, G. N. (2011). Hot flashes: A review of
pathophysiology and treatment modalities. Oncologist, 16(11), 1658-1664.
Mueller, S. C., Majcher-Peszynska, J., Uehleke, B., Klammt, S., Mundkowski, R. G.,
Miekisch, W., . . . Drewelow B. (2006). The extent of induction of CYP3A by St.
John's wort varies among products and is linked to hyperforin dose. European
Journal of Clinical Pharmacology, 62(1), 29-36.
174
Mueller, S. C., Majcher-Peszynska, J., Mundkowski, R. G., Uehleke, B., Klammt, S.,
Sievers, H., . . . Drewelow, B. (2009). No clinically relevant CYP3A induction after
St. John's wort with low hyperforin content in healthy volunteers. European Journal
of Clinical Pharmacology, 65(1), 81-87.
Musial, F., Büssing, A., Heusser, P., Choi, K. E., & Ostermann, T. (2011). Mindfulness-
based stress reduction for integrative cancer care: A summary of evidence.
Forschende Komplementärmedizin, 18(4), 192-202.
Nag, S. A., Qin, J. J., Wang, W., Wang, M. H., Wang, H., & Zhang, R. (2012).
Ginsenosides as anticancer agents: In vitro and in vivo activities, structure-activity
relationships, and molecular mechanisms of action. Frontiers in Pharmacology, 3,
25.
Naser, B., Schnitker, J., Minkin, M. J., de Arriba, S. G., Nolte, K. U., & Osmers, R. (2011).
Suspected black cohosh hepatotoxicity: No evidence by meta-analysis of
randomized controlled clinical trials for isopropanolic black cohosh extract.
Menopause, 18(4), 366-375.
National Cancer Institute. (2014). Mistletoe extracts (PDQ®). Health professional version.
Retrieved from
http://www.cancer.gov/cancertopics/pdq/cam/mistletoe/HealthProfessional/page1/A
llPages/Print
National Health and Medical Research Council (Australia). (2013). Effectiveness of
homeopathy for clinical conditions: Evaluation of the evidence. Overview report.
Retrieved from https://www.nhmrc.gov.au/your-health/complementary-
medicines/homeopathy-review
Nicolatou-Galitis, O., Sarri, T., Bowen, J., Di Palma, M., Kouloulias, V. E., Niscola, P., . . .
Lalla, R. V.; Mucositis Study Group of the Multinational Association of Supportive
Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013).
Systematic review of amifostine for the management of oral mucositis in cancer
patients. Supportive Care in Cancer, 21(1), 357-364.
Nidich, S. I., Fields, J. Z., Rainforth, M. V., Pomerantz, R., Cella, D., Kristeller, J., . . .
Schneider, R. H. (2009). A randomized controlled trial of the effects of
transcendental meditation on quality of life in older breast cancer patients.
Integrative Cancer Therapies, 8(3), 228-234.
175
Nightingale, C. L., Rodriguez, C., & Carnaby, G. (2013). The impact of music
interventions on anxiety for adult cancer patients: A meta-analysis and systematic
review. Integrative Cancer Therapies, 12(5), 393-403.
Nilsson, U. (2008). The anxiety- and pain-reducing effects of music interventions: A
systematic review. AORN Journal, 87(4), 780-807.
Oh, B., Butow, P., Mullan, B., Hale, A., Lee, M. S., Guo, X., & Clarke, S. (2012). A
critical review of the effects of medical Qigong on quality of life, immune function,
and survival in cancer patients. Integrative Cancer Therapies, 11(2), 101-110.
Orme-Johnson, D. W., & Barnes, V. A. (2014). Effects of the transcendental meditation
technique on trait anxiety: A meta-analysis of randomized controlled trials. Journal
of Alternative and Complementary Medicine, 20(5), 330-341.
Ostermann, T., Raak, C., & Büssing, A. (2009). Survival of cancer patients treated with
mistletoe extract (Iscador): A systematic literature review. BMC Cancer, 9, 451.
Ostermann, T, & Büssing, A. (2012). Retrolective studies on the survival of cancer patients
treated with mistletoe extracts: A meta-analysis. Explore (NY), 8(5), 277-281.
O'Sullivan, E. M., & Higginson, I. J. (2010). Clinical effectiveness and safety of
acupuncture in the treatment of irradiation-induced xerostomia in patients with head
and neck cancer: A systematic review. Acupuncture in Medicine, 28(4), 191-199.
Pace, J. C. (1986). Oral ingestion of encapsulated ginger and reported self-care actions for
the relief of chemotherapy-associated nausea and vomiting (Unpublished doctoral
dissertation). University of Alabama, Birmingham.
Pais, R., & Dumitraşcu, D. L. (2013). Do antioxidants prevent colorectal cancer? A meta-
analysis. Romanian Journal of Internal Medicine, 51(3-4), 152-163.
Paley, C. A., Johnson, M. I., & Bennett, M. I. (2011). Should physiotherapists use
acupuncture for treating patients with cancer-induced bone pain? A discussion
paper. Physiotherapy, 97(3), 256-263.
Pan, Y. Q., Yang, K. H., Wang, Y. L., Zhang, L. P., & Liang, H. Q. (2013). Massage
interventions and treatment-related side effects of breast cancer: A systematic
review and meta-analysis. International Journal of Clinical Oncology. Advance
online publication. Retrieved from http://dx.doi.org/10.1007/s10147-013-0635-5
Paramanandam, V. S., & Roberts, D. (2014). Weight training is not harmful for women
with breast cancer-related lymphoedema: A systematic review. Journal of
Physiotherapy, 60(3), 136-143.
176
Pawar, D., Neve, R. S., Kalgane, S., Riva, A., Bombardelli, E., Ronchi, M., . . . Morazzoni,
P. (2013). SAMITAL® improves chemo/radiotherapy-induced oral mucositis in
patients with head and neck cancer: Results of a randomized, placebo-controlled,
single-blind Phase II study. Supportive Care in Cancer, 21(3), 827-834.
Perrone, G., Hideshima, T., Ikeda, H., Okawa, Y., Calabrese, E., Gorgun, G., . . . Anderson,
K. C. (2009). Ascorbic acid inhibits antitumor activity of bortezomib in vivo.
Leukemia, 23(9), 1679-1686.
Piet, J., Würtzen, H., & Zachariae, R. (2012). The effect of mindfulness-based therapy on
symptoms of anxiety and depression in adult cancer patients and survivors: A
systematic review and meta-analysis. Journal of Consulting and Clinical
Psychology, 80(6), 1007-1020.
Pilkington, K.; CAM-Cancer Consortium. (2012). Echinacea spp [online document].
Retrieved from http://www.cam-cancer.org/CAM-Summaries/Herbal-
products/Echinacea-spp
Pisters, K. M., Newman, R. A., Coldman, B., Shin, D. M., Khuri, F. R., Hong, W. K., . . .
Lee, J. S. (2001). Phase I trial of oral green tea extract in adult patients with solid
tumors. Journal of Clinical Oncology, 19(6), 1830-1838.
Poolsup, N., Li Wan Po A., & Knight T. L. (2000). Pharmacogenetics and
psychopharmacotherapy. Journal of Clinical Pharmacy and Therapeutics, 25, 197-
220.
Posadzki, P., Alotaibi, A., & Ernst, E. (2012). Adverse effects of aromatherapy: A
systematic review of case reports and case series. International Journal of Risk and
Safety in Medicine, 24(3), 147-161.
Posadzki, P., Watson, L., & Ernst, E. (2012). Herb–drug interactions: An overview of
systematic reviews. British Journal of Clinical Pharmacology, 75(3), 603-618.
Posadzki, P., Moon, T. W., Choi, T. Y., Park, T. Y., Lee, M. S., & Ernst, E. (2013).
Acupuncture for cancer-related fatigue: A systematic review of randomized clinical
trials. Supportive Care in Cancer, 21(7), 2067-2073.
Qi, F., Li, A., Inagaki, Y., Gao, J., Li, J., Kokudo, N., . . . Tang, W. (2010). Chinese herbal
medicines as adjuvant treatment during chemo- or radio-therapy for cancer.
Bioscience Trends, 4(6), 297-307.
177
Qi, L. W., Wang, C. Z., Du, G. J., Zhang, Z. Y., Calway, T., & Yuan, C. S. (2011).
Metabolism of ginseng and its interactions with drugs. Current Drug Metabolism,
12(9), 818-822.
Qin, B., Xun, P., & He, K. (2012). Fish or long-chain (n-3) PUFA intake is not associated
with pancreatic cancer risk in a meta-analysis and systematic review. Journal of
Nutrition, 142(6), 1067-1073.
Rades, D., Fehlauer, F., Bajrovic, A., Mahlmann, B., Richter, E., & Alberti, W. (2004).
Serious adverse effects of amifostine during radiotherapy in head and neck cancer
patients. Radiotherapy and Oncology, 70(3), 261-264.
Ries, A., Trottenberg, P., Elsner, F., Stiel, S., Haugen, D., Kaasa, S., & Radbruch, L.
(2012). A systematic review on the role of fish oil for the treatment of cachexia in
advanced cancer: An EPCRC cachexia guidelines project. Palliative Medicine,
26(4), 294-304.
Riordan, H. D., Hunninghake, R. B., Riordan, N. H., Jackson, J. J., Meng, X., Taylor, P., . .
. Rivera, A. (2003). Intravenous ascorbic acid: Protocol for its application and use.
Puerto Rico Health Sciences Journal, 22, 287-290.
Riordan, H. D., Riordan, N. H., Jackson, J. A., Casciari, J. J., Hunninghake, R., González,
M. J., . . . Rivera, A. (2004). Intravenous vitamin C as a chemotherapy agent: A
report on clinical cases. Puerto Rico Health Sciences Journal, 23, 115-118.
Riordan, H. D., Casciari, J. J., González, M. J., Riordan, N. H., Miranda-Massari, J. R.,
Taylor, P., & Jackson, J. A. (2005). A pilot clinical study of continuous intravenous
ascorbate in terminal cancer patients. Puerto Rico Health Sciences Journal, 24(4),
269-276.
Rostock, M., Fischer, J., Mumm, A., Stammwitz, U., Saller, R., & Bartsch, H. H. (2011).
Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients
with climacteric complaints - A prospective observational study. Gynecological
Endocrinology, 27(10), 844-848.
Russmann, S., Barguil, Y., Cabalion, P., Kritsanida, M., Duhet, D., & Lauterburg, B. H.
(2003). Hepatic injury due to traditional aqueous extracts of kava root in New
Caledonia. European Journal of Gastroenterology and Hepatology, 15, 1033-1036.
178
Russo, E., Scicchitano, F., Whalley, B. J., Mazzitello, C., Ciriaco, M., Esposito, S., . . . De
Sarro, G. (2014). Hypericum perforatum: Pharmacokinetic, mechanism of action,
tolerability, and clinical drug-drug interactions. Phytotherapy Research, 28(5), 643-
655.
Ryan, J. L., Heckler, C. E., Roscoe, J. A., Dakhil, S. R., Kirshner, J., Flynn, P. J., . . .
Morrow, G. R. (2012). Ginger (Zingiber officinale) reduces acute chemotherapy-
induced nausea: A URCC CCOP study of 576 patients. Supportive Care in Cancer,
20, 1479-1489.
Rychetnik, L., & Madronio, C. M. (2011). The health and social effects of drinking water-
based infusions of kava: A review of the evidence. Drug and Alcohol Review, 30(1),
74-78.
Sadja, J., & Mills, P. J. (2013). Effects of yoga interventions on fatigue in cancer patients
and survivors: A systematic review of randomized controlled trials. Explore (NY),
9(4), 232-243.
Sang, L. X., Chang, B., Li, X. H., & Jiang, M. (2013). Green tea consumption and risk of
esophageal cancer: A meta-analysis of published epidemiological studies. Nutrition
and Cancer, 65(6), 802-812.
Sarris, J., LaPorte, E., & Schweitzer, I. (2011). Kava: A comprehensive review of efficacy,
safety, and psychopharmacology. Australia and New Zealand Journal of
Psychiatry, 45(1), 27-35.
Sasazuki, S., Tamakoshi, A., Matsuo, K., Ito, H., Wakai, K., Nagata, C., . . . Tsugane, S.;
Research Group for the Development and Evaluation of Cancer Prevention
Strategies in Japan. (2012). Green tea consumption and gastric cancer risk: An
evaluation based on a systematic review of epidemiologic evidence among the
Japanese population. Japanese Journal of Clinical Oncology, 42(4), 335-346.
Schrader, E., Meier, B., & Brattström A. (1998). Hypericum treatment of mild-moderate
depression in a placebo-controlled study. A prospective, double-blind, randomized,
placebo-controlled, multicentre study. Human Psychopharmacology: Clinical &
Experimental, 13,163-169.
Schrader, E. (2000). Equivalence of St John's wort extract (Ze 117) and fluoxetine: A
randomized, controlled study in mild-moderate depression. International Clinical
Psychopharmacology, 15(2), 61-68.
179
Schreiber, J. A., & Brockopp, D. Y. (2012). Twenty-five years later – What do we know
about religion/spirituality and psychological well-being among breast cancer
survivors? A systematic review. Journal of Cancer Survivorship, 6(1), 82-94.
Schulz, V. (2006). Safety of St. John's wort extract compared to synthetic antidepressants.
Phytomedicine, 13(3), 199-204.
Seely, D., Wu, P., Fritz, H., Kennedy, D. A., Tsui, T., Seely, A. J., & Mills, E. (2012).
Melatonin as adjuvant cancer care with and without chemotherapy: A systematic
review and meta-analysis of randomized trials. Integrative Cancer Therapies, 11(4),
293-303.
Shen, X. J., Zhou, J. D., Dong, J. Y., Ding, W. Q., & Wu, J. C. (2012). Dietary intake of n-
3 fatty acids and colorectal cancer risk: A meta-analysis of data from 489 000
individuals. British Journal of Nutrition, 108(9), 1550-1556.
Shennan, C., Payne, S., & Fenlon, D. (2011). What is the evidence for the use of
mindfulness-based interventions in cancer care? A review. Psychooncology, 20(7),
681-697.
Shergis, J. L., Zhang, A. L., Zhou, W., & Xue, C. C. (2013). Panax ginseng in randomised
controlled trials: A systematic review. Phytotherapy Research, 27(7), 949-965.
Shneerson, C., Taskila, T., Gale, N., Greenfield, S., & Chen, Y. F. (2013). The effect of
complementary and alternative medicine on the quality of life of cancer survivors:
A systematic review and meta-analyses. Complementary Therapies in Medicine,
21(4), 417-429.
Shi, S, & Klotz, U. (2012). Drug interactions with herbal medicines. Clinical
Pharmacokinetics, 51(2), 77-104.
Singh, F., Newton, R. U., Galvão, D. A., Spry, N., & Baker, M. K. (2013). A systematic
review of pre-surgical exercise intervention studies with cancer patients. Surgical
Oncology, 22(2), 92-104.
Singh, Y. N. (2005). Potential for interaction of kava and St John’s wort with drugs.
Journal of Ethnopharmacology, 100, 108-113.
Staffeldt, B., Kerb, R., Brockmöller, J., Ploch, M., & Roots, I. (1994). Pharmacokinetics of
hypericin and pseudohypericin after oral intake of the Hypericum perforatum
extract LI 160 in healthy volunteers. Journal of Geriatric Psychiatry and
Neurology, 7, 47-53.
180
Stea, S., Beraudi, A., & De Pasquale, D. (2014). Essential oils for complementary treatment
of surgical patients: State of the art. Evidence-Based Complementary and
Alternative Medicine, 2014, 726341.
Stefanek, M., McDonald, P. G., & Hess, S. A. (2005). Religion, spirituality and cancer:
current status and methodological challenges, Psychooncology, 14(6), 450-463.
Stephenson, C. M., Levin, R. D., Spector, T., & Lis, C. G. (2013). Phase I clinical trial to
evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous
ascorbic acid in patients with advanced cancer. Cancer Chemotherapy and
Pharmacology, 72(1), 139-146.
Strasser, B., Steindorf, K., Wiskemann, J., & Ulrich, C. M. (2013). Impact of resistance
training in cancer survivors: A meta-analysis. Medicine & Science in Sports &
Exercise, 45(11), 2080-2090.
Tam, W. W. S., Wong, E. L. Y., & Twinn, S. F. (2008). Effect of music on procedure time
and sedation during colonoscopy: A meta-analysis. World Journal of
Gastroenterology, 14, 5336-5343.
Teschke, R., Schwarzenboeck, A., Schmidt-Taenzer, W., Wolff, A., & Hennermann, K. H.
(2011). Herb induced liver injury presumably caused by black cohosh: A survey of
initially purported cases and herbal quality specifications. Annals of Hepatology,
10(3), 249-259.
Thakor, V., Leach, M. J., Gillham, D., & Esterman, A. (2011). The quality of information
on websites selling St. John's wort. Complementary Therapies in Medicine, 19(3),
155-160.
Tomlinson, D., Diorio, C., Beyene, J., & Sung, L. (2014). Effect of exercise on cancer-
related fatigue: A meta-analysis. American Journal of Physical Medicine and
Rehabilitation, 93(8), 675-686.
Towler, P., Molassiotis, A., & Brearley, S. G. (2013). What is the evidence for the use of
acupuncture as an intervention for symptom management in cancer supportive and
palliative care: An integrative overview of reviews. Supportive Care in Cancer,
21(10), 2913-2923.
Trondalen, G., & Bonde, L. O. (2012). Music therapy: Models and interventions. In: R.
MacDonald, G. Kreutz, & L. Mitchell (Eds.), Music, health, and wellbeing (pp. 40-
64). New York: Oxford University Press.
181
Trudel, D., Labbé, D. P., Bairati, I., Fradet, V., Bazinet, L., & Têtu, B. (2012). Green tea
for ovarian cancer prevention and treatment: A systematic review of the in vitro, in
vivo and epidemiological studies. Gynecologic Oncology, 126(3), 491-498.
Tsai, H. F., Chen, Y. R., Chung, M. H., Liao, Y. M., Chi, M. J., Chang, C. C., & Chou, K.
R. (2014). Effectiveness of music intervention in ameliorating cancer patients'
anxiety, depression, pain, and fatigue: A meta-analysis. Cancer Nursing. Advance
online publication. Retrieved from
http://dx.doi.org/10.1097/NCC.0000000000000116
Turati, F., Guercio, V., Pelucchi, C., La Vecchia, C. L., & Galeone, C. (2014). Colorectal
cancer and adenomatous polyps in relation to allium vegetables intake: A meta-
analysis of observational studies. Molecular Nutrition & Food Research. Advance
online publication. Retrieved from http://dx.doi.org/10.1002/mnfr.201400169
Ucar, E., Semerci, E., Ustun, H., Yetim, T., Huzmeli, C., & Gullu, M. (2008). Prognostic
value of preoperative CEA, CA 19-9, CA 72-4, and AFP levels in gastric
cancer. Advances in Therapy, 25, 1075-1084.
van der Meij, B. S., van Bokhorst-de van der Schueren, M. A., Langius, J. A., Brouwer, I.
A., & van Leeuwen, P. A. (2011). n-3 PUFAs in cancer, surgery, and critical care:
A systematic review on clinical effects, incorporation, and washout of oral or
enteral compared with parenteral supplementation. American Journal of Clinical
Nutrition, 94(5), 1248-1265.
van Erp, N. P., Baker, S. D., Zhao, M., Rudek, M. A., Guchelaar, H. J., Nortier, J. W., . . .
Gelderblom, H. (2005). Effect of milk thistle (Silybum marianum) on the
pharmacokinetics of irinotecan. Clinical Cancer Research, 11(21), 7800-7806.
Vance, T. M., Su, J., Fontham, E. T., Koo, S. I., & Chun, O. K. (2013). Dietary
antioxidants and prostate cancer: A review. Nutrition and Cancer, 65(6), 793-801.
Vardy, J, Dhillon, H. M., Clarke, S. J., Olesen, I., Leslie, F., Warby, A., . . . McLachlan, A.
J. (2013). Investigation of herb-drug interactions with ginkgo biloba in women
receiving hormonal treatment for early breast cancer. SpringerPlus, 2(1), 126.
Vinceti, M., Dennert, G., Crespi, C. M., Zwahlen, M., Brinkman, M., Zeegers, M. P., . . .
Del Giovane, C. (2014). Selenium for preventing cancer. Cochrane Database of
Systematic Reviews, 3, CD005195.
182
Wang, J. C., Tian, J. H., Ge, L., Gan, Y. H., & Yang, K. H. (2014). Which is the best
Chinese herb injection based on the FOLFOX regimen for gastric cancer? A
network meta-analysis of randomized controlled trials. Asian Pacific Journal of
Cancer Prevention, 15(12), 4795-4800.
Wang, W., Yang, Y., Zhang, W., & Wu, W. (2014). Association of tea consumption and
the risk of oral cancer: A meta-analysis. Oral Oncology, 50(4), 276-281.
Wang, X., Lin, Y. W., Wang, S., Wu, J., Mao, Q. Q., Zheng, X. Y., & Xie, L. P. (2013). A
meta-analysis of tea consumption and the risk of bladder cancer. Urologia
Internationalis, 90(1), 10-16.
Wang, X. J., Zeng, X. T., Duan, X. L., Zeng, H. C., Shen, R., & Zhou, P. (2012).
Association between green tea and colorectal cancer risk: A meta-analysis of 13
case-control studies. Asian Pacific Journal of Cancer Prevention, 13(7), 3123-3127.
Wang, Y. M., Jin, B. Z., Ai, F., Duan, C. H., Lu, Y. Z., Dong, T. F., & Fu, Q. L. (2012).
The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy
for solid tumors: A meta-analysis of randomized controlled trials. Cancer
Chemotherapy and Pharmacology, 69(5), 1213-1220.
Wang, Z. H., Gao, Q. Y., & Fang, J. Y. (2012). Green tea and incidence of colorectal
cancer: Evidence from prospective cohort studies. Nutrition and Cancer, 64(8),
1143-1152.
Wanwimolruk, S., Bhawan, S., Coville, P. F., & Chalcroft, S. C. (1998). Genetic
polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South
Pacific Polynesian populations. European Journal of Clinical Pharmacology, 54,
431-435.
Welsh, J. L., Wagner, B. A., van't Erve, T. J., Zehr, P. S., Berg, D. J., Halfdanarson, T. R., .
. . Cullen, J. J. (2013). Pharmacological ascorbate with gemcitabine for the control
of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase
I clinical trial. Cancer Chemotherapy and Pharmacology, 71(3), 765-775.
Will-Shahab, L., Bauer, S., Kunter, U., Roots, I., & Brattström, A. (2009). St John's wort
extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral
contraceptive. European Journal of Clinical Pharmacology, 65(3), 287-294.
Witte, S., Loew, D., & Gaus, W. (2005). Meta-analysis of the efficacy of the acetonic kava-
kava extract WS1490 in patients with non-psychotic anxiety disorders.
Phytotherapy Research, 19(3), 183-188.
183
Woelk, H. (2000). Comparison of St John's wort and imipramine for treating depression:
Randomised controlled trial. British Medical Journal, 321(7260), 536-539.
Worthington, H. V., Clarkson, J. E., Bryan, G., Furness, S., Glenny, A. M., Littlewood, A.,
. . . Khalid, T. (2011). Interventions for preventing oral mucositis for patients with
cancer receiving treatment. Cochrane Database of Systematic Reviews, 4,
CD000978.
Wu, P., Dugoua, J. J., Eyawo, O., & Mills, E. J. (2009). Traditional Chinese Medicines in
the treatment of hepatocellular cancers: A systematic review and meta-analysis.
Journal of Experimental & Clinical Cancer Research, 28, 112.
Wu, S., Li, F., Huang, X., Hua, Q., Huang, T., Liu, Z., . . . Zhang, X. (2013). The
association of tea consumption with bladder cancer risk: A meta-analysis. Asia
Pacific Journal of Clinical Nutrition, 22(1), 128-137.
Wu, S., Liang, J., Zhang, L., Zhu, X., Liu, X., & Miao, D. (2011). Fish consumption and
the risk of gastric cancer: Systematic review and meta-analysis. BMC Cancer, 11,
26.
Wu, X. S. (2011). Remifemin improve gynecological malignant tumor postoperative
patients of menopause syndrome for the clinical research. (Unpublished masters
dissertation). Dalian Medical University, Dalian.
Wu, Y., Zhang, D., & Kang, S. (2013). Black tea, green tea and risk of breast cancer: An
update. SpringerPlus, 2(1), 240.
Xu, X., Yu, E., Liu, L., Zhang, W., Wei, X., Gao, X., . . . Fu, C. (2013). Dietary intake of
vitamins A, C, and E and the risk of colorectal adenoma: A meta-analysis of
observational studies. European Journal of Cancer Prevention, 22(6), 529-539.
Yan, B., Meng, X., Shi, J., Qin, Z., Wei, P., & Lao, L. (2014). Ganoderma lucidum spore
induced CA72-4 elevation in gastrointestinal cancer: A five-case report. Integrative
Cancer Therapies, 13(2), 161-166.
Yan, J. H., Pan, L., Zhang, X. M., Sun, C. X., & Cui, G. H. (2014). Lack of efficacy of Tai
Chi in improving quality of life in breast cancer survivors: A systematic review and
meta-analysis. Asian Pacific Journal of Cancer Prevention, 15(8), 3715-3720.
Yang, G., Li, X., Li, X., Wang, L., Li, J., Song, X., . . . Liu, J. (2012). Traditional Chinese
medicine in cancer care: A review of case series published in the Chinese literature.
Evidence-Based Complementary and Alternative Medicine, 2012, 751046.
184
Yang, T., Yang, X., Wang, X., Wang, Y., & Song, Z. (2013). The role of tomato products
and lycopene in the prevention of gastric cancer: A meta-analysis of epidemiologic
studies. Medical Hypotheses, 80(4), 383-388.
Yin, O. Q. P., Tomlinson, B., Waye, M. M. Y., Chow, A. H. L., & Chow, M. S. S. (2004).
Pharmacogenetics and herb-drug interactions: Experience with Ginkgo biloba and
omeprazole. Pharmacogenetics, 14, 841-850.
Zainal, N. Z., Booth, S., & Huppert, F. A. (2013). The efficacy of mindfulness-based stress
reduction on mental health of breast cancer patients: A meta-analysis.
Psychooncology, 22(7), 1457-1465.
Zava, D. T., Dollbaum, C. M., & Blen, M. (1998). Estrogen and progestin bioactivity of
foods, herbs, and spices. Proceedings of the Society of Experimental Biology and
Medicine, 21, 369-378.
Zeng, Y., Luo, T., Finnegan-John, J., & Cheng, A. S. (2013). Meta-Analysis of randomized
controlled trials of acupuncture for cancer-related fatigue. Integrative Cancer
Therapies, 13(3), 193-200.
Zeng, Y., Luo, T., Xie, H., Huang, M, & Cheng A. S. (2014). Health benefits of qigong or
tai chi for cancer patients: A systematic review and meta-analyses. Complementary
Therapies in Medicine, 22(1), 173-186.
Zhang, J., Shang, H., Gao, X., & Ernst, E. (2010). Acupuncture-related adverse events: A
systematic review of the Chinese literature. Bulletin of the World Health
Organization, 88(12), 915-921C.
Zhang, J., Yang, K. H., Tian, J. H., & Wang, C. M. (2012). Effects of yoga on psychologic
function and quality of life in women with breast cancer: A meta-analysis of
randomized controlled trials. Journal of Alternative and Complementary Medicine,
18(11), 994-1002.
Zhang, J. M., Wang, P., Yao, J. X., Zhao, L., Davis, M. P., Walsh, D., & Yue, G. H.
(2012). Music interventions for psychological and physical outcomes in cancer: A
systematic review and meta-analysis. Supportive Care in Cancer, 20(12), 3043-
3053.
Zhang, Y. F., Gao, H. F., Hou, A. J., & Zhou, Y. H. (2014). Effect of omega-3 fatty acid
supplementation on cancer incidence, non-vascular death, and total mortality: A
meta-analysis of randomized controlled trials. BMC Public Health, 14, 204.
185
Zheng, J., Yang, B., Huang, T., Yu, Y., Yang, J., & Li, D. (2011). Green tea and black tea
consumption and prostate cancer risk: An exploratory meta-analysis of
observational studies. Nutrition and Cancer, 63(5), 663-672.
Zheng, J. S., Hu, X. J., Zhao, Y. M., Yang, J., & Li, D. (2013). Intake of fish and marine n-
3 polyunsaturated fatty acids and risk of breast cancer: Meta-analysis of data from
21 independent prospective cohort studies. British Medical Journal, 346, f3706.
Zheng, J. S., Yang, J., Fu, Y. Q., Huang, T., Huang, Y. J., & Li, D. (2013). Effects of green
tea, black tea, and coffee consumption on the risk of esophageal cancer: A
systematic review and meta-analysis of observational studies. Nutrition and Cancer,
65(1), 1-16.
Zheng, P., Zheng, H. M., Deng, X. M., & Zhang, Y. D. (2012). Green tea consumption and
risk of esophageal cancer: A meta-analysis of epidemiologic studies. BMC
Gastroenterology, 12, 165.
Zick, S. M., Ruffin, M. T., Lee, J., Normolle, D. P., Siden, R., Alrawi, S., & Brenner, D. E.
(2009). Phase II trial of encapsulated ginger as a treatment for chemotherapy-
induced nausea and vomiting, Supportive Care in Cancer, 17(5), 563-572.
Zhou, Q., Qin, W. Z., Liu, S. B., Kwong, J. S., Zhou, J., & Chen, J. (2014). Shengmai (a
traditional Chinese herbal medicine) for heart failure. Cochrane Database of
Systematic Reviews, 4, CD005052.
Zhou, X. F., Ding, Z. S., & Liu, N. B. (2013). Allium vegetables and risk of prostate
cancer: Evidence from 132,192 subjects. Asian Pacific Journal of Cancer
Prevention, 14(7), 4131-4134.
Zhou, Y., Zhuang, W., Hu, W., Liu, G. J., Wu, T. X., & Wu, X. T. (2011). Consumption of
large amounts of Allium vegetables reduces risk for gastric cancer in a meta-
analysis. Gastroenterology, 141(1), 80-89.
Zhu, B., Zou, L., Qi, L., Zhong, R., & Miao, X. (2014) Allium vegetables and garlic
supplements do not reduce risk of colorectal cancer, based on meta-analysis of
prospective studies. Clinical Gastroenterology and Hepatology. Advance online
publication. Retrieved from http://dx.doi.org/10.1016/j.cgh.2014.03.019
Zhuang, L., Yang, Z., Zeng, X., Zhua, X., Chen, Z., Liu, L., & Meng, Z. (2013). The
preventive and therapeutic effect of acupuncture for radiation-induced xerostomia in
patients with head and neck cancer: A systematic review. Integrative Cancer
Therapies, 12(3), 197-205
186
Zong, A., Cao, H., & Wang, F. (2012). Anticancer polysaccharides from natural resources:
A review of recent research. Carbohydrate Polymers, 90(4), 1395-1410.
187
3.8 Preface to Commentary Article Based on Study 2 − “Embracing Complementary
and Alternative Medicine (CAM) for All the Right Reasons”
The manuscript describing a general discussion of the present PhD thesis (with
special focus on study 2) in the form of an expert comment article, written for a wider
medical audience including general practitioners and allied healthcare professionals,
underwent peer review and was published by the Medical Journal of Australia (MJA)
InSight. The manuscript in the raw format form in which it was published is presented
overleaf. Appendix E also contains the published work, as it appears in publication online.
To provide further background, the commentary article was an invited publication
extended by Kath Ryan, editor of MJA Insight, following presentation of the systematic
review findings of study 2 at an international/domestic cancer conference held in Brisbane,
Australia (see page overleaf), which attracted a media release from the conference
organisers and precipitated several media reports/interviews. The invited commentary
contributes to the present thesis by illustrating an endeavour toward achieving the
challenging, lofty heights of translational research in medicine and health, whereby the aim
was to "translate" basic research findings into medical and clinical practice in oncology and
enhance meaningful health outcomes and the overall well-being of current and future
cancer patients.
Original Publications
Pirri, C. (2013). Embracing complementary and alternative medicine. Medical Journal of
Australia (MJA) InSight, 5. Retrieved from
https://www.mja.com.au/insight/2013/5/carlo-pirri-embracing-cam
Pirri, C. (2012, November 13). An evidence-based systematic review of complementary and
alternative medicine (CAM): Recommendations concerning the efficacy and safety
of popular CAMs used by cancer patients. Part II. The best of the best in integrative
cancer care. IPOS 14th World Congress of Psycho-Oncology & Clinical Oncology
Society of Australia (COSA) 39th Annual Scientific Meeting, Brisbane, Australia.
Abstract retrieved from
http://onlinelibrary.wiley.com/doi/10.1111/ajco.12029/abstract
188
SECTION: Comment
HEADLINE: Carlo Pirri: Embracing CAM
BLURB: Patients should be encouraged to talk about alternative medicines …
COPY:
REGARDLESS of whether doctors like it or believe in it, complementary and alternative
medicine is used by more than half of all Australians
http://www.ncbi.nlm.nih.gov/pubmed/17718647 each year.
Uptake among chronically ill patients is often greater, with up to 65% of Australian cancer
patients http://onlinelibrary.wiley.com/doi/10.1111/j.1743-7563.2010.01329.x/abstract using
complementary and alternative medicine (CAM) to complement standard treatments rather than
as an alternative to conventional treatments.
What’s worrying, though, is that many patients do not talk about their CAM use with doctors
— only one-third of primary care patients consult
http://www.sciencedirect.com/science/article/pii/S0965229911001373 their GP and as few as
20% of cancer patients discuss http://www.ncbi.nlm.nih.gov/pubmed/22933591 it with their
specialists.
There are many stumbling blocks for patients in talking about CAM with doctors. They range
from the very real prospect of receiving a negative or indifferent response, to doctors simply
not asking about CAM, through to the worrying belief of many patients that CAM is entirely
“natural” and safe alongside conventional treatment.
Doctors need to nurture an environment where patients can talk about their use of CAM
without fear of disapproval, if for no reason other than the prospect that their use may cause
serious drug interactions with conventional treatments (cancer or otherwise) or adverse side-
effects on their own.
189
A recent systematic review http://cosa-ipos-2012.p.asnevents.com.au/event/abstract/2985 that I
carried out sheds more light on the safety risks of CAM use to cancer patients.
The safety and efficacy of over 50 individual complementary and alternative therapies were
evaluated across more than 300 meta-analytic and systematic reviews. Weighing up risk vs
benefit, the top 10 therapies that cancer patients should be discouraged from using are St.
John’s wort, laetrile/amygdalin/vitamin B17, kava, ginkgo biloba (EGb 761), lingzhi/reishi
mushroom, green tea, ginseng, black cohosh, shark cartilage and garlic.
Generally, botanical agents pose the greatest risk of harm to cancer patients. In particular, their
use as unproven alternative therapies (eg, laetrile/amygdalin) in place of conventional medicine
should be strongly discouraged.
Some herbal medicines, dietary supplements and other “natural” therapies have toxic and
potentially life-threatening effects (eg, laetrile/amygdalin can cause cyanide poisoning and
death; kava and black cohosh may cause liver problems). Others interact with chemotherapy
and prescription drugs (eg, St. John’s wort potentially interacts with 70%-80% of all
prescription medicines, and reduces the efficacy of some chemotherapy drugs). Some cause
complications during radiotherapy and surgery (eg, garlic, ginkgo biloba and ginseng may
increase bleeding).
That said, we shouldn’t tar all CAM interventions with the same brush as there is substantial
evidence to support the safe and effective use of some interventions. Clinical trials have shown
that some therapies, when used in support of conventional treatments, are beneficial in reducing
symptoms or emotional distress and improving the quality of life of cancer patients.
Weighing up risk vs benefit once again, the top 10 most effective and safe therapies from my
review for people with cancer are relaxation techniques, support groups led by health
professionals, physical activity programs, music therapy, meditation (including mindfulness),
acupuncture, massage, omega-3 fatty acids, yoga and ginger (combined with prescription
antiemetics).
Generally, mind-body and manipulative/body-based therapies have the greatest potential for
benefit among cancer patients. Relaxation techniques, for example, are the most effective non-
190
pharmacological approach for the relief and prevention of depression and anxiety in patients
undergoing cancer treatment.
Relaxation can also reduce nausea/vomiting, cancer-related pain and fatigue and, in respiratory
cancer patients, breathing difficulties. Physical activity programs involving aerobic or
resistance exercise can also be particularly beneficial for physical/emotional wellbeing and
fatigue, even in metastatic cancer patients.
Patients may seek guidance about CAM therapies and medical practitioners are in the prime
position to provide this. Therefore, doctors ought to be educated about CAM.
Medical schools and hospitals should integrate teaching about CAM into medical training.
Doctors need to become familiar with websites and online databases that provide information
about the wide range of therapies available. The Cancer Council Australia
http://www.cancer.org.au/about-cancer/treatment/complementary-therapies-and-cancer.html
and Australasian Integrative Medicine Association https://www.aima.net.au/resources/data-
bases/ are good starting points.
Cancer specialists should consider offering access to safe and effective complementary
therapies (or at least safe forms of them) alongside conventional treatments through their own
cancer services.
As long as complementary therapies used by cancer patients are safe and under medical
supervision, where is the harm? Hippocrates once said: “As to diseases, make a habit of two
things — to help, or at least, to do no harm.”
When patients don’t feel that they can talk about CAM with their doctors for fear of
disapproval and doctors don’t routinely take the time to ask, is that likely to help or harm the
patient with cancer? It’s certainly a question every doctor should ponder.
Carlo Pirri is a research psychologist/consultant and PhD candidate based at Murdoch
University, Perth. He is a working party member of the Complementary and Integrated
Therapies Interest Group established by the Clinical Oncological Society of Australia.
191
Chapter 4: Integrating Complementary and Conventional Medicine
4.1 Preface to General Discussion and Summary Conclusions
The manuscript describing a general discussion of the current status of
complementary and alternative medicine in cancer, in Australia and elsewhere, underwent
peer review and was published in a special issue of Cancer Forum dedicated to
complementary and alternative medicine. The invited publication included a broad
summary of the two studies reported in the present PhD thesis and several others, their
clinical implications and recommendations for future research and clinical practice, and
thus serves as the concluding chapter of this thesis. The manuscript in the form in which it
was published is presented overleaf.
Original Publication
Pirri, C. (2011). Integrating complementary and conventional medicine. Cancer Forum,
35(1), 31-39. Retrieved from
http://www.cancerforum.org.au/file/2011/March/Mar_2011_Forum8.pdf
192
INTEGRATING COMPLEMENTARY AND
CONVENTIONAL MEDICINES
Carlo PIRRI1
1Faculty of Health Sciences (Psychology), Murdoch University, Murdoch, Australia
*Correspondence: Carlo Pirri (Research Associate/PhD Candidate), Faculty of Health Sciences
(Psychology), Murdoch University, South Street, Murdoch WA 6150, Australia.
Email: [email protected]
Tel.: 61 (0) 8 9360 7382
Fax: 61 (0) 8 9360 6492
Abstract
Complementary and alternative medicine (CAM) continues to evoke fierce debate and
divergent views within the medical community. It remains an attractive and commonly
used treatment option for many cancer patients regardless of whether their doctors like it or
believe in it. Consequently, it divides health professionals providing conventional cancer
care and CAM practitioners offering unconventional care. CAM, for reasons varying from a
desire to control symptoms and prevent and treat cancer to accessibility, has assumed
significant importance in cancer treatment for many patients. An estimated 14% to 65% of
Australian adults diagnosed with cancer use CAMs (with estimates as high as 80% to 91%
in Europe and the US). Cancer patients who use CAM are typically female, younger, more
educated, and of higher socioeconomic status. Moreover, 33% to 77% of patients do not
disclose CAM use to their physicians. Given the increasing desire of cancer patients to use
CAM, it is important that clinicians have a good understanding of the evidence available
for the efficacy and safety of specific complementary and alternative therapies.
Current evidence from high quality cancer clinical trials indicates that some complementary
therapies, used as adjuncts to conventional medical treatments, are beneficial in reducing
disease or treatment symptoms and improving quality of life (QoL) and psychological
functioning. Problematically, however, CAMs are often perceived by cancer patients as
being more “natural” and, by association, safer than conventional treatments. CAMs can
193
directly harm patients via toxic or allergic reactions to their use alone, interactions with
chemotherapy agents and prescribed medications, or contaminants in their manufacturing
or from the environment. Some herbal medicines, nutritional supplements and other natural
therapies have toxic and potentially life-threatening effects (e.g. kava, comfrey and black
cohosh may cause hepatotoxicity); interact with chemotherapy and prescription drugs (e.g.
St. John’s wort may result in serotonin syndrome when taken with antidepressants, and
reduce the efficacy of chemotherapy involving irinotecan and imatinib);53,56 or cause
complications during surgery (e.g. garlic, ginkgo biloba and ginseng may increase
bleeding), radiotherapy and other anticancer treatments. Consequently, some
complementary therapies should not be used under any circumstances irrespective of
potential benefit (e.g. St. John’s wort), while others may be beneficial when cancer patients
are not undergoing these treatments and have no other contraindications. CAMs may also
cause indirect harm to patients. Resultant delays in conventional treatment potentially
compromise treatment outcomes, QoL and survival.
It is therefore imperative that those involved in the medical care of cancer patients are
equipped with the skills and knowledge to help patients appropriately evaluate
complementary and alternative therapies, in order to receive benefit while avoiding harm.
Additionally, as a consequence of the safety risks associated with CAM use, clinicians are
strongly encouraged to routinely ask patients about complementary and alternative therapy
use. Several recommended approaches (including a preliminary set of communication
guidelines) for discussing CAM with cancer patients have been published.
In conclusion, whether termed integrative cancer care or complementary medicine, cancer
physicians in Australia should strongly consider offering evidence-based complementary
therapies (or at least safe forms of them) alongside conventional treatments through their
own cancer services. Conceivably, this will influence patients to continue with mainstream
care and help them avoid any potential harm that may occur with autonomous CAM use. In
this way, optimal holistic care will be ensured for cancer patients by clinicians providing
conventional oncology treatment and care.
194
Introduction
Complementary and alternative medicine (CAM) continues to evoke fierce debate and
divergent views within the medical community. It remains an attractive and commonly
used treatment option for many cancer patients regardless of whether their clinicians like it
or believe in it. Consequently, it divides health professionals providing conventional cancer
care and CAM practitioners offering unconventional care.
Background
Definitions
The US National Center for Complementary and Alternative Medicine (NCCAM) defines
CAM as ‘a group of diverse medical and health care systems, practices and products that
are not presently considered part of conventional medicine’.1 Complementary and
alternative therapies must be distinguished, however. “Complementary therapies” are
adjuncts to conventional medical treatment that are increasingly perceived as an important
part of supportive care;2,3 they are often used for symptom management and to enhance
quality of life (QoL) and overall patient care.4 “Alternative therapies”, in contrast, are
clinically unproven and are used instead of conventional treatments.2 They can be
particularly damaging to cancer patients as delay or outright refusal of conventional
treatment often compromises their likelihood of cure or remission.5 More recently, the term
“integrative oncology” has emerged and involves a standard of care for cancer patients that
utilises safe, evidence-based complementary therapies in conjunction with conventional
anticancer treatments via a multidisciplinary approach designed to evaluate and treat the
whole person rather than the disease per se.6
Prevalence and Cost of Complementary and Alternative Medicine (CAM) Use
In the most recent population surveys in 2005/06 an estimated 67% of Australians used
CAM,7 which was at least equivalent to prescription drug use7,8 and represented out-of-
pocket spending of AUD$4.13 billion, with as many visits being made to CAM
practitioners as medical practitioners (approximately 68 million each).9 In adult cancer
patients, a systematic review of 21 studies worldwide reported an average prevalence of
CAM use of 31.4% (range: 7-64%).10 Other studies report even higher prevalence
depending on CAM definitions used and cancer populations studied (e.g. up to 91% of US
195
patients reported CAM use including prayer and exercise).11,12 In Australia, CAM use by
cancer patients has varied widely from 14.5%13 to 65%.14
Profile of CAM Users, Reasons Cancer Patients Use CAM, and Disclosure of CAM Use
by Patients
Cancer patients may make the decision to use CAM upon diagnosis, during conventional
treatment, in response to disease progression or recurrence, or during
remission/survivorship. Cancer patients who use CAM are typically female, younger, more
educated, and of higher socioeconomic status.2,15,16,17-19 There are many reasons why cancer
patients use CAM (Table 1), including cancer cure or prolongation of life;20-29 relief from
cancer symptoms and conventional treatment side-effects;19,27,30,31 to assist conventional
treatments;21,25 boosting immunological function or energy;16,19,27,30 enhancing physical,
emotional and spiritual well-being;15,16,32,33 and maintaining a sense of control or
hope.16,19,20-22,24,25,32,34 Finally, research indicates that 33% to 77% of patients do not
disclose CAM use to their physicians,44 including 40% of cancer patients in one Australian
study.20
Cancer Physicians’ Concerns and Attitudes Regarding CAM
Collectively, there is a lack of scientific evidence for the efficacy of CAMs in
oncology.10,45-47 Certainly, no CAM has proven effective in reliably curing or suppressing
any form of cancer.6 A useful distinction, however, is that between cancer cure and cancer
care.48 Some CAMs (e.g. mind-body techniques such as relaxation, acupuncture, massage)
have proven relatively effective and safe in relieving disease/treatment symptoms and
enhancing QoL/psychosocial functioning and, thus, are important in caring for patients
throughout the cancer experience.4,6,49-52 Other CAMs (e.g. herbs, nutritional supplements,
antioxidants), however, have drawn steadfast opposition from oncologists, primarily
because they remain unproven in clinical trials; possess greater health risks due to adverse
interactions with prescribed cancer treatments or medications (e.g. CAM-drug interactions,
196
Table 1. Reasons why cancer patients use complementary and alternative medicine (CAM) Common Reasons Other Reasons
Cure or prolongation of life20-29 Perceptions that CAMs are natural, beneficial and will cause no harm82
Symptom relief from cancer and its treatment19,27,30,32
Encouragement from family, friends and other cancer patients/survivors19,28,35-37
Assist conventional anticancer treatments (e.g. surgery, chemotherapy, radiotherapy)21,25
Media influence38,39
Boost immunological function16,19,27,30 Cultural values and beliefs33
Boost energy levels16,19,27,30 Poor cancer prognosis40
Enhance physical, emotional and/or spiritual well-being15,16,32,33
Strengthen the body to cope with conventional anticancer treatments3
Maintain a sense of control over their cancer and its treatment16,19,20-22,24,25,32,34
Reduce the need for invasive, painful or expensive anticancer treatments3
Maintain hope of successfully overcoming cancer16,19,20-22,24,25,32,34
Enhance quality of life3
Prevent recurrence following conventional anticancer treatment41,42
High accessibility of CAMs (e.g. due to non-prescription or self-referral)43
Greater one-on-one attention from CAM practitioners
Dissatisfaction with conventional medical care43
Poor doctor-patient relationship43
Table 2. Concerns held by physicians for cancer patients using complementary and alternative medicine (CAM)53,96
Primary Concerns Other Concerns Specific CAMs are unproven in clinical trials
Financial harm due to the excessive cost associated with CAMs
Adverse interactions with conventional treatments or medications (e.g. CAM-drug interactions, surgical complications such as bleeding)
Psychological harm caused by CAM use (e.g. by creating false hope in medically hopeless situations)
Reduced chance of cure or remission (due to CAM use delaying or reducing the efficacy of conventional treatments)
Abandonment of conventional treatment
Shorter survival time (due to CAM use delaying or reducing the efficacy of conventional treatments)
Patients confusing physicians’ willingness to discuss and support their choice to use CAMs with actual medical support for them
Litigation against physicians if they (appear to) advocate use of CAMs that prove to be a failure
197
surgical complications such as bleeding); and may delay or reduce the efficacy of
conventional treatments and, subsequently, compromise the likelihood of cure/remission
and shorten survival time (Table 2).53
Efficacy and Safety of CAM
In one population survey, 75% of people agreed that combining conventional medical
treatment and CAM was preferable to using either alone.54 Problematically, however,
CAMs are often perceived by cancer patients as being more “natural” and, by association,
safer than conventional treatments.82 CAMs can directly harm patients via toxic or allergic
reactions to their use alone, interactions with chemotherapy agents and prescribed
medications, or contaminants in their manufacturing or from the environment (e.g. heavy
metals, pesticides, bacteria, fungi).51,53 Some herbs, nutritional supplements and other
botanical agents have toxic and potentially life-threatening effects (e.g. kava, comfrey and
black cohosh may cause hepatotoxicity);55,56 interact with chemotherapy and prescription
drugs (e.g. St. John’s wort may result in serotonin syndrome when taken with
antidepressants, and reduce the efficacy of chemotherapy involving irinotecan and
imatinib);53,56 or cause complications during surgery (e.g. garlic, ginkgo biloba and ginseng
may increase bleeding) and radiotherapy (see Table 3 for a summary of direct harm that
may result from CAM use).53,57,58
CAMs may also cause indirect harm to patients (Table 4). Resultant delays in conventional
treatment potentially compromise treatment outcomes, QoL and survival.59,60 Financial or
emotional burden (e.g. prolonged denial), or the squandering of precious, limited time that
some patients have left also constitute indirect harm. Finally, patients may fall victim to
harm as a result of the unsafe practices of CAM practitioners with inadequate training or
competence, often owing to the absence of self-regulatory bodies and unsatisfactory
government legislation protecting health consumers. Moreover, harm may be exacerbated
by regulatory deficiencies in monitoring the biological potency of herbal crops or use of the
correct plant species (causing wide variation in therapeutic efficacy); product
standardisation in terms of purity and dosage (resulting in possible substitution/adulteration
and incorrect dosing or preparation); and product labelling or advertising.61
198
Table 3. Safety of complementary and alternative medicine: direct harm resulting from CAM use by cancer patients58
Direct Harm Toxic reactions to specific CAMs per se e.g. laetrile/amygdalin causes cyanide poisoning, which may result in death e.g. high-dose beta-carotene increases lung cancer incidence and cancer mortality in smokers e.g. ephedrine alkaloids, such as ephedra/ma huang, may cause cardiovascular events including hypertension, tachycardia, heart attack and stroke e.g. chronic use of valerian (≥ 2-4 months) may result in insomnia, as well as withdrawal effects (e.g. delirium, tachycardia) if also used heavily Allergic reactions to specific CAMs per se e.g. oral/topical use of garlic may cause contact dermatitis, garlic burns and anaphylaxis resulting in possible death Adverse CAM-drug interactions with chemotherapy agents e.g. kava, black cohosh, laetrile/amygdalin and echinacea, among other herbal medicines and nutritional supplements, may increase the risk of acute or chronic liver failure (and resultant death or liver transplant) when receiving hepatotoxic chemotherapy drugs, including cyclophosphamide, methotrexate, camptothecins (for instance, irinotecan), taxanes (for instance, paclitaxel), vinca alkaloids (for instance, vinorelbine) and EGFR-TK inhibitors (for instance, erlotinib and cetuximab) Adverse CAM-drug interactions with other prescribed medications e.g. ginseng, garlic, ginkgo biloba, ginger, Lingzhi and St. John’s wort, among others, may increase bleeding when used concurrently with anticoagulant/antiplatelet medications (e.g. warfarin, aspirin) e.g. St. John’s wort may cause serotonin syndrome (e.g. hypervigilance, agitation, muscle twitching, mental status changes, sweating, fever, shivering, rigidity, tachycardia/hypertension resulting in possible shock and death) when combined with prescription antidepressants e.g. valerian may increase the effects of sedatives (benzodiazepines and barbiturates), hypnotics and anxiolytics when used concurrently Adverse interactions with other CAMs e.g. laetrile/amygdalin combined with dietary intake of fruit seeds (for instance, apricot, bitter almond, peach, apple), raw almonds or megadoses of vitamin C increases the risk of cyanide poisoning and resultant death
199
Table 3. (Continued) Direct Harm Adverse interactions with comorbid medical or psychiatric illnesses e.g. ginseng, garlic, ginkgo biloba, ginger, Lingzhi, St. John’s wort and massage therapy, among other CAMs, may increase bleeding and risk of resultant death in cancer patients with coagulation disorders e.g. kava, black cohosh, laetrile/amygdalin and echinacea, among others, are potentially hepatotoxic and increase the risk of irreversible liver damage (and resultant death or liver transplant) in cancer patients with liver disorders e.g. ephedrine alkaloids (for instance, ephedra/ma huang) and Siberian ginseng/eleuthero (Eleutherococcus senticosus) possess immunostimulatory properties, thus use increases the risk of cardiovascular events (e.g. heart attack) and resultant death in cancer patients with cardiovascular disease e.g. meditation, hypnotherapy and Reiki may exacerbate psychological problems in cancer patients with psychosis, personality disorders and/or other psychiatric illnesses (for instance, schizophrenia, borderline personality disorder and bipolar disorder, respectively) Adverse effects during or following (cancer) surgery due to CAM-drug interactions (for instance, anaesthetics), inhibition of platelet function, excessive sedation, hypertensive effects, or slow wound healing e.g. ginseng, garlic, ginkgo biloba, ginger, Lingzhi and St. John’s wort, among others, may increase bleeding during or following surgery if not ceased at least 4-7 days prior to surgery e.g. St. John’s wort, valerian, garlic and kava, among others, may increase/decrease the effects of anaesthetics administered prior to surgery if not ceased at least 4-7 days beforehand e.g. shark cartilage is best avoided prior to surgery as it may slow wound healing postoperatively Adverse interactions with radiotherapy e.g. Microwave/UHF therapy + radiotherapy may result in greater adverse effects than radiotherapy alone for bladder or other invasive cancers Adverse interactions with hormonal therapy or other conventional anticancer treatments e.g. ephedrine alkaloids such as ephedra/ma huang increase the risk of cardiovascular disease in prostate/testicular cancer patients receiving hormone therapy Adverse interactions with genetic predispositions or tendencies e.g. laetrile/amygdalin increases the risk of cyanide poisoning and resultant death in genetically predisposed patients with a diminished capacity to detoxify cyanide e.g. atopic patients with a genetic tendency towards hypersensitivity may be more prone to allergic reactions (rashes, increased asthma, anaphylaxis resulting in possible death) when using echinacea
200
Table 3. (Continued) Direct Harm Decreased efficacy of prescription medications e.g. St. John’s wort may reduce the efficacy of opioids (for instance, morphine, fentanyl, oxycodone, buprenorphine) for cancer pain in (palliative) patients when used concurrently e.g. St. John’s wort may reduce the efficacy of antidepressants (for instance, SSRIs such as sertraline; SNRIs such as venlafaxine; tricyclics such as amitryptiline, MAOIs such as phenelzine) when used concurrently Decreased efficacy of chemotherapy e.g. St. John’s wort can reduce the efficacy of irinotecan and increase myelosuppression in advanced colorectal and lung cancer patients; and may reduce the efficacy of imatinib for gastrointestinal stromal tumours, chronic myeloid leukaemia and other malignancies e.g. green tea may reduce the efficacy of bortezomib in multiple myeloma and mantle cell lymphoma patients Decreased efficacy of radiotherapy e.g. limited evidence suggests that use of antioxidants may protect tumour cells and reduce the efficacy of radiotherapy Decreased efficacy of hormonal therapy or other conventional anticancer treatments e.g. female ginseng (Angelica sinensis)/dong quai, red clover and soy exert oestrogenic effects, and may reduce the efficacy of hormonal (anti-oestrogen) therapy for breast and other hormone-sensitive cancers Adverse effects due to contamination of CAM products in manufacturing or from the environment (e.g. by heavy metals, pesticides, bacteria, fungi or other impurities) e.g. excessive consumption of shark cartilage or fish may result in adverse effects due to toxic levels of mercury and other contaminants e.g. contamination of laetrile/amygdalin manufactured in Mexico (the world’s largest supplier) and Chinese herbal medicines by bacteria and other impurities may lead to infection or disease (e.g. hepatitis B or C, herpes simplex, varicella zoster, tuberculosis) Adverse effects due to substitution or adulteration of CAM products with prescription or non-prescription drugs (e.g. corticosteroids, hormones, salicylates, antihistamines, caffeine) e.g. adulteration/substitution of Chinese herbal medicines and nutritional supplements such as laetrile/amygdalin are not uncommon (for instance, unspecified adulteration with corticosteroids may lead to the hormonal disorder Cushing’s syndrome and adverse interactions with diabetic and heart medications among others)
201
Table 3. (Continued) Direct Harm Adverse effects or negligible/decreased efficacy of CAM products as a result of not being standardised (i.e. in terms of purity and dosage)
e.g. excessive doses of shark cartilage supplements may produce common side-effects (for instance, gastrointestinal symptoms such as nausea, vomiting, stomach upset, constipation/diarrhoea and taste alteration) and more serious adverse effects due to toxic levels of mercury, cadmium and other contaminants, given there is no generally accepted recommended dosage or duration for administration
e.g. shark cartilage products typically contain varying amounts of active ingredients, and therefore may not have any biological activity (for instance, liquid shark cartilage preparations reportedly contain over 99% water and less than 1% protein; powdered shark cartilage may contain excessive binding agents and fillers, including collagen, gelatin, talc, magnesium stearate and silica) Adverse effects or negligible/decreased efficacy of CAMs due to product mislabelling or misleading advertising
e.g. mislabelling of Chinese herbal medicines and nutritional supplements such as laetrile/amygdalin are not uncommon in regard to unlisted adulterants and may cause adverse effects (for instance, unspecified adulteration with corticosteroids may lead to the hormonal disorder Cushing’s syndrome and adverse interactions with diabetic and heart medications amongst others)
e.g. BeneFin (powdered shark cartilage), SkinAnswer (glycoalkaloid skin cream) and MGN-3 (rice-bran extract) were falsely promoted and marketed by Lane Labs-USA from 1997 to 2004 as effective and safe treatments for cancer and other diseases through books, articles, brochures, websites and employee statements. In 2004, Lane Labs were fined $1 million and ordered to refund customers and destroy all inventory of these products, except for a quantity of BeneFin needed for research purposes. Subsequently, two RCTs involving advanced cancer patients demonstrated that BeneFin was ineffective in improving survival or quality of life compared to standard conventional care. Adverse effects or negligible/decreased efficacy of CAMs as a result of CAM practitioners with inadequate training or competence
e.g. acupuncturists lacking experience or competence are more likely to cause minor adverse effects (for instance, local bleeding and needling pain), as well as major adverse events (for instance, pneumothorax) e.g. the skill of instructors in meditation or relaxation techniques may be important in determining whether the occurrence of paradoxical anxiety symptoms become valuable learning opportunities for teaching management of stress/anxiety or, alternatively, adverse events
e.g. massage therapists should avoid applying direct pressure over known tumours to prevent adverse effects in cancer patients; no massage or reduced pressure is also advisable for cancer patients with coagulation disorders, bone metastases, open wounds or radiation dermatitis, and prosthetic devices (for instance, infusaport, colostomy bag, stents) e.g. homeopaths lacking experience or competence may prescribe homeopathic medicines in such ultra-low concentrations that they possess no clinical therapeutic efficacy whatsoever CAM = complementary and alternative medicine; MAOIs = monoamine oxidase inhibitors; RCTs = randomised controlled trials; SNRIs = serotonin and noradrenaline reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors
202
Table 4. Safety of complementary and alternative medicine (CAM): indirect harm resulting from CAM use by cancer patients
Indirect Harm Potentially compromised treatment efficacy, quality of life and survival of cancer patients
if CAM use results in the delay, abandonment or complete refusal of conventional
anticancer treatment59,60
Decreased likelihood of comprehensive multidisciplinary input in conventional treatment
plans and important evidence-based follow-up plans for cancer patients
Financial burden due to the excessive costs associated with CAMs
Psychological distress (e.g. due to prolonged denial, by creating false hope in medically
hopeless situations)
Precious, limited time of some cancer patients (e.g. advanced disease patients with poor
prognosis, patients with disease progression or recurrence) may be squandered
Indirect harm stemming from CAM practitioners lacking experience or competence (e.g.
misdiagnosis resulting in the delay of appropriate cancer treatment)61
Compromised clinical trial outcomes if the effects of unknown CAM use by trial patients
are misattributed to new conventional anticancer treatments being investigated62,63
Despite the long history of most CAMs, rigorous scientific research evaluating their
efficacy and safety is a recent phenomenon. A diverse range of CAMs are utilised by
cancer patients in Australia and elsewhere, and the heterogeneity of these techniques appear
to be reflected in their reported efficacy also.6,51,58,64-66 Some show considerable promise
and in years to come may be integrated into everyday clinical practice, while others are
ineffective and, worse still, directly harmful. Subsequently, there is a sizable gap between
the use of some popular CAMs and the evidence to support that use.
Future Research in CAM and Establishing Research Priorities
Relatively little CAM research has been performed in Australia. Unfortunately, research
gaps are the rule rather than the exception in the CAM area. Disincentives to CAM research
are not purely financial, but also involve a lack of qualified investigators among CAM
practitioners and methodological and ethical difficulties unique to conducting CAM clinical
trials. Furthermore, until recently Australia had no national research body to encourage and
203
prioritise CAM research, or co-ordinate collaborative research between CAM and
conventional medical practitioners (cf. US NCCAM, UK National Cancer Research
Institute, European Commission). A formal collaborative approach to establish common
research goals was initiated in 2007 by the creation of the Australian National Institute of
Complementary Medicine (NICM) and the inclusion of complementary medicine in the
overall health and medical research strategic plan of the National Health and Medical
Research Council.67 The mission of the NICM is to increase complementary medicine
research and investment across Australia, effectively linking complementary medicine
researchers and practitioners with the broader research community, industry and other
stakeholders to provide strategic focus and foster excellence in research.67,68
Ultimately, the NICM’s primary objective is to translate complementary medicine research
evidence (safety, quality, efficacy, cost effectiveness) into clinical practice and relevant
policy. To this end, the NICM has established three collaborative research centres:
(1) Traditional Chinese Medicine, (2) Natural Medicines and (3) Neurocognition, and
Nutraceuticals and Herbal Medicine, which have secured approximately $8M in research
funding from government, universities and other collaborative partners.68 Emphasis is
currently focused on areas of high disease burden, where preliminary evidence is strong and
demonstrates likelihood of positive impact. Cancer is one of those areas and integrative
oncology research has been initiated as a result of a partnership between the NICM and the
National Breast Cancer Foundation.68 Importantly, this research falls in two high priority
areas for cancer patients: (1) complementary therapies in the management of disease
symptoms and side-effects of conventional anticancer treatments; and (2) adverse effects of
CAM-drug interactions during conventional treatments (i.e. drug toxicity, therapeutic
failure).68 Other high priority areas that need to be addressed, however, include: (3) quality
control and labelling of herbal medicines, nutritional supplements and other natural
products, and quality control of practitioner-administered CAMs; (4) the role of nutrition
and other forms of CAM in cancer prevention, as well as the potential role they serve in
cancer survivorship and prevention of recurrence; and (5) the mechanisms of action
underpinning beneficial complementary therapies.
204
Integrative Cancer Care in Australia Today
Most medical schools offer CAM-based courses and/or training in the US and Europe (91%
of US medical schools for the graduating class of 2009, up from 26% in 2001),69 and many
hospitals there offer integrative therapies for patients.70 However, relatively little has been
accomplished to make evidence-based complementary therapies available to (cancer)
patients in Australian hospitals, despite growing demand. A few notable exceptions exist,
though.
The SolarisCare Foundation Cancer Support Centre was established in 2001 at Sir Charles
Gairdner Hospital (SCGH), the second largest teaching hospital in Perth, Western
Australia. Complementary therapy and supportive care services offered by SolarisCare
include psychological and group support, relaxation/meditation, several types of massage
therapy and other manipulative and body-based practices, touch therapies and
education/information, but purposely exclude therapies that involve ingesting substances
(e.g. nutritional supplements).71 Initially met with considerable opposition from some
medical practitioners,72 more than 25,000 free sessions have been provided to over 1800
cancer patients and their carers statewide by a team of over 100 qualified/trained
volunteers.73 SolarisCare has recently expanded its free and paid services to the privately-
run St. John of God Hospital, Subiaco and to rural cancer patients and their carers in
Bunbury and other regional centres in Western Australia. Of interest, however, is that 85%
of individuals using their services have been women, and 55% have reported a diagnosis of
breast cancer.72,73
The Peter MacCallum Cancer Centre, Australia’s only dedicated cancer hospital, in
Melbourne, Victoria provides complementary therapy and supportive care services to
patients and their families in the form of psychological support, different types of massage
therapy, relaxation/meditation, stress management and education/information, with some
emphasis on music therapy.74 Also under construction is the Olivia Newton-John Cancer
and Wellness Centre, which is based at Austin Hospital in Heidelberg, Victoria. The
centre’s “wellness” therapies and support services will complement the centre’s mainstream
medical care and treatment, and collaborative research into new anticancer treatments with
the US Ludwig Institute for Cancer Research.75
205
Integrating Complementary Medicine into Mainstream Cancer Care: Bridging the
Gap Between Patients and Doctors and Making the Move from CAM Toward
Integrative Oncology
Integrative cancer care or oncology is a patient-centred approach that nurtures the physical,
emotional and spiritual well-being of cancer patients by integrating safe, evidence-based
complementary therapies with conventional anticancer treatments, using a multidisciplinary
approach that assesses and treats the patient as a whole rather than addressing their disease
alone. Complementary therapies used by cancer patients are diverse in their origin, premise,
practice, efficacy and safety. In Australia, CAMs may be categorised by the Therapeutic
Goods Administration (TGA) as registered (prescribed or non-prescribed medications
which meet Australian standards of quality, safety and efficacy) or listed (low risk products
that are not routinely evaluated with respect to a manufacturer’s claims before marketing,
but are subject to a random audit after listing).76 Listed medicines consist almost entirely of
CAMs, which implies that they are produced according to appropriate standards for quality
and safety but guarantees nothing in regard to their efficacy. Cancer patients and other
members of the public are mostly unaware of such distinctions and may believe that a
complementary (or alternative) medicine listed by the TGA has been assessed as both
effective and safe and approved for use by the Federal Government. Additionally, many
complementary therapies have long histories as components of ancient traditional medical
practices, but have only been subjected to rigorous scientific investigation in the last 10-20
years. More research is required to evaluate or confirm the efficacy and safety of many of
these therapies.
As stated previously, evidence from high quality cancer clinical trials indicates that some
complementary therapies, used as adjuncts to conventional medical treatments, are
beneficial in reducing disease or treatment symptoms and improving QoL and
psychological functioning.6,51,58,64-66 There is evidence of potential harm also (Tables 3 and
4). Herbal medicines, nutritional supplements and other natural therapies may pose direct
safety risks because of their potential adverse effects or interactions with conventional
anticancer treatments (chemotherapy, radiotherapy, surgery, hormonal therapies) and other
medications. Some should not be used under any circumstances irrespective of potential
benefit (e.g. St. John’s wort), while others may be beneficial when cancer patients are not
undergoing these treatments and have no other contraindications.
206
It is therefore imperative that those involved in the medical care of cancer patients are
equipped with the skills and knowledge to help patients appropriately evaluate CAMs, in
order to receive benefit while avoiding harm. Unfortunately, most physicians have limited
knowledge of the safety and efficacy of specific complementary and alternative therapies
and have not had any formal training in the CAM area.77-80 Furthermore, few oncology
health professionals feel comfortable discussing CAM, and are concerned that they cannot
effectively communicate with patients or have the skills to help them maintain hope.81-84
Surveys indicate that clinicians desire greater access to evidence-based CAM information,
to improve the quality of their care, and to enhance communication with patients.85,86 Due
to safety risks associated with CAM, clinicians are strongly encouraged to routinely ask
patients about complementary and alternative therapy use.
Several recommended approaches for discussing CAM with cancer patients have been
published,87-94 including a set of communication guidelines.95 These approaches and
guidelines to effective communication generally involve: (1) eliciting the patient’s
perspective of his or her illness; (2) being open-minded/non-judgmental and respectful in
regard to cultural and linguistic diversity and different belief systems; (3) asking patients
questions about CAM use at critical points in their cancer experience; (4) actively listening
to patients and responding to their emotional state in exploring the details of CAM use or
motivations to use it; (5) discussing relevant concerns while respecting the patient’s beliefs
and emphasising that “natural” does not necessarily equate with safety in explaining known
safety risks; (6) providing patients with balanced, evidence-based information and advice
about specific complementary and alternative therapies; and (7) providing close clinical
follow-up and psychological support of patients using CAM, even if they choose therapies
which their clinician disagrees with.
Conclusion
Complementary therapies or CAM, as they are commonly referred to by patients and
clinicians, are much sought after by Australian cancer patients as a means of coping with
the physical and emotional impact of their disease and/or treatment. Irrespective of whether
doctors like them or believe in them, patients will use them. If physicians in the medical
profession are to provide cancer patients with the best care and advice possible, then they
cannot ignore this sign of the times.
207
Whether termed integrative cancer care or complementary medicine, cancer physicians in
Australia should strongly consider offering evidence-based complementary therapies (or at
least safe forms of them) alongside conventional treatments through their own cancer
services.72 Conceivably, this will influence patients to continue with mainstream care and
help them avoid any potential harm that may occur with autonomous CAM use. In this
way, optimal holistic care will be ensured for cancer patients by clinicians providing
conventional oncology treatment and care.
Acknowledgements
I would like to thank Professor Ian Olver (Guest Editor), Professor Peter Drummond and
Mr Paul Katris for their comments on an early draft of this article.
References
1. National Center for Complementary and Alternative Medicine (NCCAM) [Internet].
CAM basics: what is CAM? Bethesda: NCCAM; 2009 [cited 2009 July 28].
Available from: http://nccam.nih.gov/health/whatiscam/D347.pdf.
2. Cassileth BR. Complementary and alternative cancer medicine. J Clin Oncol.
1999;17:44-52.
3. Cancer Council New South Wales (NSW). Understanding complementary
therapies: a guide for people with cancer, their families and friends. 2nd ed.
Woolloomooloo: Cancer Council NSW; 2009. 117 p.
4. Deng G, Cassileth BR, Yeung KS. Complementary therapies for cancer-related
symptoms. J Support Oncol. 2004;2:419-26.
5. Cassileth BR, Deng G. Complementary and alternative therapies for cancer.
Oncologist. 2004; 9(1):80-9.
6. Deng GE, Frenkel M, Cohen L, Cassileth BR, Abrams DI, Capodice JL, Courneya
KS, Dryden T, Hanser S, Kumar N, Labriola D, Wardell DW, Sagar S; Society for
Integrative Oncology. Evidence-based clinical practice guidelines for integrative
oncology: complementary therapies and botanicals. J Soc Integr Oncol.
2009;7(3):85-120.
7. National Prescribing Service (NPS) [Internet]. NPS National consumer survey no.
5. Sydney: NPS; 2005 [cited 2010 Jan 22]. Available from:
http://www.nps.org.au/__data/assets/pdf_file/0009/26874/cons_survey_5_exec.pdf.
208
8. Australian Bureau of Statistics (ABS) [Internet]. Australian Social Trends 1998.
Canberra: ABS; 1998 [cited 2009 Jul 28]. Available from:
http://www.abs.gov.au/AUSSTATS/[email protected]/DetailsPage/4102.01998?OpenDocu
ment.
9. Xue CC, Zhang AL, Lin V, Da Costa C, Story DF. Complementary and alternative
medicine use in Australia: a national population-based survey. J Altern Complement
Med. 2007;13(6):643-50.
10. Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in
cancer. Cancer. 1998;83:777-82.
11. Yates JS, Mustian KM, Morrow GR, Gillies LJ, Padmanaban D, Atkins JN, Issell
B, Kirshner JJ, Colman LK. Prevalence of complementary and alternative medicine
use in cancer patients during treatment. Support Care Cancer. 2005;13(10):806-11.
12. Datamonitor [Internet]. Complementary and alternative medicines in cancer.
Publication BFHC0462. New York: Datamonitor; 2002 Jun 30 [cited 2010 Jan 22].
Available from: http://tinyurl.com/39jad78.
13. Sibbritt D, Adams J, Easthope G, Young A. Complementary and alternative
medicine (CAM) use among elderly Australian women who have cancer. Support
Care Cancer. 2003;11(8):548-50.
14. Oh B, Butow P, Mullan B, Clarke S, Tattersall M, Boyer M, Beale P, Vardy J,
Pavlakis N, Larke L. Patient-doctor communication: use of complementary and
alternative medicine by adult patients with cancer. J Soc Integr Oncol.
2010;8(2):56-64.
15. Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, Margulies
A, Browall M, Magri M, Selvekerova S, Madsen E, Milovics L, Bruyns I,
Gudmundsdottir G, Hummerston S, Ahmad AM, Platin N, Kearney N, Patiraki E.
Use of complementary and alternative medicine in cancer patients: a European
survey. Ann Oncol. 2005;16(4):655-63.
16. Pirri C, Katris P, Trotter J, Bayliss E, Bennett R, Drummond P. Use of
complementary and alternative therapies by Australian cancer patients. Asia-Pacific
J Clin Oncol. 2008;4(3):161-9.
17. Burstein HJ, Gelber S, Guadagnoli E, Weeks JC. Use of alternative medicine by
women with early-stage breast cancer. N Engl J Med. 1999;340:1733-9.
209
18. Girgis A, Adams J, Sibbritt D. The use of complementary and alternative therapies
by patients with cancer. Oncol Res. 2005;15:281-9.
19. Verhoef MJ, Balneaves LG, Boon HS, Vroegindewey A. Reasons for and
characteristics associated with complementary and alternative medicine use among
adult cancer patients: a systematic review. Integr Cancer Ther. 2005;4(4):274-86.
20. Begbie SD, Kerestes ZL, Bell DR. Patterns of alternative medicine use by cancer
patients. Med J Aust. 1996;165(10):545-8.
21. Miller M, Boyer MJ, Butow PN, Gattellari M, Dunn SM, Childs A. The use of
unproven methods of treatment by cancer patients: frequency, expectations and cost.
Support Care Cancer. 1998;6:337-47.
22. Yates PM, Beadle G, Clavarino A, Najman JM, Thomson D, Williams G, Kenny L,
Roberts S, Mason B, Schlect D. Patients with terminal cancer who use alternative
therapies: their beliefs and practices. Sociol Health Illn. 1993;15(2):199-216.
23. Sawyer MG, Gannoni AF, Toogood IR, Antoniou G, Rice M. The use of alternative
therapies by children with cancer. Med J Aust. 1994;160:320-2
24. Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE.
Complementary/alternative medicine use in a comprehensive cancer center and the
implications for oncology. J Clin Oncol. 2000;18(13):2505-14.
25. Boon H., Stewart M, Kennard MA, Gray R, Sawka C, Brown JB, McWilliam C,
Gavin A, Baron RA, Aaron D, Haines-Kamka T. Use of complementary/alternative
medicine by breast cancer survivors in Ontario: prevalence and perceptions. J Clin
Oncol. 2000;18(13):2515-21.
26. Correa-Velez I, Clavarino A, Barnett AG, Eastwood H. Use of complementary and
alternative medicine and quality of life: changes at the end of life. Palliat Med.
2003;17(8):695-703.
27. Correa-Velez I, Clavarino A, Eastwood H. Surviving, relieving, repairing, and
boosting up: reasons for using complementary/alternative medicine among patients
with advanced cancer: a thematic analysis. Palliat Med. 2005;8(5):953-61.
28. Boon H, Brown JB, Gavin A, Kennard MA, Stewart M. Breast cancer survivors'
perceptions of complementary/alternative medicine (CAM): making the decision to
use or not to use. Qual Health Res. 1999;9(5):639-53.
210
29. Sparber A, Bauer L, Curt G, Eisenberg D, Levin T, Parks S, Steinberg SM, Wootton
J. Use of complementary medicine by adult patients participating in cancer clinical
trials. Oncol Nurs Forum. 2000;27(4):623-30.
30. Shen J, Andersen R, Albert PS, Wenger N, Glaspy J, Cole M, Shekelle P. Use of
complementary/alternative therapies by women with advanced-stage breast cancer.
BMC Complement Altern Med. 2002;2:8.
31. Harris P, Finlay IG, Cook A, Thomas KJ, Hood K. Complementary and alternative
medicine use by patients with cancer in Wales: a cross sectional survey,
Complement Ther Med. 2003;11(4):249-53.
32. Scott JA, Kearney N, Hummerston S, Molassiotis A. Use of complementary and
alternative medicine in patients with cancer: a UK survey. Eur J Oncol Nurs.
2005;9(2):131-7.
33. Singh H, Maskarinec G, Shumay DM. Understanding the motivation for
conventional and complementary/alternative medicine use among men with prostate
cancer. Integr Cancer Ther. 2005;4(2):187-94.
34. Söllner W, Maislinger S, DeVries A, Steixner E, Rumpold G, Lukas P. Use of
complementary and alternative medicine by cancer patients is not associated with
perceived distress or poor compliance with standard treatment but with active
coping behavior: a survey. Cancer. 2000;89(4):873-80.
35. Boon H, Westlake K, Stewart M, Gray R, Fleshner N, Gavin A, Brown JB, Goel V.
Use of complementary/alternative medicine by men diagnosed with prostate cancer:
prevalence and characteristics. Urology. 2003;62(5):849-53.
36. Ohlén J, Balneaves LG, Bottorff JL, Brazier AS. The influence of significant others
in complementary and alternative medicine decisions by cancer patients. Soc Sci
Med. 2006;63(6):1625-36.
37. Evans M, Shaw A, Thompson EA, Falk S, Turton P, Thompson T, Sharp D.
Decisions to use complementary and alternative medicine (CAM) by male cancer
patients: information-seeking roles and types of evidence used. BMC Complement
2007;Altern Med. 7:25.
38. Bonevski B, Wilson A, Henry DA. An analysis of news media coverage of
complementary and alternative medicine. PLoS One. 2008;3(6):e2406.
211
39. Mercurio R, Eliott JA. Trick or treat? Australian newspaper portrayal of
complementary and alternative medicine for the treatment of cancer. Support Care
Cancer. Epub 2009 Nov 27. doi: 10.1007/s00520-009-0790-4.
40. Broom A, Tovey P. Therapeutic pluralism? Evidence, power and legitimacy in UK
cancer services. Sociol Health Illn. 2007;29(4):551-69.
41. Eng J, Ramsum D, Verhoef M, Guns E, Davison J, Gallagher R. A population-
based survey of complementary and alternative medicine use in men recently
diagnosed with prostate cancer, Integr Cancer Ther. 2005;2(3):212-6.
42. Hann D, Baker F, Denniston M, Entrekin N. Long-term breast cancer survivors' use
of complementary therapies: perceived impact on recovery and prevention of
recurrence. Integr Cancer Ther. 2005;4(1):14-20.
43. Ernst E. The role of complementary and alternative medicine in cancer, Lancet
Oncol. 2000;1:176-80.
44. Robinson A, McGrail MR. Disclosure of CAM use to medical practitioners: a
review of qualitative and quantitative studies. Complement Ther Med. 2004;12(2-
3):90-8.
45. Ernst E. A primer of complementary and alternative medicine commonly used by
cancer patients. Med J Aust. 2001;174: 88-92.
46. Schraub S. Unproven methods in cancer: a worldwide problem, Support Care
Cancer. 2000;8:10-5.
47. Risberg T, Lund E, Wist E, Kaasa S, Wilsgaard T. Cancer patients use of non-
proven therapy: a 5-year follow-up study. J Clin Oncol. 1998;16:6-12.
48. Ernst E. Complementary cancer treatments: hope or hazard? Clin Oncol (R Coll
Radiol). 1995;7(4):259-63.
49. Deng G, Cassileth BR. Integrative oncology: complementary therapies for pain,
anxiety, and mood disturbance. CA Cancer J Clin. 2005;55(2):109-16.
50. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults
with cancer: meta-analysis of 116 studies. Oncol Nurs Forum. 1995;22(9):1369-81.
51. Joske DJ, Rao A, Kristjanson L. Critical review of complementary therapies in
haemato-oncology. Intern Med J. 2006;36(9):579-86.
52. Newell SA, Sanson-Fisher RW, Savolainen NJ. Systematic review of psychological
therapies for cancer patients: overview and recommendations for future research. J
Natl Cancer Inst. 2002;94(8):558-84.
212
53. Seely D, Oneschuk D. Interactions of natural health products with biomedical
cancer treatments. Curr Oncol. 2008;15(Suppl 2):S81-6.
54. Eisenberg DM, Kessler RC, Van Rompay MI, Kaptchuk TJ, Wilkey SA, Appel S,
Davis RB. Perceptions about complementary therapies relative to conventional
therapies among adults who use both: results from a national survey. Ann Intern
Med. 2001;135(5):344-51.
55. Cassileth B, Yeung KS, Gubili J. Herbs and other botanicals in cancer patient care,
Curr Treat Options Oncol. 2008;9(2-3):109-16.
56. Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the
laboratory, animal, and human data for 8 common botanicals. Integr Cancer Ther.
2009;8(3):208-27.
57. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should
supplemental antioxidant administration be avoided during chemotherapy and
radiation therapy? J Natl Cancer Inst. 2008;100(11):773-83.
58. Pirri C. An evidence-based systematic review of complementary and alternative
medicine (CAM): recommendations concerning the efficacy and safety of CAM use
by adult cancer patients. In: Olver IO, Robotin MC, editors. Perspectives of
complementary and alternative medicines (CAMS). Sydney: Imperial College Press.
In press 2011.
59. Bagenal FS, Easton DF, Harris E, Chilvers CE, McElwain TJ. Survival of patients
with breast cancer attending Bristol Cancer Help Centre. Lancet.
1990;336(8715):606-10.
60. Cassileth BR, Lusk EJ, Guerry D, Blake AD, Walsh WP, Kascius L, Schultz DJ.
Survival and quality of life among patients receiving unproven as compared with
conventional cancer therapy. N Engl J Med. 1991;324(17):1180-5.
61. Robotin MC, Penman AG. Integrating complementary therapies into mainstream
cancer care: which way forward? Med J Aust. 2006;185(7):377-9.
62. Hlubocky FJ, Ratain MJ, Wen M, Daugherty CK. Complementary and alternative
medicine among advanced cancer patients enrolled on phase I trials: a study of
prognosis, quality of life, and preferences for decision making. J Clin Oncol.
2007;25(5):548-54.
213
63. Dy GK, Bekele L, Hanson LJ, Furth A, Mandrekar S, Sloan JA, Adjei AA.
Complementary and alternative medicine use by patients enrolled onto phase I
clinical trials. J Clin Oncol. 2004;22(23):4810-5.
64. Cassileth B, Heitzer M, Gubili J. Integrative oncology: complementary therapies in
cancer care. Cancer Chemother Rev. 2008;3(4):204-11.
65. Munshi A, Ni LH, Tiwana MS. Complementary and alternative medicine in present
day oncology care: promises and pitfalls. Jpn J Clin Oncol. 2008;38(8):512-20.
66. Lotfi-Jam K, Carey M, Jefford M, Schofield P, Charleson C, Aranda S.
Nonpharmacologic strategies for managing common chemotherapy adverse effects:
a systematic review. J Clin Oncol. 2008;26(34):5618-29.
67. Clinical Oncological Society of Australia (COSA) [Internet]. Complementary and
alternative medicine (CAM): setting an Australian research agenda. Surry Hills:
COSA; 2007 Nov [cited 2010 Jun 23]. Available from: http://tinyurl.com/34tepj7.
68. The National Institute of Complementary Medicine (NICM) [Internet].
Campbelltown: NICM; c2010 [cited 2010 Jun 24]. Available from:
http://www.nicm.edu.au/.
69. Association of American Medical Colleges. In: National Institute of
Complementary Medicine (NICM), editor. Facts and statistics. Campbelltown:
NICM; 2008 [updated 2009 Jan 22; cited 2010 Jun 24]. Available from:
http://www.nicm.edu.au/content/view/65/36/.
70. American Hospital Association (AHA) [Internet]. Latest survey shows more
hospitals offering complementary and alternative medicine services. Washington:
AHA; 2008 Sep 15 [cited 2010 Jun 25]. Available from:
http://www.aha.org/aha/press-release/2008/080915-pr-cam.html.
71. Bulsara C, Ward A, Joske D. Haematological cancer patients: achieving a sense of
empowerment by use of strategies to control illness. J Clin Nurs. 2004;13(2):251-8.
72. Lowenthal RM. Integrative oncology in Australia. J Soc Integr Oncol.
2006;4(2):82-5.
214
73. Joske DJL, Petterson AS, Phillips M. Psychosocial support: providing
complementary therapies for cancer patients in a WA teaching hospital, results from
SolarisCare’s eight years of experience. WA Cancer Research Symposium 2009:
Proceedings of the 3rd WA Cancer Research Symposium ― ‘Advancing Cancer
Research in WA’; 2009 Dec 3; Fremantle, Australia. West Perth: Cancer Council
Western Australia; 2009 [cited 2010 Jan 15]. Available from:
http://solariscare.org.au/cache/fcfd78c2f4fe0d4162021957e7952b87/CCOF_WA_R
esearch_Symposium_Psychosocial_Support.pdf.
74. O'Callaghan C, McDermott F. Music therapy's relevance in a cancer hospital
researched through a constructivist lens. J Music Ther. 2004;41(2):151-85.
75. The Olivia-Newton John Cancer Centre [Internet]. Heidelberg: Austin Health;
c2004 [cited 2010 Jun 24]. Available from:
http://www.oliviaappeal.com/help/default.asp.
76. McEwen J. What does TGA approval of medicines mean? Aust Prescriber.
2004;27:156-8.
77. Newell S, Sanson-Fisher RW. Australian oncologists' self-reported knowledge and
attitudes about non-traditional therapies used by cancer patients. Med J Aust.
2000;172(3):110-3.
78. Crocetti E, Crotti N, Montella M, Musso M. Complementary medicine and
oncologists’ attitudes: a survey in Italy. Tumori. 1996;82:539-42.
79. Bourgeault IL. Physicians’ attitudes towards patients’ use of alternative cancer
therapies. Can Med Assoc J. 1996;155:1679-85.
80. Giveon SM, Liberman N, Klang S, Kahan E. A survey of primary care physicians’
perceptions of their patients’ use of complementary medicine. Complement Ther
Med. 2003;11:254-60.
81. Tasaki K, Maskarinec G, Shumay DM, Tatsumura Y, Kakai H. Communication
between physicians and cancer patients about complementary and alternative
medicine: exploring patients' perspectives. Psychooncology. 2002;11(3): 212-20.
82. Adler SR, Fosket JR. Disclosing complementary and alternativemedicine use in the
medical encounter: a qualitative study in women with breast cancer. J Fam Pract.
1999;48:453-8.
215
83. Hann DM, Baker F, Denniston MM. Oncology professionals' communication with
cancer patients about complementary therapy: a survey. Complement Ther Med.
2003;11(3):184-90.
84. Roberts C, Benjamin H, Chen L, Gavigan M, Gesme D, McCarthy P, Samuels R,
Baile W. Assessing communication between oncology professionals and their
patients. J Cancer Educ. 2005;20(2):113-8.
85. Angell M, Kassirer JP. Alternative medicine―the risks of untested and unregulated
remedies. N Engl J Med. 1998;339(12):839-41.
86. Studdert DM, Eisenberg DM, Miller FH, Curto DA, Kaptchuk TJ, Brennan TA.
Medical malpractice implications of alternative medicine, JAMA.
1998;280(18):1610-5.
87. Weiger WA, Smith M, Boon H, Richardson MA, Kaptchuk TJ, Eisenberg DM.
Advising patients who seek complementary and alternative medical therapies for
cancer. Ann Intern Med. 2002;137(11):889-903.
88. Eisenberg D. Advising patients who seek alternative and complementary medical
therapies. Annal Intern Med. 1997;127:61-9.
89. Epstein RM, Street RL Jr. Patient-centered communication in cancer care:
promoting healing and reducing suffering. NIH Publication No. 07-6225. Bethesda:
National Cancer Institute; 2007 [cited 2010 Jun 24]. Available from:
http://outcomes.cancer.gov/areas/pcc/communication/monograph.html.
90. Burstein H. Discussing complementary therapies with cancer patients: what should
we be talking about? J Clin Oncol. 2000;18:2501-4.
91. Zollman C, Vickers A. ABC of complementary medicine: complementary medicine
and the doctor. Br Med J. 1999;319:1558-61.
92. Mackenzie G, Parkinson M, Lakhani A, Pannekoek H. Issues that influence
patient/physician discussion of complementary therapies. Patient Educ Couns.
1999;38:155-9.
93. Frenkel M, Ben-Arye E, Baldwin CD, Sierpina V. Approach to communicating with
patients about the use of nutritional supplements in cancer care. South Med J.
2005;98:289-94.
94. Steyer TE. Complementary and alternative medicine: a primer, Fam Pract Manag.
2001;8(3):37-42.
216
95. Schofield P, Diggens J, Charleson C, Marigliani R, Jefford M. Effectively
discussing complementary and alternative medicine in a conventional oncology
setting: communication recommendations for clinicians. Patient Educ Couns.
2010;79(2):143-51.
96. O'Beirne M, Verhoef M, Paluck E, Herbert C. Complementary therapy use by
cancer patients. Physicians' perceptions, attitudes, and ideas. Can Fam Physician.
2004;50:882-8.
217
Appendix A: Methodology (Study 1)
Appendix A contains a superseded methodology chapter (sans a reference list) written in
thesis quality. It is only included for interested readers who seek more extensive
methodological detail than the study 1 manuscript provides in chapter 2.
218
CHAPTER 6
6 METHODOLOGY
6.1 Ethics Approval
This study was approved by the ethics committees of Royal Perth Hospital and Murdoch
University, and was conducted in compliance with National Health and Medical Research
Council (NHMRC) guidelines for human research (NHMRC, 1999).
6.2 Patients
The study participants consisted of a heterogeneous group of 200 Western Australian adult
cancer patients attending a medical oncology outpatient clinic. All patients provided
voluntary written and informed consent and, at the time of recruitment, were awaiting the
commencement of chemotherapy or radiation therapy as part of individualised cancer
treatment.
6.3 Setting
All participants attended the Medical Oncology outpatient clinic at Royal Perth Hospital in
Perth, Western Australia between September 1997 and December 2002. At the clinic, four
consultant oncologists, two registrars, and two chemotherapy nurses dealt with 200-250
outpatients per week. Every six months registrars in the clinic were usually replaced as part
of regular rotations in their medical training. Of the outpatients seen each week,
approximately 5-10 patients were new presentations to the clinic, two thirds comprised
regular follow-up visits related to ongoing cancer treatment, and the remainder attended
review appointments for check-ups having completed treatment previously. In a year, over
4000 chemotherapy administrations were delivered to patients and a further 800 procedures
performed.
6.4 Eligibility Criteria
Patients were eligible for this study if they met the following criteria–
Age: Adults were aged 18 years or over.
Health Insurance Coverage: Public and private health care cancer patients alike attended
Royal Perth Hospital and were accepted for study participation.
219
Diagnosis: Only patients with a formal cancer diagnosis via histological or cytological
confirmation of disease were eligible for the study.
Disease History/Status: Patients were not excluded from study participation on the basis of
disease history or status (for example, if they had been previously diagnosed with cancer or
had a current diagnosis of metastatic cancer).
Prognosis: Patients were not excluded from study participation on the basis of poor
prognosis except on the advice of the attending medical oncologist.
Cancer Treatment: Patients were excluded if they had received prior cancer treatment
(except surgery) for their current episode of cancer. Surgery was the exception as it was
deemed too difficult to make contact with patients in the short intervals that frequently
separated diagnosis and surgery. Additionally, any impairment in psychosocial adjustment
or QOL observed at this point may have represented a normal and transient response of
individuals to the bad news of diagnosis, rather than the existence of clinically-relevant
cancer- or treatment-related problems with the potential for far-reaching effects. Patients
were also excluded if they were not planned for chemotherapy; if treatment was not
planned to last at least 8 weeks; or if cancer treatment was not overseen by Royal Perth
Hospital for the entire duration.
Literacy: Patients were required to understand spoken English and read and write English
sufficiently to provide written informed consent and answer open-ended items in
questionnaires. The ability to speak fluent English was not essential for study participation
provided reading and writing levels were adequate.
Psychopathology/Medical Condition: Patients with significant psychopathology or
cognitive impairment were excluded if their condition was severe enough to prevent them
providing rational and coherent written responses in the questionnaires. Such individuals,
including those experiencing senile and other dementing states, were excluded on the basis
of information provided by attending medical staff or because of behaviours identified
during the study by the author, a clinical psychologist registrar. Also, patients who were
unwell or had physical impairment impeding the completion of questionnaires were
220
assisted by the author, who asked questions verbally and transcribed responses, as
appropriate.
6.5 Patient Recruitment
Using the eligibility criteria described, participants were actively recruited from a
sequential series of cancer patients attending the Medical Oncology clinic at Royal Perth
Hospital between August 1997 and June 1999. All patients received chemotherapy and
many underwent other treatment modalities also.
Four consultant medical oncologists and twelve registrars were involved in the course of
the study. Each were verbally briefed and provided with a written summary outlining the
study and their role. The primary role of the medical oncologists was to complete QOL
rating and medical data forms for both experimental and control patients when required
(see Appendix B). Additionally, if time permitted, they were encouraged to introduce the
study to prospective patients in consultations immediately prior to the initiation of
treatment, and then to direct patients to the author for further explanation and elicitation of
informed consent. The physicians were instructed not to discuss any details regarding
research methods with patients and to direct any related enquiries to the author.
The author’s role was one of a full-time research assistant. For the bulk of the study, he
worked in that capacity as a member of staff at the Department of Medical Oncology,
Royal Perth Hospital. Identification of potential study participants was the responsibility of
the author, who consulted outpatient appointment and medical oncology inpatient lists,
medical oncologists and other staff, and medical records to ascertain patient eligibility.
Prospective participants were approached about the study by the author as close to the
initiation of cancer treatment as possible, either at the Medical Oncology clinic or on
hospital wards if they were inpatients. Each patient was explained the study, given a study
information sheet to read to help decide about participation, and was given the opportunity
to ask questions. If patients agreed to proceed with the study, they were asked to complete a
consent form, which was signed and dated by the author also, and patients were allocated
an identifying participant number. Alternatively, if patients declined to participate, they
were asked the reason why so that it could be recorded for research purposes, and were
subsequently assigned as a control participant with an identifying number.
221
6.6 Design
The study employed a prospective, longitudinal, observational design (see Figure A1 for a
graphical overview of the study). All experimental patients were assessed at four times,
pretreatment (baseline), on-treatment (8 weeks into treatment), post-treatment, and follow-
up (6 months), using a number of repeated measures administered to patients and their
medical oncologists (see Table A1). To examine sample bias, physician ratings of QOL and
physical health were gathered for control participants at these times also, in addition to
demographic data.
At the pretreatment assessment, all patients had received a formal diagnosis of cancer and
were waiting to begin chemotherapy and/or radiation therapy. Most patients completed the
pretreatment assessment on the day of starting chemotherapy or radiation therapy. The
on-treatment assessment was undertaken 8 weeks after the start of chemotherapy or
radiation therapy, allowing for a leeway of 1 week. The post-treatment assessment occurred
at the end of cancer treatment (excluding hormone therapy), with a 1 week leeway. The
majority of patients completed the post-treatment assessment on their final day of cancer
treatment. The follow-up assessment was conducted 6 months after the termination of
treatment, with a 1 week leeway. Physician assessments of the patients were completed
concurrently at these times, almost without failure. All patients completed the pretreatment
assessment in the presence of the author at the Medical Oncology clinic to ensure that
questionnaires were understood and that assistance could be given if required. On
subsequent assessments, patients completed questionnaires, whenever possible, during
appointments at the Medical Oncology clinic. When circumstances prevented this, patients
were permitted to take questionnaires home, and were reminded to complete them
independently and to read the instructions in bold type before each section. Patients were
asked to return the questionnaires at their next appointment if it was within 1-2 weeks, or
via post using a supplied reply-paid envelope if it was longer than 2 weeks.
222
Figure A1 Study overview
6.7 Assessment Measures
6.7.1 Demographic and Disease- and Treatment-related Variables
Data concerning demographics (age, sex, nationality, current employment status, level of
education) and disease- and treatment-related variables (previous cancer history, primary
diagnosis, treatment intent, types of treatment received) was collected from multiple
sources, including patients, oncologists and medical records, for all patients approached to
participate in the study.
6.7.2 Questionnaires
Patients were administered questionnaires primarily comprising standardised instruments
assessing psychosocial distress and health-related quality of life (QOL; see Table A1).
Patient Population Stratification Assessment
200 medical oncology outpatients with confirmed malignancy, starting
chemotherapy or radiation therapy Pretreatment
♦ 18+ years of age ♦
Gender: male/female On-treatment
(8 weeks) ♦ Treatment duration ≥ 2 months ♦
Age: 18-49 yrs; 50+ yrs Post-treatment
♦ No prior treatment (except ♦
Treatment: combination of
surgery) for current cancer episode
Follow-up ♦ Sufficient English literacy – surgery (6 months)
– chemotherapy
♦ Voluntary participation and – radiotherapy
written informed consent
Q Q
U U
E E
SS
T T
I I
O O
N N
N N
A A
I I
R R
E E
SS
223
Short forms of instruments were used where available and psychometrically prudent to ease
the burden on patients of completing lengthy questionnaires. Individual components of the
100-item assessment battery (see Appendix B) are discussed below.
6.7.2.1 The European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire– Core 30 [EORTC QLQ-C30] Version 2.0 (Aaronson et
al, 1993; Osoba, Aaronson, Zee, Sprangers & te Velde, 1997a)
The EORTC QLQ-C30 is a self-administered, cancer-specific, multidimensional measure
of QOL, designed for cross-cultural use in clinical trials (Aaronson et al, 1993). It assesses
core QOL domains relevant across a wide range of cancer sites and treatments, and is
complemented by modules specific to particular types of cancer (e.g. breast, lung, ovarian).
In the present study, the QLQ-C30 was used as the primary measure of QOL. Additionally,
its psychosocial scales, Emotional, Cognitive, Role and Social Functioning, served as
secondary measures of psychosocial distress, and Emotional Functioning was used as a
validation check for depression and cancer-specific distress assessed by dedicated
instruments described below. The QLQ-C30 Version 2.0 contains 30 items, 24 of which are
arranged into 9 multi-item scales, representing various aspects or dimensions of QOL: five
functional scales, Physical (PF), Role (RF), Emotional (EF), Cognitive (CF), and Social
(SF); three symptom scales, Fatigue (FA), Nausea and Vomiting (NV) and Pain (PA); and a
Global Health Status/QOL scale. The remaining items correspond to six single-item scales
assessing other common cancer symptoms (for example, sleep disturbance, appetite loss)
and the perceived financial impact of disease and treatment. The QLQ-C30 takes
approximately 11 minutes to complete (Aaronson et al, 1993). Literacy requirements for
respondents are modest (Sharp et al, 1999) and mode of administration (self-administration
versus interview) has a negligible effect on score distributions (Aaronson et al, 1993).
At each assessment time, patients completed a modified version of the QLQ-C30
comprising 38 items. Items were rated for the preceding 7 days using dichotomous scales
(yes/no) for the PF items and 4-point Likert scales (1 = "not at all", 2 = "a little", 3 = "quite
a bit", 4 = "very much”) for the remaining items. The content of the modified QLQ-C30 is
described in more detail below.
224
Table A1 Assessment instruments used in the present study
Instrument [no. of items]
Target Group
Description Scoring
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire– Core 30 (EORTC QLQ-C30) [38 items]
Cancer patients
Self-report measure. Assesses QOL domains. Uses dichotomous and 4-point Likert scales. 5 Functional scales 3 Symptom scales 6 Single-item scales 1 Global Health Status/QOL scale (replaced by the QOL Uniscale and GH Uniscale) * 4 items replaced; 4 items and 1 symptom scale added
Range = 0-100
Higher scores =
better functioning OR
more severe symptomatology
Quality of Life (QOL) Uniscale [1 item]
Cancer patients
Self-report measure of global quality of life. Used a modified 10-point Likert/visual analogue scale.
Range = 1-10 Higher scores = better global quality of life
Global Health (GH) Uniscale [1 item]
Cancer patients
Self-report measure of overall physical health. Used a modified 10-point Likert/visual analogue scale.
Range = 1-10 Higher scores = better overall physical health
Beck Depression Inventory– Short Form (BDI-SF) [13 items]
Medical patients
Self-report measure assessing cognitive-affective depression. BDI somatic items removed. Uses 4-point Likert scales.
Range = 0-39 Higher scores = greater depressive symptomatology
Impact of Event Scale– Intrusion (IES-I) [7 items]
Traumatised populations
Self-report measure. Assesses cognitive-emotional distress related to a specific stressor. Uses 4-point Likert scales.
Range = 0-35 Higher scores = greater distress
Eysenck Personality Questionnaire Revised Short Scale– Neuroticism (EPQRS-N) [12 items]
General population–adults
Self-report measure of neuroticism. Items are dichotomous (yes/no).
Range = 0-12 Higher scores = higher levels of neuroticism
Psychological Adjustment to Illness Scale (Self-Report)– Vocational Environment (PAIS-VE) [6 items]
Medical populations including cancer patients
Self-report measure. Assesses the vocational impact of medical illness including satisfaction with job and work performance. Uses 4-point scales.
Range = 0-18 Higher scores = poorer overall vocational adjustment
Marital Communication Problems Scale (MCPS) [4 items]
Cancer patients
Self-report measure. Assesses couple communication. Uses 4-point scales.
Range = 1-4 Higher scores = poorer couple communication
Qualitative Items [4 items]
Cancer patients
Open-ended, self-report measure probing cancer-related problems and use of non-traditional therapies.
Not applicable
225
Global Health Status/QOL (2 items): This scale was omitted and replaced by the Global
Health Uniscale and the Quality of Life Uniscale (see sections 6.7.2.2 and 6.7.2.3).
Functional Scales
Physical Functioning (8 items): This scale evaluated whether patients were capable of
undertaking physical activities ranging from the fundamental (for example, eating,
washing, dressing) to the strenuous (for example, taking long walks, lifting heavy objects).
Three items were appended. One concerned the extent to which patients were forced
indoors by illness and another asked if they had felt ill overall. The third item was
positively worded and asked how well they physically felt.
Role Functioning (2 items): This scale assessed whether any limitations had been imposed
on patients’ work or leisure activities by cancer and its treatment.
Emotional Functioning (6 items): This domain examined the psychological impact of
cancer and its treatment on patients in terms of depression, anxiety and stress. Two items
pertaining to loneliness were appended for greater breadth.
Cognitive Functioning (2 items): These items probed any difficulties patients may have
encountered with memory and concentration in performing everyday tasks.
Social Functioning (2 items): This domain dealt with the impact that patients’ medical
condition or treatment had on family life and social activities.
Symptom Scales
Nausea and Vomiting (2 items): Asked patients if they had vomited or felt nauseated.
Pain (3 items): Evaluated the incidence of pain and its interference in daily activities. One
item was appended asking patients if any measures had been taken to achieve relief and
with what effect.
Fatigue (3 items): Assessed the incidence of fatigue and how much rest was needed. One
positively worded item regarding how energetic patients felt was also appended.
226
Sexual Functioning (3 items): This appended scale examined the impact of cancer and its
treatment on sexual interest and performance. Additionally, patients were asked whether
they had explored methods of sexual expression to complement or replace intercourse.
Single-Item Scales
Seven single-item scales focused on additional cancer symptoms. These included sleep
disturbance, appetite loss, alopecia, weight gain, weight loss, hot flushes, and skin changes.
It should be noted that all appended items were taken from standardised EORTC QLQ
disease-specific modules (Aaronson et al, 1987).
Raw scale scores of the QLQ-C30 were calculated by summing the ratings of each item and
dividing by the number of items (Fayers, Aaronson, Bjordal & Sullivan, 1997).
Subsequently, they were linearly transformed to scores ranging from 0 to 100 as specified
in the QLQ-C30 scoring manual (Fayers et al, 1997). Higher scores on the functional scales
represented better functioning and hence greater QOL. On the symptom and single-item
scales they indicated more frequent and/or severe symptom experience and hence lower
QOL. In the case of missing items within a scale, multivariate techniques were used to
estimate the most likely value given information about an individual patient’s previous
responses to the same item (Fayers et al, 1997).
A change of at least 10 points from one assessment time to another represented a clinically
significant change in patients’ QLQ-C30 scale scores. QOL researchers have held that the
clinical meaningfulness of an observed change in QOL scores should be judged via a
comparison to the minimal clinically important difference (MCID), which is defined as ‘the
smallest difference in score in the domain of interest which patients perceive as beneficial
and which would mandate, in the absence of troublesome side-effects and excessive cost, a
change in the patient's management.’ (Jaeschke, Singer & Guyatt, 1989, p408). Intuitively,
a MCID of 10 points, which represents a change of 10% on QLQ-C30 scales ranging from
0-100, is appealing. However, this criterion has been psychometrically determined by a
quantitative review of 14 collated QLQ-C30 studies that grouped patients according to
disease- and treatment-related variables (King, 1996), and a study that formally assessed
clinically significant changes in QOL as perceived by cancer patients (Osoba, Rodrigues,
227
Myles & Zee, 1998). Questionnaires examining QOL in other chronic illnesses have also
interpreted a change of at least 10 points to be clinically significant (Jaeschke et al, 1989;
Ware, Kosinski & Keller, 1994; Juniper et al, 1994).
It should be noted, however, that the MCID differs with context. In adjuvant treatment
settings, it may be defined as the smallest decrease in QOL that cancer patients will tolerate
to gain an increased chance of survival (Coates, 1993). Alternatively, for patients receiving
palliative treatment, it may be the smallest improvement in QOL due to say, relief from
dysphagia, despite other treatment side effects such as fatigue and alopecia.
Reliability
It has been established that a Cronbach’s alpha coefficient of at least 0.7 indicates
acceptable internal consistency for multi-item questionnaires (Cronbach, 1951; Nunnally,
1978). The internal consistency of the functional and symptom scales of the EORTC QLQ-
C30 (Version 2.0) has ranged from moderate to excellent (r = 0.55-0.90) across 6 studies
involving heterogeneous and homogenous cancer populations (Aaronson et al, 1993;
Ringdal & Ringdal, 1993; Bjordal, Kaasa & Mastekaasa, 1994; Fossa, 1994; Osoba, Zee,
Warr, Kaizer & Latreille, 1994; Osoba et al, 1997a). Scales that exhibited the most
consistently high internal reliability were Fatigue (r = 0.80-0.91), Emotional Functioning (r
= 0.73-0.85) and Pain (r = 0.70-0.85). Scales that most commonly yielded less than
satisfactory internal consistency were Cognitive Functioning (r = 0.56-0.73) and Nausea
and Vomiting (r = 0.55-0.84).
Similar results have been reported in more recent large-scale validation studies of the QLQ-
C30 (Version 2.0). In a general population study of 1965 Norwegian people, Pain and
Fatigue had the highest internal consistency (α > 0.85), whilst Cognitive Functioning (α =
0.65) and Nausea and Vomiting (α = 0.67) had the lowest (Hjermstad, Fayers, Bjordal &
Kaasa, 1998). In a study of 489 older African American and Caucasian primary care
patients, good internal consistency was demonstrated for all QLQ-C30 functional and
symptom scales (α ≥ 0.77) except Cognitive Functioning (r = 0.4-0.69) and Nausea and
Vomiting (α = 0.49-0.51; Ford, Havstad & Kart, 2001). Additionally, in a study of 2000
cancer patients, all QLQ-C30 scales except Cognitive and Role Functioning were reported
to have acceptable internal reliability (α > 0.7; Ringdal et al, 1999). In the current study, the
228
internal consistency of the QLQ-C30 functional and symptom scales ranged from moderate
to excellent (α = 0.65-0.91) across the four assessment times, with one exception. The
strongest scales were Role Functioning (α = 0.86-0.91) and Emotional Functioning (α =
0.86-0.90). Consistent with previous studies, Nausea and Vomiting (α = 0.53-0.78) was the
weakest scale, whilst Social Functioning (α = 0.66-0.76), Pain (α = 0.66-0.81) and the
appended Sexual Functioning scale (α = 0.65-0.89) narrowly failed to meet criterion at
various assessment times.
Few studies have examined the test-retest reliability of the QLQ-C30. In one study of 190
cancer outpatients with stable disease, 4 day test-retest reliability was high for all QLQ-C30
functional scales (r = 0.82-0.91); good for the symptom scales (r > 0.8) with one exception,
Nausea and Vomiting (r = 0.63); and satisfactory to good for the single-item scales (r =
0.72-0.84; Hjermstad, Fossa, Bjordal & Kaasa, 1995). In another study of 102 cancer
inpatients, test-retest reliability coefficients were high for all the QLQ-C30 scales (r = 0.78-
0.95) for an interval ranging from 1.5-5.0 hours (Velikova et al, 1999). Finally, satisfactory
test-retest reliability (r > 0.7) of the QLQ-C30 scales was reported for 105 newly-diagnosed
or recurrent malignant glioma patients with a retest interval of several weeks (Osoba et al,
1997b).
Validity
Studies employing factor analysis and multitrait scaling have supported the construct
validity of the QLQ-C30. In the original validation study by Aaronson and colleagues
(1993) involving 305 inoperable lung cancer patients in 13 countries, the QLQ-C30 scales,
in general, exhibited moderate intercorrelations before and during treatment, thus indicating
that, although related, they assessed distinct components of the QOL construct. Factor
analysis demonstrated reasonably good agreement with the hypothesised factor structure of
the QLQ-C30 in a sample of 535 mixed cancer patients and subsamples of lung, breast, and
ovarian cancer patients (Osoba et al, 1994). In another study of 120 palliative care cancer
patients, an exploratory factor analysis of the QLQ-C30 yielded a 6-factor solution that
explained 77% of the total variance (Kyriaki, Eleni, Efi, Ourania, Vassilios & Lambros,
2001). Additionally, the QLQ-C30 scales exhibited low to moderate intercorrelations,
indicating that they measured distinctly separate QOL components (Kyriaki et al, 2001).
229
Related to construct validity are content and convergent validity. In one study of 171
newly-referred palliative care cancer patients, the QLQ-C30 exhibited good content validity
in covering 10 out of the 12 most common symptoms and problems recorded in their
medical records (Stromgren, Groenvold, Pedersen, Olsen & Sjogren, 2002). Several studies
have examined the convergent validity of the QLQ-C30 scales using Spearman correlation
coefficients. The statistical significance of a correlation coefficient may be gauged using
the following criteria: <0.3 negligible; 0.3-0.44 moderate; 045-0.60 substantial, and >0.60
high (Burnand, Kernan & Feinstein, 1990). In one study of 110 low-income, metastatic
prostate cancer patients, substantial to high convergent validity (r = 0.54-0.72) was found
for Emotional, Physical and Role Functioning, but not for Social Functioning (r = 0.12),
when compared to corresponding scales of the Functional Assessment of Cancer Therapy–
General (FACT-G) inventory (Sharp et al, 1999). Similar results have been found for
homologous or related subscales in studies comparing the QLQ-C30 and the Short Form-36
(breast and colorectal survivors, Apolone, Filiberti, Cifani, Ruggiata & Mosconi, 1998; 234
mixed cancer patients, Kuenstner, Langelotz, Budach, Possinger, Krause & Sezer, 2002),
the Functional Living Index Cancer questionnaire (98 mixed patients, King, Dobson &
Harnett, 1996; 200 mixed patients, Mercier, Bonneterre, Schraub, Lecomte & el Hasnaoui,
1998; Kuenstner et al, 2002), the General Health Questionnaire (126 head and neck cancer
patients, Bjordal & Kaasa, 1992; 96 mixed patients, Niezgoda & Pater, 1993), the McGill
Pain Questionnaire (96 mixed patients, Niezgoda & Pater, 1993), the Cancer Rehabilitation
Evaluation System (96 mixed patients, Niezgoda & Pater, 1993), and the Sickness Impact
Profile (96 mixed patients, Niezgoda & Pater, 1993). In another interesting study of 150
metastatic breast cancer patients participating in a randomised trial of supportive group
therapy, a correlation matrix of the psychosocial scales of the QLQ-C30 (Role, Social,
Emotional and Cognitive Functioning and Global Health Status/QOL) and other
psychosocial measures was constructed to evaluate convergent validity (McLachlan,
Devins & Goodwin, 1998). Substantial convergent validity was shown between Role
Functioning and the PAIS Vocational (r = 0.57) and Domestic Environment (r = 0.52)
subscales. Substantial to very high convergent validity was also demonstrated between
Emotional Functioning and PAIS Psychological Distress (r = 0.68); the Profile of Mood
States (POMS) total mood disturbance, tension and depression/dejection subscales (r >
0.74); the Mental Adjustment to Cancer anxious preoccupation subscale (r = 0.45); and
IES-I (r = 0.55).
230
The two essential features of a QOL instrument for use in longitudinal studies or clinical
trials are sensitivity to differences in clinical status (King, 2001), and responsiveness (i.e.
the ability to detect change in QOL across time) (Lohr et al, 1996). The QLQ-C30 has
generally shown good predictive validity in discriminating patient subgroups on the basis
of particular QOL dimensions. In the original validation study, Aaronson and colleagues
(1993) found that most of the functional and symptom scales of the QLQ-C30 clearly
distinguished between patients differing in performance status, weight loss and treatment
toxicity. Subsequent studies have examined a host of group variables in relation to the
QLQ-C30, including age (Klee, Groenvold & Machin, 1997; Hjermstad et al, 1998), sex
(Hjermstad et al, 1998), disease status (Hjermstad et al, 1998; Hammerlid & Taft, 2001),
primary cancer diagnosis (Osoba et al, 1994), prognosis (Ringdal, Ringdal, Kvinnsland &
Götestam, 1994), disease stage (de Boer et al, 1994; Osoba et al, 1994, 1997b; Montazeri et
al, 1999), performance status (de Boer, Sprangers, Aaronson, Lange & van Dam, 1994;
Osoba et al, 1994, 1997b; Wisloff et al, 1996; Kobayashi et al, 1998; Montazeri et al, 1999;
Bjordal et al, 2000; Kyriaki et al, 2001), response to treatment (Wisloff et al, 1996), and
disease progression (King, Dobson & Harnett, 1995). Ignoring the QLQ-C30 single-item
scales, Physical Functioning, Role Functioning and Fatigue have exhibited consistently
high predictive validity in discriminating between patients in these studies. Moderate to
good predictive validity has been demonstrated by Pain, Emotional Functioning and Social
Functioning, whilst Cognitive Functioning and Nausea and Vomiting exhibited the weakest
predictive validity.
The QLQ-C30 has shown generally good predictive validity in detecting changes in
patients’ QOL across time. In the original validation study, significant changes in the
expected direction were found with respect to four of the eight QLQ-C30 functional and
symptom scales (Physical and Role Functioning, Fatigue, Nausea and Vomiting) for lung
cancer patients whose performance status had improved or declined during chemotherapy
or radiation therapy (Aaronson et al, 1993). In a subsequent validation study of 535 mixed
cancer patients, significant deterioration was observed after 8 days of chemotherapy in
Physical, Role and Social Functioning, Global Health Status/QOL, Fatigue and Nausea and
Vomiting, relative to pretreatment (Osoba et al, 1994). Recent validation studies have
yielded more impressive results concerning the responsiveness of the QLQ-C30. In a study
of 232 newly-diagnosed and recurrent head and neck cancer patients, significant
231
deterioration was reported from pretreatment to post-treatment on all QLQ-C30 scales
except Emotional Functioning and two single-item scales (Bjordal et al, 2000). Finally, in a
study of 120 cancer patients receiving palliative treatment, significant improvements were
reported between pretreatment and 15 days on-treatment for all QLQ-C30 scales, with the
biggest changes observed in Physical and Role Functioning, Global Health Status/QOL,
Pain and Sleep Distrurbance (Kyriaki et al, 2001).
6.7.2.2 Global Health (GH) Uniscale (adapted from Aaronson et al, 1993)
The GH Uniscale is a single item, self-report measure of overall physical health for cancer
patients. In the present study, it served as a primary measure of QOL and as a validation
check for the Physical Functioning scale of the QLQ-C30. At each assessment time,
patients and their attending medical oncologists were asked to rate the patient’s physical
health for the preceding 7 days on a modified version of the Global Health Status item of
the EORTC QLQ-C30. The scale was converted from a 7-point Likert scale to a hybrid 10-
point Likert/visual analogue scale (1 = “extremely bad”, 10 = “extremely good”) to
improve validity, and appropriate changes in wording were made for the physicians’
version (see Appendix B). Higher scores indicated better overall physical health.
6.7.2.3 Quality of Life (QOL) Uniscale (adapted from Selby, Chapman,
Etazadi-Amoli, Dalley & Boyd, 1984; Herr, Kornblith, & Ofman, 1992)
The QOL Uniscale is a single-item, self-report measure of the overall effect of cancer and
its treatment on the QOL of a patient. In the present study, the QOL Uniscale was
employed as a primary measure of QOL. More specifically, it was utilised as a global index
of patients’ QOL that monitored change over time in response to cancer and its treatment.
At each assessment time, the scale was rated by patients and their attending medical
oncologists using a modified hybrid 10-point Likert/visual analogue scale designed to
enhance validity. For patients, the QOL Uniscale scale was anchored at its ends by the
statements, “My life is extremely unpleasant because of my state of health” (1) and “My
life is normal for me, with no change because of my state of health” (10). The wording was
appropriately modified in the physician’s version (see Appendix B). Higher scores
indicated better QOL.
232
Reliability
Satisfactory test-retest reliability has been reported for the QOL Uniscale in recurrent
disease (r = 0.72, 9-12 hours interval; Selby et al, 1984) and newly-diagnosed metastatic
prostate cancer patients (1 month interval, no significant differences from baseline; Herr et
al, 1992).
Validity
The QOL Uniscale has demonstrated very good predictive validity. In a study of a mixed
sample of 96 metastatic breast cancer and chemotherapy patients, patients’ QOL Uniscale
scores correlated highly with other QOL measures, including physicians’ QOL Uniscale
ratings (r > 0.7), Sickness Impact Profile total scores (r > 0.7), and Karnofsky Index scores
(r > 0.6) (Selby et al, 1984). Additionally, when compared to no-current-treatment control
patients, the QOL Uniscale was able to detect significant declines in clinical status over
time from one week to the next in mixed cancer patients receiving chemotherapy (Selby et
al, 1984), and at 6 months post-treatment in metastatic prostate cancer patients receiving
hormone therapy (Herr et al, 1992). These findings together with those of more recent
studies examining single-item cancer QOL scales (Hurny et al, 1996; Sloan et al, 1998;
Bernhard, Sullivan, Hurny, Coates & Rudenstam, 2001) support the use of the QOL
Uniscale in evaluating the impact that cancer and its treatment has on QOL over time for
patients.
6.7.2.4 Beck Depression Inventory– Short Form (BDI-SF) (Beck & Beck, 1972)
The Beck Depression Inventory is one of the most widely used measures of depression,
proving particularly useful as a screening tool in both psychiatric and non-psychiatric
populations (Beck & Steer, 1993). The short form of the BDI (BDI-SF) is an abridged, self-
administered 13-item self-report scale assessing the cognitive, affective and behavioural
symptoms of clinical depression to the exclusion of somatic symptoms manifested in
medical illness. The BDI-SF takes approximately 5 minutes to complete and respondents
require a grade 5-6 reading level (Groth-Marnat, 1990).
In the current study, the BDI-SF was used as a primary measure of psychosocial distress,
specifically assessing major depression amongst cancer patients. Patients completed the
BDI-SF embedded within the 21-item full form of the BDI (Beck, Ward, Mendelson,
233
Mock, & Erbaugh, 1961) to preserve construct validity (Berndt, 1979), and to allow
comparison of short form and full form scores. Patients were asked to endorse one or more
statements for each item on a 4-point Likert scale ranging from 0 (absence of symptom) to
3 (persistent or salient symptom) that best described how they had felt during the previous
week including the day of assessment. Total scores were calculated by summing the highest
responses for each item.
Depression levels were classified accordingly: (a) none/minor (0-4), (b) mild (5-7), (c)
moderate (8-15), and (d) severe (16-39) (Beck & Beck, 1972). A cut-off score ≥8
(moderate or severe depression) was used to identify cases of major depression at each
assessment time (Beck & Beck, 1972). This cut-off has been shown to maximise the
sensitivity (percentage of cases correctly identified compared to a diagnostic interview) and
specificity (percentage of non-cases correctly identified) of the BDI-SF with metastatic
cancer patients (Chochinov, Wilson, Enns & Lander, 1997) and other medical populations,
such as primary care patients (Volk, Pace & Parchman, 1993). A cut-off score of 5 has been
used in other studies (for example, Kissane, Bloch, Onghena, McKenzie, Snyder & Dowe,
1996; McGuire, Kiecolt-Glaser & Glaser, 2002), but was rejected for the present study out
of concern that it may be too sensitive for use with a physically ill sample such as cancer
patients and realise an unacceptable level of false positives.
One of the biggest problems in assessing depression in medical populations is that scores
are affected by the physical illness of patients. The BDI-SF circumvents this problem by
removing all somatic items from the revised full form without compromising reliability or
validity (Beck & Beck, 1972).
Reliability
In a meta-analytic study, internal consistency of the BDI full form was reported to range
from 0.73 to 0.92, with a mean Cronbach alpha coefficient of 0.86 in psychiatric
populations and 0.81 in non-psychiatric populations (Beck, Steer & Garbin, 1988).
Similarly results have been found for the BDI-SF (Groth-Marnat, 1990; Reynolds & Gould,
1981; Gould, 1983). In the present study, Cronbach alpha coefficients ranged from 0.74 to
0.84, indicating satisfactory to good internal consistency for the BDI-SF across the four
assessment times.
234
Correlations between the BDI-SF and the full form have ranged from 0.89 to 0.97 in
populations, including general medical outpatients and depressed inpatients (Beck, Rial &
Rickels, 1974), substance users (Reynolds & Gould, 1981) and university undergraduates
(Gould, 1983). Consequently, the short form is a highly acceptable substitute for the full
form. In regard to test-retest reliability, Beck and colleagues (1961) argued that meaningful
results could not be derived for the BDI because repeated administrations involving long
intervals would underestimate the reliability as a result of therapeutic changes or,
alternatively, overestimate it because of memory effects in the case of short intervals.
Nevertheless, many studies have estimated the test-retest reliability of the BDI full form (r
= 0.48-0.86) and have shown that it is dependent on the interval separating repeated
administrations and the composition of the sample (Beck, Steer & Garbin, 1988; Groth-
Marnat, 1990; Richter, Werner & Bastine, 1994). Given high alternate form reliability, the
test-retest reliability of the BDI-SF is likely to be influenced by similar factors, although
this line of investigation has unfortunately been ignored by researchers.
Validity
The construct validity of the BDI-SF is very good. Studies examining its factor structure
have consistently reported the presence of three underlying factors, negative self-esteem,
anergy and dysphoria, corresponding to the cognitive, behavioural and affective
components of depression (Reynolds & Gould, 1981; Foelker, Shewchuk & Niederehe,
1987; Leahy, 1992). High convergent validity (r = 0.6-0.8) has also been reported in
relation to other measures of depression, such as the Self-Rating Depression Scale,
Rosenberg Self-Esteem Scale and the UCLA Loneliness Scale for substance abuse and
university undergraduate samples (Reynolds & Gould, 1981; Gould, 1983), and to clinician
ratings for medical patients (Beck & Beck, 1972).
A meta-analysis of studies evaluating the psychometric properties of the BDI full form
found that in addition to high content validity, the inventory had very good predictive
validity in distinguishing between depressed and non-depressed individuals and detecting
change in clinical status over time (Richter, Werner, Heerlein, Kraus & Sauer, 1998).
Similar predictive validity has been demonstrated by the BDI-SF in studies discriminating
depressed metastatic cancer patients (Chochinov et al, 1995) and medical clinic outpatients
(Dreyfus, 1987) from non-depressed individuals, as well as controlled studies with
235
successful treatment outcomes involving depressed elderly outpatients (Scogin, Beutler,
Corbishley & Hamblin, 1988) and chronic pain patients (Plesh, Curtis, Levine & McCall,
2000). This augurs well for the BDI-SF’s ability to discriminate depressed from non-
depressed cancer patients in the current study.
6.7.2.5 Impact of Event Scale– Intrusion (IES-I) (Horowitz, Wilner & Alvarez,
1979)
The Impact of Event Scale (IES) is one of the most widely used cross-cultural measures of
post-traumatic stress symptoms (Joseph, 2000). It consists of two subscales, Intrusion and
Avoidance. The Intrusion subscale of the IES (IES-I) is a 7-item self-report scale measuring
cognitive-emotional distress in response to a specific stressor, defined as having cancer in
the present study. Intrusion was characterised by ‘unbidden thoughts and images, troubled
dreams, strong pangs or waves of feelings and repetitive behaviour’ (Horowitz et al, 1979,
p210). The IES-I takes 2-3 minutes to complete and respondents require a primary school
reading level.
In the current study, the IES-I was used as a primary measure of psychosocial distress,
chiefly assessing cancer-specific distress. It was also used to screen for post-traumatic
stress symptoms and post-traumatic stress disorder (PTSD). At each assessment time,
patients were asked to estimate the frequency of intrusive thoughts relating to having
cancer that occurred in the preceding week using a 4-point Likert scale (1 = "not at all", 2 =
“rarely”, 3 = “sometimes”, 4 = "often"). Modified scale values of 1-4 were used instead of
original scale values of 0, 1, 3 and 5 to facilitate uniformity with previous measures
completed by participants and thus avoid added burden or confusion. Total IES-I scores
were calculated by summing ratings converted to original scale values (0-5). Levels of
cognitive-emotional distress were classified accordingly: (a) low (0-8), (b) medium (9-19)
and (c) high (20-35) (Horowitz, 1982). A cut-off score ≥9 (medium or high cognitive
emotional distress) was used at each assessment time to identify cases of significant cancer-
specific distress that may have warranted further investigation.
In addition, levels of post-traumatic stress symptoms were classified accordingly: (a) sub-
clinical (0-3), (b) mild (4-11), (c) moderate (12-19), and (d) severe (20-35) (based on
Corneil, Beaton & Solomon, cited in Hutchings & Devilly, 2001). A cut-off score ≥12
236
(moderate or severe post-traumatic stress symptoms) was used to indicate instances of
significant post-traumatic stress symptoms and a cut-off score ≥20 signified probable
caseness for PTSD.
The IES has been utilised in the normal adult population (Briere & Elliott, 1998) and a
wide range of traumatised adult populations, including combat veterans (for example,
Pitman, Orr, Altman, Longpre, Poire & Macklin, 1996), sexual assault victims (for
example, Resick & Schynike, 1992), the bereaved (for example, Zilberg, Weiss &
Horowitz, 1982), motor vehicle accident survivors (for example, Bryant & Harvey, 1995),
and natural disaster survivors (for example, Carr, Lewin, Webster, Hazell, Kenaerdy &
Carter, 1995). The IES has also been widely used in clinical outcome studies involving
drug trials (for example, Davidson, Roth & Newman, 1991) and psychological therapies
(for example, relaxation training– Hossack & Bentall, 1996; behavioural therapy–
Richards, Lovell & Marks, 1994; time-limited psychotherapy– Ford, Greaves, Chandler,
Thacker, Sennhauser & Schwartz, 1997; eye movement desensitisation and reprocessing–
Grainger, Levin, Allyn-Byrd, Doctor & Lee, 1997).
In regard to cancer, the IES has been utilised with breast (for example, Wenzel et al, 1999;
Spiegel et al, 1999; Classen et al, 2001), prostate (Herr, Kornblith & Ofman, 1992;
Kornblith, Herr, Ofman, Scher & Holland, 1994), Hodgkin’s lymphoma (Cella & Tross,
1986; Cella, Mahon & Donovan, 1990), malignant melanoma (Kelly, Smithers, Swanson,
McLeod, Thomson & Walpole, 1995), and mixed cancer patients (Edgar, Rosberger &
Nowlis, 1992; Baider, Peretz & Kaplan De-Nour, 1992; Baider, Peretz, Hadani & Koch,
2001). Additionally, the IES has been used with individuals at increased risk of developing
breast (for example, Lerman, Seay, Balshem & Audrain, 1995; Thewes, Meiser & Hickie,
2001), prostate (Bratt et al, 2000), and bladder cancer (Hornsby, Sappington, Mongan,
Gullen, Bono & Altekruse, 1985).
Reliability
Internal consistency of the IES-I has ranged from 0.72 to 0.92, with a mean Cronbach alpha
coefficient of 0.86 for eighteen studies involving non-cancer populations (Sundin &
Horowitz, 2002). Good results have also been reported for cancer (α = 0.78; Wenzel et al,
1999) and at-risk populations (α = 0.88; Thewes et al, 2001). In the present study,
237
Cronbach alpha coefficients ranged from 0.82 to 0.87, indicating that the IES-I had good
levels of internal consistency across the four assessment times. The IES-I has also
demonstrated satisfactory to excellent test-retest reliability over short intervals (≤ 2 months)
for both traumatised (r = 0.89, Horowitz et al, 1979; r = 0.94, Weiss & Marmar, 1997) and
at-risk cancer populations (r = 0.89, Zakowski et al, 1997; r = 0.75, Thewes et al, 2001).
Validity
Two qualitative reviews of the psychometric properties of the IES have found adequate
support for the construct validity of the IES-I, albeit with a few notable exceptions (Joseph,
2000; Sundin & Horowitz, 2002). A number of studies have replicated the factor structure
of the IES-I across a variety of populations including sea disaster survivors (Joseph,
Williams, Yule & Walker, 1992; Joseph et al, 1993), bank hold-up victims (Hodgkinson &
Joseph, 1995), combat veterans (Shevlin, Hunt & Robbins, 2000), the bereaved (Zilberg et
al, 1982), malignant melanoma patients (Kelly et al, 1995), and women at-risk to breast
cancer (Thewes et al, 2001). A few studies, however, have found evidence of a second
intrusion factor characterised as sleep disturbance (Joseph, 2000; Amdur & Liberzon,
2001), but this may be due to differences in the factor analytic techniques employed
(Cordova, Studts, Hann, Jacobsen & Andrykowski, 2000).
Amongst specific measures of PTSD, the IES-I has demonstrated substantial to high
convergent validity in the normal population (Los Angeles Symptom Checklist- Intrusion, -
Avoidance, -Arousal; r = 0.68, 0.60, 0.61, respectively; Trauma Symptom Inventory-
Intrusive Experiences, -Defensive Avoidance, -Anxious Arousal; r = 0.67, 0.66, 0.49,
respectively; Briere & Elliott, 1988), combat veterans (PTSD Inventory, r = 0.79; Solomon
& Mikulincer, 1988; Mississippi Scale for Combat-Related PTSD, r = 0.56; Structured
Clinical Interview for DSM-II Revised, r = 0.49; McFall, Smith, Roszell, Tarver & Malas,
1990), mixed military/civilian samples (Structured Clinical Interview- Total, -Intensity; r
=0.75, 0.77, respectively; Minnesota Multiphasic Personality Inventory- PTSD, r = 0.76;
Neal, Busuttil, Rollins, Herepath, Strike & Turnbull, 1994). This suggests that the IES-I is a
valid measure of post-traumatic stress symptoms and may serve as a brief screening
instrument for PTSD, but cannot be used as a measure of PTSD per se, most notably
because it does not measure the hyperarousal symptoms of PTSD that have been included
in recent diagnostic criteria (American Psychiatric Association, 1994).
238
The IES-I has also exhibited moderate to substantial convergent validity in relation to
measures of generalised distress for a range of populations, including psychiatric patients
(General Health Questionnaire- Anxiety, -Depression; r = 0.53, 0.44, respectively; Spurrell
& McFarlane, 1995), nuclear accident survivors (Symptom Checklist-90 Revised- Anxiety,
-Depression; r = 0.54, 0.48, respectively; Davidson & Baum, 1986), malignant melanoma
patients (General Health Questionnaire- Anxiety, r = 0.43; Hospital Anxiety and
Depression Scale- Anxiety, r = 0.40; Kelly et al, 1995), and at-risk breast cancer patients
(State-Trait Anxiety Inventory- State, r = 0.24; General Health Questionnaire, r = 0.23;
BDI, r = 0.22; Thewes et al, 2001). Correlations between the IES-I and generalised distress
measures in these studies tended to be lower than correlations between the measures of
generalised distress themselves, suggesting that the IES-I measures stressor-specific
distress rather than generalised distress. These findings regarding convergent validity
support the use of the IES-I in the current study to gauge cancer-specific distress and screen
for PTSD.
Qualitative reviews have found that the IES has good predictive validity across a range of
populations in terms of detecting changes in clinical status over time and discriminating
different levels of stress reaction among individuals (Corcoran & Fischer, 1994; Briere,
1997; Sundin & Horowitz, 2002). Such predictive validity has been demonstrated by the
IES-I also. For example, in one study of 111 breast cancer patients undergoing group
psychotherapy, significant reductions in distress, as assessed by various psychosocial
measures including IES Intrusion, Avoidance and total scores, were observed at post-
treatment and at 3- and 6- months follow-up (Spiegel et al, 1999). Similar results using the
IES-I have been reported across time in a number of populations including clinic
outpatients (Horowitz et al, 1979), combat veterans (Kosten, Frank, Dan, McDougle &
Giller, 1991; Rothbaum, Hodges, Ready, Graap & Alarcon, 2001), the bereaved (Corcoran
& Fischer, 1994), relatives of breast cancer patients (Schwartz et al, 1998), surgical breast
cancer patients (Tjemsland, Soreide & Malt, 1998), and holocaust survivors with cancer
(Baider, Peretz & Kaplan De-Nour, 1997).
Research has also shown that the IES-I discriminates between groups exhibiting mild and
more severe stress reactions. Horowitz and colleagues (1979) found significant differences
on IES Intrusion, Avoidance and total scores between stress clinic outpatients and medical
239
students exposed to cadaver dissection. Similar differences in IES-I scores have been
reported between combat veterans and comparable controls (Solomon & Kleinhauz, 1996),
women with and without a family history of breast cancer (Valdimarsdottir, Bovjberg,
Kash, Holland, Osborne & Miller, 1995; Lloyd et al, 1996; Zakowski et al, 1997; Croyle,
Smith, Botkin, Baty & Nash, 1997; McCaul, Branstetter, O’Donnell, Jacobson & Quinlan,
1998), advanced and localised malignant melanoma patients (Kelly et al, 1995), prostate
cancer patients and their spouses following cancer treatment (Kornblith et al, 1994),
younger and older women after breast cancer treatment (Wenzel et al, 1999), and male and
female Hodgkin’s lymphoma survivors (Norum & Wist, 1996). Finally, research has shown
that higher scores on the IES-I may predict greater subsequent psychosocial distress. For
example, IES-I scores at 2 months predicted PTSD at 6 months in burn victims (Perry,
Difede, Musngi, Frances & Jacobsberg, 1992). Additionally, the IES-I alone or in
combination with other psychosocial measures has identified gastrointestinal cancer
patients (Nordin & Glimelius, 1999) and women with familial breast cancer (McCaul et al,
1998) that are at-risk to delayed psychosocial distress.
6.7.2.6 Eysenck Personality Questionnaire Revised Short Scale– Neuroticism
(EPQRS-N) (Eysenck & Eysenck, 1991)
The adult version of the Eysenck Personality Questionnaire Revised (EPQR) is a self-report
inventory evaluating normal and abnormal personality. It is based on factor analytic
research and measures three orthogonal factors or personality traits, Neuroticism (N),
Extraversion (E) and Psychoticism (P). The short form of the EPQR Neuroticism scale
(EPQRS-N) is an abbreviated 12-item scale used to measure neuroticism or emotionality.
Eysenck and Gudjonsson (1989) characterised the neurotic individual as an anxious,
depressed, tense, irrational, shy, moody and emotional person, who suffers from feelings of
guilt and low self-esteem. The EPQRS-N takes 2-3 minutes to complete and respondents
require a primary school reading level.
In the present study, the EPQRS-N was employed as a secondary measure of psychosocial
distress. Neuroticism was assessed at pretreatment only to determine whether it was a
predictor of psychosocial distress experienced by patients during or following cancer
treatment. Studies have shown that there is a significant relationship between neuroticism
and psychosocial distress, including the development or recurrence of sub-clinical or
240
clinical depression (Christie & Venables, 1973; Hill, Kemp-Wheeler & Jones, 1986; Hill &
Kemp-Wheeler, 1986; Gilbert & Reynolds, 1990; Berlanga, Heinze, Torres, Apiquian &
Caballero, 1999; Roberts & Kendler, 1999; Schroevers, Sanderman, van Sonderen &
Ranchor, 2000), PTSD (Holeva & Tarrier, 2001), attempted suicide (Colson, 1972), and
general psychological distress (Jang, Livesley & Vernon, 1999). Similar relationships
between neuroticism and psychosocial distress exist in cancer patients. Prospective studies
have shown that patients with high neuroticism scores developed significantly greater
psychosocial distress in the short and longer term (Morris et al, 1977; Thomas, Mehden &
Jehu, 1987; Schroevers et al, 2000; Ranchor, Sanderman, Steptoe, Wardle, Miedema &
Ormel, 2002).
Patients were asked to respond to dichotomous items of the EPQRS-N with an answer of
“yes” (1) or “no” (0). Neuroticism scores ranged from 0 to 12 and were calculated by
summing “yes” responses. High N scores indicated nervousness, depression, maladjustment
and excessive emotionality, whilst low scores signified emotional stability (Eysenck &
Eysenck, 1991).
The EPQ and EPQR have been used in a myriad of normal (for example, Loo, 1979;
Artistico & Laicardi, 2002), psychiatric (for example, Berlanga et al, 1999) and medical
populations (for example, Wilhelmsen, Haug, Ursin & Berstad, 1994), including cancer
patients (for example, Yamaoka et al, 1998; Walker et al, 1999). Similarly, the EPQRS-N
has been used in a wide variety of populations including normal adults (for example,
Eysenck, Eysenck & Barrett, 1985; Barrett & Eysenck, 1992), university undergraduates
(for example, Francis, Philipchalk & Brown, 1991; Glicksohn & Abulafia, 1998), the
elderly (Mackinnon et al, 1995), young offenders (McMurran, Hollin & Bowen, 1990),
trauma victims (Chung, Easthope, Chung & Clark-Carter), psychiatric inpatients (for
example, Raine & Manders, 1988; Pearson, 1990; Wade et al, 1995), and medical
populations (for example, Hepburn, Deary, MacLeod & Frier, 1994; Miles, Shevlin &
McGhee, 1999).
Reliability
Internal consistency of the EPQRS-N has ranged from 0.80 to 0.84 in normal adults
(Eysenck et al, 1985) and individuals with skin disease (Miles et al, 1999), with no
241
significant gender differences reported. In the current study, the EPQRS-N exhibited good
internal consistency at pretreatment with a Cronbach alpha coefficient of 0.81.
Correlations between the EPQRS-N and the standard scale have ranged from 0.94 to 0.96
(Francis et al, 1991; Barrett & Eysenck, 1992) across cultures, including an Australian
student sample (Francis et al, 1991). Consequently, the EPQRS-N is a highly acceptable
substitute for the standard scale. One month test-retest reliabilities of 0.76 (males) and 0.81
(females) have been reported for the EPQR-N standard scale in a general population sample
(Eysenck & Eysenck, 1991). Similar results were found for the EPQRS-N in a study of 92
university students (r = 0.79, 6 month interval; Hosokawa & Ohyama, 1993).
Validity
The most impressive feature of the original EPQ is its construct validity (Kline, 1993). For
example, in one factor analytic study the three factors of the EPQ were confirmed and
shown to be almost completely orthogonal (Barrett & Kline, 1980). Factor analysis of the
EPQRS in general population and student samples has supported the same underlying
factor structure, including Neuroticism (Hosokawa & Ohyama, 1993; Glicksohn &
Abulafia, 1998). The EPQRS-N has also demonstrated substantial to excellent convergent
validity in relation to the longer Eysenckian Neuroticism scales, the Junior Eysenck
Personality Inventory (r = 0.81), the Junior EPQ (r = 0.78) and the EPQ (r = 0.95), in a
young sample (Francis & Pearson, 1988); and the Neuroticism scores of the Maudsley
Personality Inventory (r = 0.62) and the high anxiety (r = 0.62), high ergic tension (r =
0.57), and guilt proneness scales (r = 0.50) of the Sixteen Personality Factor (16PF)
inventory, in university student samples (Hosokawa & Ohyama, 1993).
The Eysenckian Neuroticism scales have demonstrated good predictive validity with
respect to discriminating different levels of emotionality or risk/occurrence of other kinds
of psychosocial distress. For example, one study found that university undergraduates with
high EPQ-N scores experienced more intense emotional states than low scorers
(Bachorowski & Braaten, 1995). In another study, high trait neuroticism, as measured by
the EPQ-N, distinguished breast cancer patients who had psychosocial distress (anxiety and
depression) from those who did not when interviewed at the time of local recurrence
(Jenkins, May & Hughes, 1991). Neuroticism in combination with a previous psychiatric
242
history was also found to be predictive of risk to psychosocial distress in breast cancer
patients at local recurrence (Jenkins et al, 1991). Similar power, often in combination with
other variables, has been demonstrated by the Eysenckian Neuroticism scales in predicting
vulnerability to, or recurrence of, major depression (Roy, 1999; Roberts & Kendler, 1999;
Berlanga et al, 1999) and predicting the development of PTSD following trauma (Holeva &
Tarrier, 2001). These findings of good predictive validity bode well for the primary use of
the EPQRS-N in the present study, namely, the prediction of psychosocial distress in cancer
patients during or following cancer treatment.
6.7.2.7 Psychological Adjustment to Illness Scale (Self-Report)– Vocational
Environment (PAIS-VE) (Derogatis & Lopez, 1983)
The self-report version of the Psychosocial Adjustment to Illness Scale (PAIS-SR) is a
questionnaire comprising 7 subscales that assesses the quality of a patient’s psychosocial
adjustment to a current medical illness or the residual effects of a previous illness
(Derogatis & Lopez, 1983). The Vocational Environment subscale of the PAIS (PAIS-VE)
is a 6-item self-report scale assessing the vocational impact of medical illness, including
perceived job performance, vocational impairment, job satisfaction, time lost, changes in
vocational interest and work goals, and problems with co-workers. The PAIS-VE takes 2-3
minutes to complete and respondents require a primary school reading level.
In the current study, the PAIS-VE was utilised as a primary measure of QOL, which
evaluated the specific, but often ignored, QOL domain of vocational adjustment for cancer
patients who worked or studied in some capacity during the course of the study. Vocation
was defined as paid or unpaid work or study not related to family or home duties. This
narrow definition was purposeful in order to capture an aspect of patients’ QOL that was
distinctly different to that examined by the EORTC QLQ-C30, yet was likely to have been
an integral part of life outside family and home life for those who worked prior to cancer
diagnosis. Patients completed the PAIS-VE at each assessment time, if applicable, and
rated items for the preceding 30 days using a 4-point Likert scale (a-d corresponded to 0-3
with scale reversal occurring for alternate items to reduce response bias). Higher ratings on
the PAIS-VE indicated poorer vocational adjustment. Raw scores were summed and
converted to standardised T-scores using norms provided in the test manual for mixed
cancer patients (Derogatis & Lopez, 1983). Non-respondents received a raw score of 0 and
243
were assigned a standardised T-score using the mixed cancer patient norms (Derogatis &
Lopez, 1983). However, for reasons of greater precision and interpretation, raw scores were
maintained to evaluate changes over time.
Reliability
The reliability of the PAIS-SR has been established in a variety of medical populations,
including cancer patients (Derogatis, 1986). Satisfactory internal consistency for the PAIS-
VE was reported in the test manual for 69 cardiac patients (α = 0.76; Derogatis & Lopez,
1983). Good results were also found in a large study of 502 mixed cancer patients (α =
0.84; Merluzzi, & Martinez Sanchez, 1997), whilst only moderate to satisfactory internal
consistency was indicated in a longitudinal study of 128 post-surgical breast cancer patients
(α = 0.64-0.75) and 121 partners (α = 0.59-0.66) involving four assessments ranging from
7-10 days to 90 days post-surgery (Murphy, 1994). In the present study, Cronbach alpha
coefficients ranged from 0.65 to 0.75, indicating that the PAIS-VE had moderate to
satisfactory internal consistency across the four assessment times. Unfortunately, test-retest
reliability of the PAIS-VE (or any of the other PAIS subscales) has not been reported in the
test manual or elsewhere.
Validity
Factor analytic studies have confirmed the construct validity of the PAIS. In one study of
120 lung cancer patients, seven factors corresponding to the PAIS subscales accounted for
63% of the total variance in the factor matrix, of which the PAIS-VE contributed 10%
(Derogatis & Lopez, 1983). Furthermore, all 6 items of the PAIS-VE loaded heavily on it (r
> 0.5) and not on other PAIS subscales. Similar results were also found in large studies
involving 502 mixed cancer patients (Merluzzi, & Martinez Sanchez, 1997), 557
gastrointestinal disorder patients (Wilhelmsen, Bakke, Tangen Haug, Endresen & Berstad,
1994), and 280 chronic disease patients (Rodrigue, Kanasky, Jackson & Perri, 2000).
Moderate to substantial convergent validity of the PAIS-VE has been reported in relation to
other adjustment measures, including the Global Adjustment to Illness Scale (r = 0.54;
Derogatis, Abeloff & Melisaratos, 1979), Symptom Checklist-90 Revised (r = 0.39;
Derogatis et al, 1979), Affect Balance Scale Index (r = 0.46; Derogatis et al, 1979),
Sickness Impact Profile (r = 0.54; Merluzzi & Martinez Sanchez, 1997), and Karnofsky
Performance Scale (r = 0.44; Merluzzi & Martinez Sanchez, 1997) in breast cancer
244
patients; the Cancer Behavior Inventory (r = 0.38) and Mental Health Index (r = 0.5) in
mixed cancer patients (Merluzzi & Martinez Sanchez, 1997), and physician assessments of
vocational rehabilitation in chronic haemodialysis patients (Kaplan De-Nour, 1982).
Additionally, the PAIS-VE has demonstrated weaker correlations with more diverse
measures, such as the Patient’s Attitudes, Information and Expectancies Scale (r = 0.28;
Derogatis et al, 1979) and the Interview Schedule for Social Interaction (r = 0.15; Merluzzi
& Martinez Sanchez, 1997).
Several studies have investigated the predictive validity of the PAIS. For example, of all the
PAIS subscales, the PAIS-VE was shown to be most sensitive to differences in adjustment
observed 1 to 3 months after lung cancer screening between patients who returned positive
tests (n=128) and those that returned negative results (n=86; p<0.01; Derogatis et al, 1979).
Additionally, the PAIS-VE has been an indicator of significantly greater psychosocial
distress amongst cancer patients with new recurrences relative to normative samples of
cancer patients (Mahon, Cella & Donovan, 1990). The PAIS-VE has also demonstrated
predictive validity in relation to changes in clinical status over time. In one longitudinal
study, metastatic cancer patients exhibited significant increases in vocational problems as
measured by the PAIS-VE over time (Kaye & Gracely, 1993). Conversely, significant
reductions in vocational problems were observed at 6 and 12 months post-surgery in 89
heart bypass patients (Langeluddecke, Fulcher, Baird, Hughes & Tennant, 1989).
6.7.2.8 Marital Communication Problems Scale (MCPS; Herr et al, 1992)
The MCPS is perhaps the only communication scale tailored to cancer patients. The MCPS
is a 4-item self-report scale that assesses the degree to which cancer patients and their
partners can openly discuss their feelings with each other. It takes 1-2 minutes to complete
and respondents require a primary school reading level.
In the present study the MCPS was employed as a secondary measure of psychosocial
distress and QOL. It was administered at pretreatment only to determine whether it was a
predictor of subsequent psychosocial distress or impaired QOL amongst cancer patients.
Controlled studies (for example, Dorval, Maunsell, Taylor-Brown & Kilpatrick, 1999; Joly
et al, 2002) and qualitative reviews (for example, Taylor-Brown, Kilpatrick, Maunsell &
245
Dorval, 2000) have shown that pre-existing relationship difficulties or dissatisfaction
predict further relationship problems during cancer treatment and in survival, and that the
rate of relationship breakdown amongst cancer survivors does not differ significantly from
the normal population.
Patients rated MCPS items on a 4-point scale (1 = "not at all", 2 = “a little”, 3 =
“moderately”, 4 = "very much") with scoring reversed on alternate items to reduce response
bias. MCPS scores ranged from 1-4 and were the calculated mean of summed ratings.
Higher scores indicated greater communication problems between cancer patients and their
partners.
Psychometric Properties
Construction of the MCPS was based largely on expert opinion, with the authors selecting
three items from existing standardised scales, the Cancer Inventory of Problem Situations
(Heinrich, Schag & Ganz, 1984), ENRICH (Olson, Fournier & Druckman, 1985) and the
McMaster Family Assessment Device (Epstein, Balswin & Bishop, 1983), and appending
an item of their own (Kornblith, Herr & Ofman, 1994). Internal consistency of the scale
was unacceptable (Cronbach, 1951; Nunnally, 1978), with Cronbach alpha coefficients of
0.47 for prostate cancer patients and 0.52 for spouses (Kornblith et al, 1994). In the current
study, however, a Cronbach alpha coefficient of 0.73 was attained at pretreatment, which is
most acceptable given the brevity of the MCPS and its restricted use as a secondary
measure.
6.7.2.9 Qualitative Items
Qualitative items soliciting written comments from patients were included. Patients were
asked what the most important problem was for them in the previous few weeks.
Additionally, they were asked what complementary and alternative therapies (if any) had
been tried since diagnosis and to describe the benefits of their use. Qualitative data was
collated by two independent raters, who extracted themes from patients’ written responses
and compiled descriptive statistics for them. One rater was a cancer researcher in public
health and the other was a postgraduate student in psychology. Both raters were recruited
on a voluntary basis via the Western Australian Clinical Oncology Group.
246
6.8 Pilot Study
Prior to the commencement of the main study, a pilot study evaluating the relevance and
acceptability of the assessment battery was undertaken with 12 mixed cancer outpatients at
Medical Oncology, Royal Perth Hospital. The assessment battery used was the same as
described above, except that the Neuroticism Extraversion Openness Five-Factor
Inventory– Neuroticism (NEO FFI-N) scale (Costa & McRae, 1992) was included instead
of the EPQRS–N and the State-Trait Anxiety Inventory– State (STAI-S) scale (Spielberger,
1983) was additionally incorporated. The NEO FFI-N is a standardised, self-administered
12-item scale measuring neuroticism or the tendency to experience negative emotions, such
as anxiety, depression and hostility (Costa & McRae, 1992). Patients rated items on a 5-
point Likert scale ranging from “strongly agree” (1) to “strongly disagree” (5). The STAI-S
is a standardised, 20-item self-report measure of anxiety or the current level of tension and
apprehension (Spielberger, 1983). Items were rated on a 4-point Likert scale ranging from
“not at all” (1) to “very much so” (4).
All patients approached to participate were explained that the purpose of the pilot study was
to gain feedback regarding the suitability of a questionnaire to be used in a forthcoming
study that evaluated the experiences of cancer patients undergoing treatment. They were
advised that participation was voluntary, would have no direct benefit for them, and that
refusal would not compromise their medical treatment. No patient refused to participate.
Patients were equally divided according to gender, all aged ≥ 50 years, and were
predominantly married, retired, of Anglo-Saxon descent and educated to a secondary
school level or better. All patients had undergone ≥ 3 months of chemotherapy and had
received and/or were receiving other cancer treatments also.
Patients were asked to complete assessment batteries containing 120 items. For comparison
of completion rates, six patients were randomly assigned to complete the questionnaires at
the clinic and the other six were asked to complete them at home and return them at their
next clinic appointment. All patients were given a brief explanation of the questionnaire,
including the general layout and the broad areas assessed, and were advised that it was
necessary to read the instructions in bold type at the start of each section before answering
the questions. Assistance was given as required to patients who completed questionnaires at
247
the clinic, whilst patients who took them home were told to leave out questions that
confused them and that they would be given help upon return to the clinic.
Upon return of questionnaires, verbal feedback was solicited from all patients irrespective
of completion. All the patients who filled in questionnaires at the clinic completed them
adequately (6/6) compared to only half the patients who took them home (3/6). Reasons for
non-completion included treatment-related illness and excessive questionnaire length. All
patients who completed questionnaires found that the layout and response format of the
questionnaire was generally good, and that the content was highly relevant and
comprehensively covered issues relating to cancer patients’ QOL and psychosocial
adjustment. Patients did not make any suggestions for inclusion of additional material when
asked. The majority of completers (7/10) also found that the length of the questionnaire was
within reason, although felt 50-75 items would maximise study participation. Finally,
patients who completed questionnaires at the clinic took 20-25 minutes.
The most important negative feedback received concerned the NEO FFI-N scale. The
majority of patients felt that the scale was made unnecessarily difficult by the lengthy,
complicated instructions and the 5-point Likert scale. They reported that they either had to
frequently refer back to the instructions or ask the author for clarification in order to
complete the section properly. The author concurred with the latter given that all requests
for assistance with the questionnaire were for the NEO FFI-N section.
The results of the pilot study were discussed with the clinic’s two most senior consultant
medical oncologists. Firstly, it was agreed that the EPQRS-N should be used to replace the
NEO FFI-N as a brief neurotic personality measure given its good face validity and
comparable psychometric rigour and length. Secondly, it was decided that the questionnaire
should have a maximum length of 100 items, although the medical oncologists felt that
even a 100-item questionnaire may be too burdensome for some cancer patients. They
advocated the culling of both the BDI and STAI-S. The author felt that exclusion of the
STAI-S scale was warranted given that the Emotional Functioning scale of the EORTC
QLQ-C30 has been shown to predominantly assess anxiety (Skarstein, Aass, Fossa,
Skovlund & Dahl, 2000). However, the author rejected the removal of the BDI because the
only other measure tapping depression in the questionnaire, the QLQ-C30 Emotional
248
Functioning scale, lacked the BDI’s psychometric rigour in screening for depression
(Skarstein et al, 2000). The medical oncologists subsequently requested that the author
consult on this issue with a psychiatrist that had previously worked at the clinic. The
psychiatrist concurred with the author and this was accepted by the medical oncologists.
Subsequently, the 100-item questionnaire contained in Appendix B was finalised for use in
the main study.
249
Appendix B: Study 1 Questionnaires
The Physician Ratings questionnaire employed in this study appears below. It was completed at each assessment time by the patient’s attending medical oncologist. PATIENT’S INITIALS DATE: ____ / ____ / ____ DOCTOR: _____________________________ UMRN: ________________ CHECKPOINT:_________ 1. Overall how do you feel the patient’s life has been affected by the state of his/her health as of today? (Please circle the number on the line below.)
1------2------3------4------5------6------7------8------9------10 A Lot Not at All 2. How would you rate the patient’s overall physical condition during the past week? (Please circle the number on the line below.)
1------2------3------4------5------6------7------8------9------10 Extremely Extremely Bad Good
250
The full questionnaire for patients employed in this study is reproduced below. It was administered in its entirety at the pretreatment (baseline) assessment time point only. Questions 37-40 (marital/ partner communication), 76-87 (premorbid neuroticism) and 91-99 (demographics) were omitted at subsequent assessments as they were only pertinent to baseline assessment.
PATIENT’S INITIALS DATE: __ / __ / _ _ Subject No.: ________
CANCER PATIENTS' QUALITY OF LIFE QUESTIONNAIRE We are interested in understanding better how cancer may have affected your life. For each of the questions listed below, please circle the number that best applies to you. The information that you provide will remain strictly confidential. Because of your present condition? No Yes 1. Do you need help with eating, 1 2 dressing, bathing or using the toilet? 2. Do you have to stay in bed or a chair 1 2 for most of the day? 3. Do you have to stay indoors most or all of the day? 1 2 4. Do you have any trouble either walking a short 1 2 distance or climbing one flight of stairs? 5. Do you have trouble either taking a walk or climbing a few flights of stairs? 1 2 6. Do you have any trouble bending, lifting, 1 2 or stooping? 7. Are you limited in any way in doing 1 2
your work or household jobs? 8. Does your condition keep you from working 1 2 at a job or doing household jobs? Not A Moder- Very During the past week: at All Little ately Much 9. Did you feel energetic? 1 2 3 4 10. Were you physically well? 1 2 3 4 11. Were you tired? 1 2 3 4
12. Did you need to rest? 1 2 3 4
Please go on to the next page
251
Not A Moder- Very During the past week: at All Little ately Much
13. Did you have any trouble sleeping? 1 2 3 4 14. All in all, did you feel ill? 1 2 3 4 15. Did you have pain in other parts of your body? 1 2 3 4 16a. Did you have any treatment for pain? NO: 1 YES: 2 16b. If YES, How much did it help? 1 2 3 4 17. Did you have hot flashes? 1 2 3 4 18. Have you had any skin changes? 1 2 3 4 19. Have you had any weight gain? 1 2 3 4 20. Have you had any weight loss? 1 2 3 4 21. Have you had any secondary hair loss 1 2 3 4 that is, your beard or pubic hair? 22. Have you lost muscle bulk? 1 2 3 4 23. Did you lack appetite? 1 2 3 4 24. Were you nauseated? 1 2 3 4 25. Did you vomit? 1 2 3 4 26. Did your condition limit your interest in sex? 1 2 3 4 27. Did your condition interfere with your enjoyment of sex? 1 2 3 4 N/A 28. Have you used other methods of sexual expression with your partner, other than or in addition to sexual intercourse ? 1 2 3 4 N/A 29. Did you feel tense? 1 2 3 4 30. Did you feel irritable? 1 2 3 4 31. Did you feel lonely? 1 2 3 4 32. Did you worry? 1 2 3 4 33. Did you feel depressed? 1 2 3 4
Please go on to the next page
252
Not A Moder- Very During the past week: at All Little ately Much 34. Did you feel lonely even when you were with people? 1 2 3 4 35. Has your condition interfered with your 1 2 3 4 family or social life? 36. Has your medical treatment interfered 1 2 3 4 with your family or social life? Below are some statements about relationships. For each please circle the answer that reflects how often the statement is true of your relationship with your spouse/partner. Not A Moder- Very Statements: at All Little ately Much 37. It is easy for me to express my true 1 2 3 4 feelings to my spouse/partner 38. My spouse/partner can't tell what I am 1 2 3 4 feeling from what I am saying 39. I can talk openly with my spouse/partner 1 2 3 4 about my fears about cancer and what might happen 40. So as not to upset my spouse/partner, I find it easier 1 2 3 4 to discuss my problems with other people. Below is a list of questions related to the impact your illness may have had on your employment situation. If you were employed at the time of your diagnosis please complete the following questions by circling the answer most appropriate to yourself. 41. Do you have a job, either paid and/or unpaid that is outside of the home? a) No (please go to Question 48) b) Yes (Continue straight on) 42. Has this event interfered with your ability to do your job a) No problems with my job b) Some problems, but only minor ones c) Some serious problems d) Illness has totally prevented me from doing my job
Please go on to the next page
253
43. How well do you physically perform your job now? a) Poorly b) Not too well c) Adequately d) Very well 44. During the past 30 days, have you lost any time off work because of this condition? a) 3 days or less b) 1 week c) 2 weeks d) More than two weeks 45. Is your job as important to you now as it was before this all started? a) Little or no importance to me now b) A lot less important c) Slightly less important d) Equal or greater importance than before. 46. Have you had to change your goals concerning your job as a result of these events? a) My goals are unchanged b) There has been a slight change in my goals c) My goals have changed quite a bit d) I have changed my goals completely 47. Have you noticed any increase in problems with your co-workers since these events? a) A great increase in problems b) A moderate increase in problems c) A slight increase in problems d) None Below is a list of comments made by people after stressful events, such as having cancer. Please check each item, indicating how frequently these comments were true for you during the past week about your illness.
Not A Moder- Very Comments at All Little ately Much 48. I thought about it when I didn’t mean to. 1 2 3 4 49. I had trouble falling or staying asleep because of 1 2 3 4 pictures or thoughts about it that came into my mind. 50. I had waves of strong feelings about it. 1 2 3 4 51. I had dreams about it. 1 2 3 4
Please go on to the next page
254
Not A Moder- Very Comments at All Little ately Much 52. Pictures about it popped into my mind 1 2 3 4 53. Other things kept making me think about it. 1 2 3 4 54. Any reminder brought back feelings 1 2 3 4 about it.
This section consists of 21 groups of statements. After reading each group of statements carefully circle the number (0, 1, 2 or 3) next to the one statement in each group which best describes the way you have been feeling the past week, including today. If several statements within a group seem to apply equally well, circle each one. Be sure to read all the statements in each group before making your choice. 55. 0 I do not feel sad 1 I feel sad 2 I am sad all the time and I can’t snap out of it 3 I am so sad or unhappy that I can’t stand it 56. 0 I am not particularly discouraged about the future 1 I feel discouraged about the future 2 I feel I have nothing to look forward to 3 I feel that the future is hopeless and that things cannot improve 57. 0 I do not feel like a failure 1 I feel that I have failed more than the average person. 2 As I look back on my life, all I can see is a lot of failures 3 I feel I am a complete failure as a person 58. 0 I get as much satisfaction out of things as I used to 1 I don’t enjoy things the way I used to 2 I don’t get real satisfaction out of anything anymore 3 I am dissatisfied or bored with everything 59. 0 I don’t feel particularly guilty 1 I feel a good part of the time 2 I feel quite guilty most of the time 3 I feel guilty all the time 60. 0 I don’t feel I am being punished 1 I feel I may be punished 2 I expect to be punished 3 I feel I am being punished 61. 0 I don’t feel disappointed in myself 1 I am disappointed in myself 2 I am disgusted with myself 3 I hate myself
Please go on to the next page
255
62. 0 I don’t feel I am any worse than anybody else 1 I am critical of myself for my weaknesses or mistakes 2 I blame myself all the time for my faults 3 I blame myself for everything bad that happens 63. 0 I don’t have any thoughts of killing myself 1 I have thoughts of killing myself, but I would not carry them out 2 I would like to kill myself 3 I would kill myself if I had the chance 64. 0 I don’t cry any more than usual 1 I cry more now than I used to 2 I cry all the time now 3 I used to be able to cry, but now I can’t cry even though I want to 65. 0 I am no more irritated now than I ever am 1 I get annoyed or irritated more easily than I used to 2 I feel irritated all the time now 3 I don’t get irritated at all by the things that used to irritate me 66. 0 I have not lost interest in other people 1 I am less interested in other people than I used to be 2 I have lost of my interest in other people 3 I have lost all my interest in other people 67. 0 I make decisions about as well as I ever could 1 I put off making decisions more than I used to 2 I have greater difficulty in making decisions than before 3 I can’t make decisions at all anymore 68. 0 I don’t feel I look any worse than I used to 1 I am worried that I am looking old or unattractive 2 I feel that there are permanent changes in my appearance that make me look
unattractive 69. 0 I can work about as well as before 1 It takes an extra effort to get started at doing something 2 I have to push myself very hard to do anything 3 I can’t do any work at all 70. 0 I can sleep as well as usual 1 I don’t sleep as well as I used to 2 I wake up 1-2 hours earlier than usual and find it hard to get back to sleep 3 I wake up several hours earlier than I used to and cannot get back to sleep 71. 0 I don’t get more tired than usual 1 I get tired more easily than I used to 2 I get tired from doing almost anything 3 I am too tired to do anything
Please go on to the next page
256
72. 0 My appetite is no worse than usual 1 My appetite is not as good as it used to be 2 My appetite is much worse now 3 I have no appetite at all anymore 73. 0 I haven’t lost much weight, if any, lately 1 I have lost more than 5 pounds 2 I have lost more than 10 pounds 3 I have lost more than 15 pounds
I am purposely trying to lose weight by eating less. Yes ______ No ______ 74. 0 I am no more worried about my health than usual 1 I am worried about physical problems such as aches and pains; or upset stomach; or
constipation 2 I am very worried about physical problems and it’s hard to think of much else 3 I am so worried about my physical problems that I cannot think about anything else 75. 0 I have not noticed any recent change in my interest in sex 1 I am less interested in sex than I used to be 2 I am much less interested in sex now 3 I have lost interest in sex completely Please answer each question in this section by putting a circle around the ‘YES’ or ‘NO’ following the question. There are no right or wrong answers, and no trick questions. Work quickly and do not think too long about the exact meaning of the questions. 76. Does your mood often go up and down? Yes No 77. Do you ever feel ‘just miserable’ for no reason? Yes No 78. Are you an irritable person? Yes No 79. Are your feelings easily hurt? Yes No 80. Do you often feel ‘fed-up’? Yes No 81. Would you call yourself a nervous person? Yes No 82. Are you a worrier? Yes No 83. Would you call yourself tense or ‘highly-strung’? Yes No 84. Do you worry too long after an embarrassing experience? Yes No 85. Do you suffer from ‘nerves’? Yes No 86. Do you often feel lonely? Yes No 87. Are you often troubled by feelings of guilt? Yes No
Please go on to the next page
257
88. Overall how do you feel your life has been affected by the state of your health as of today? (Please circle the number on the line below.)
1------2------3------4------5------6------7------8------9------10 My life is My life is extremely normal for unpleasant me with no because of changes the state of because of my health the state of my health 89. How would you rate your physical condition during the past week? (Please circle the number on the line below.)
1------2------3------4------5------6------7------8------9------10 Extremely Extremely
Bad Good 90. We would also like to know which problem you felt was the most important for you during the past few weeks. Please write about it in your own words in the space below. If space does not permit your comments please also use the back page: Problem: ......................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................……………………………………….. 91. Since your diagnosis, have you tried any complementary and alternative therapies? Y/N 92a. If YES, please state below what and describe what you get out of them: .......................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................... .............................................................................................................................................................................. 92b. If NO, have you thought about it? Y/N
Please go on to the next page
258
The last few questions relate to your background. Please fill in or tick the appropriate answer.
93. How old were you on your last birthday? years. 94. What is your marital status?
__(1) Single, never married __(2) Married __(3) Separated __(4) Divorced __(5) Widowed
95. What is your current employment status?
__(1) Working full-time __(2) Working part-time __(3) Retired __(4) Unemployed __(5) Other (please specify) ______________________________
96. What is the highest level of education you have completed?
__(1) Primary School (12 years of age) __(2) Year 10/Third Year High School/Achievement Certificate (15 years of age) __(3) Year 12/Completed High School/TEE/Leaving Certificate (17 years of age) __(4) TAFE or Trade Qualification __(5) University or College Degree
97. What is your ethnic background? 98. Have you had cancer previously? Y/N 99. Please state the site of the cancer you have right now? 100. What treatment, if any, have you received for your cancer prior to filling in this questionnaire (for example, surgery, chemotherapy, radiotherapy etc.)? ______________________________
THANK YOU VERY MUCH FOR YOUR HELP!
259
Appendix C: Complementary and Alternative Medicine Used by Patients with
Cancer– Evidence for Efficacy and Safety (Draft Manuscript – Study 2)
Appendix C contains an earlier revision of the study 2 manuscript provided in chapter 3. It
contains omitted summary tables and a significant amount of material that was otherwise
culled due to its duplication in other chapters of the edited handbook in which it was
published (as determined by peer review), and concerns about the length of chapters held
the publisher .
260
COMPLEMENTARY AND
ALTERNATIVE MEDICINE (CAM) USED
BY PATIENTS WITH CANCER:
EVIDENCE FOR EFFICACY AND
SAFETY Carlo PIRRI1
1Faculty of Health Sciences (Psychology), Murdoch University, Murdoch, Australia
*Correspondence: Carlo Pirri (Research Associate/PhD Candidate), Faculty of Health
Sciences (Psychology), Murdoch University, South Street, Murdoch WA 6150, Australia.
Email: [email protected]
Tel.: 61 (0) 8 9360 7382
Fax: 61 (0) 8 9360 6492
Abstract
Many cancer patients use complementary and alternative medicine (CAM) in an effort to
control symptoms and to prevent and treat disease. Recent estimates suggest an overall
prevalence for complementary medicine use of 14% to 65% among Australian adults
diagnosed with cancer (with estimates as high as 80% to 91% in the US and Europe), and
8% to 14% for alternative medicine use among adult cancer patients. Given the increasing
desire of cancer patients to use CAM, it is important that clinicians have a good
understanding of the evidence available for the efficacy and safety of specific
complementary and alternative therapies.
CAMs may be classified into 5 categories: whole medical systems, mind-body techniques,
biologically-based practices, manipulative and body-based practices, and energy therapies.
The present systematic review aims to provide an overview of the current evidence
pertaining to the efficacy and safety of a range of CAMs in each of these categories used by
261
cancer patients (upon diagnosis, during conventional treatment, in response to disease
progression or recurrence, or during remission/survivorship) in Australia and elsewhere.
Where possible, evidence from meta-analytic and systematic reviews is utilised.
Complementary and alternative therapies considered include homeopathy, traditional
Chinese medicine, mind-body techniques (ranging from relaxation and meditation to yoga
and tai chi through to music therapy and religious/spiritual coping and prayer),
biologically-based practices broadly comprising nutritional supplements (e.g. antioxidants,
shark cartilage) and Chinese and Western herbal medicine (e.g. ginseng and St. John’s
wort, respectively), manipulative and body-based practices (massage, acupuncture,
exercise), and energy therapies (biofield therapies including Qigong and touch therapies
such as Reiki; bioelectromagnetic therapies including microwave/UHF/Tronado therapy).
Currently, there is evidence from high quality clinical trials that some complementary
therapies, used as adjuncts to conventional medical treatments, are beneficial in reducing
disease or treatment symptoms and improving quality of life and psychological functioning
(e.g. relaxation). There is evidence of potential harm also. Nutritional supplements, herbal
preparations, and other natural therapies among the biologically-based practices may pose
direct safety risks because of their potential adverse effects or interactions with
conventional anticancer treatments and other medications. Some should not be used under
any circumstances in cancer patients irrespective of potential benefit (e.g. St. John’s wort),
while others may be beneficial when patients are not undergoing these treatments and have
no other contraindications (e.g. valerian for short-term amelioration of sleep problems in
non-surgical cancer patients). Alternative therapies promoted as “cures” in place of
conventional treatments (e.g. shark cartilage) have the potential to cause patients (and their
loved ones) the most harm, however, when they forego evidence-based cancer treatments
that are likely to be more effective.
It is therefore imperative that those involved in the medical care of cancer patients are
equipped with the skills and knowledge to help patients appropriately evaluate
complementary and alternative therapies, in order to receive benefit while avoiding harm.
Additionally, as a consequence of the safety risks associated with CAM use, clinicians are
strongly encouraged to routinely ask patients about complementary and alternative therapy
use.
262
In conclusion, whether termed complementary medicine or integrative oncology, cancer
physicians in Australia should strongly consider offering evidence-based complementary
therapies (or at least safe forms of them) alongside conventional treatments through their
own cancer services. Conceivably, this will influence patients to continue with mainstream
care and help them avoid any potential harm that may occur with autonomous CAM use. In
this way, optimal holistic care will be ensured for cancer patients by clinicians providing
conventional oncology treatment and care.
1. Introduction
A multitude of complementary and alternative medicines (CAMs) are in contemporary use,
which the US National Center for Complementary and Alternative Medicine (NCCAM) has
classified into 5 categories, whole medical systems, mind-body techniques, biologically-
based practices, manipulative and body-based practices, and energy therapies (Table 1).
The evidence for popular CAM approaches in these categories that are used in Australia
and elsewhere by cancer patients will be reviewed below.
2. Popular CAM Approaches and Evidence for Use
2.1 Whole medical systems
Whole medical systems are complete systems of diagnosis and practice, which have some
overlap with the other four categories. Several whole medical systems exist including those
that have been developed in Western cultures (e.g. homeopathy), as well as non-Western
cultures (e.g. traditional Chinese medicine, Ayurveda).
2.1.1 Homeopathy
Homeopathy is based on the proposed law of similars that “like cures like”, whereby low
concentrations of substances that cause symptoms in healthy individuals can be used to
treat patients with similar symptoms. Homeopathic medicines are generally safe in terms of
adverse effects and interactions with conventional treatments. A systematic review of 53
studies found that homeopathic medicines prescribed by trained practitioners in low
concentrations are probably safe and unlikely to cause serious adverse events, with the
main risks being indirect and stemming from inexperienced practitioners (e.g.
misdiagnosis).1
263
Homeopathy is predominantly used in supportive and palliative care for cancer patients,
mainly to strengthen the body in battling cancer, improve general well-being and relieve
cancer pain.2 Two systematic reviews of controlled trials have found that homeopathic
medicines appeared to improve symptom management during chemotherapy and
radiotherapy (specifically chemotherapy-induced stomatitis and acute radiotherapy-induced
dermatitis).3,4 While producing encouraging preliminary evidence, the authors in both
reviews expressed concern about the general lack of evidence and the clinical heterogeneity
of the studies and cautioned that further research was required before any definitive
recommendations on use to cancer patients could be made.
2.1.2 Naturopathy
Naturopathy is an alternative medical system based on the core beliefs that nature has the
ability to heal and that the human body has the vital ability to maintain and heal itself.
Naturopaths favour natural remedies and minimally-invasive approaches in preference to
surgery and drugs. Practitioners use a wide variety of treatment modalities including dietary
and lifestyle changes (e.g. eating more whole and unprocessed foods, abstaining from
alcohol and sugar, stress reduction); vitamins, minerals and nutritional supplements; herbal
medicine; homeopathy; mind-body techniques (e.g. meditation, yoga, counselling); and
manipulative and body-based therapies (e.g. hydrotherapy, physical exercise). Given the
overlap of naturopathic remedies with other categories of CAM, they will be reviewed in
their respective sections below.
2.1.3 Traditional Chinese medicine
Traditional Chinese medicine (TCM) is based on the concept that the human body is a
dynamic universe of interconnected energy systems and aims to maintain balance, harmony
and order of these systems to ensure healthy functioning of the body. TCM treatments
include acupuncture and related techniques (e.g. acupressure, moxibustion), Chinese herbal
medicine, massage (e.g. tui na, cupping), exercise and breathing techniques (e.g. Qigong),
and dietary and lifestyle advice. In Australia, the most popular forms of TCM are Chinese
herbal medicine and acupuncture.
TCM is predominantly used by cancer patients to improve immunological function,
symptom management (i.e of general constitutional symptoms such as fatigue, pain and
264
depression, and specific symptoms such as gastrointestinal distress, appetite loss and
myelosuppression) and overall well-being, as well as to enhance the effects of conventional
treatments in chemotherapy and radiotherapy. In a review of randomised controlled trials
(RCTs) and observational studies of TCM in supportive cancer care,5 the authors concluded
that overall there was sufficient preliminary evidence to undertake high quality clinical
trials to evaluate the effects on QoL and survival of integrating TCM into conventional
oncology care (see below for discussion of specific TCM treatments).
2.2 Mind-body techniques
Mind-body techniques involve individuals learning coping strategies to deal with emotional
distress that may be manifested in physical symptoms. Techniques include practitioner-
administered therapies such as hypnotherapy and mindfulness-based stress reduction, and
self-help strategies such as relaxation, meditation and creative therapies (including art,
music and dance therapy). Some techniques that were considered CAM in the past have
become mainstream (e.g. patient support groups), but are discussed below nonetheless
because they complement conventional anticancer treatment.
2.2.1 Relaxation
Relaxation techniques originated in the early 1900s in the U.S. and Europe. They are
designed to elicit a state of mental and physical relaxation, most commonly by focusing
attention on the sensations associated with systematically tensing and relaxing muscle
groups as in progressive muscle relaxation (PMR), or achieve a hypometabolic state of
reduced sympathetic arousal (e.g. via autogenic training, PMR augmented with
diaphragmatic breathing and/or guided imagery). Relaxation techniques often involve
diaphragmatic or deep breathing (slow, deep rhythmic breathing) to aid in the release of
muscle tension, and may incorporate guided imagery/visualisation (evoking images, usually
sensory or affective) to calm the mind.
Relaxation is generally safe and adverse events are rare. Common side-effects include
intrusive thoughts, sense of losing control, unsettling sensory experiences, and muscle
cramps and spasms.299 Other adverse effects may include feelings and sensations of
unfamiliarity or vulnerability, intrusive images, dizziness, floating, depersonalisation,
dissociation, paradoxical increases in tension or anxiety, irritability, hallucinations, panic,
265
and abreaction (anxiety release through the reliving of traumatic events).300 Some of these
side-effects are to be expected transiently in the short-term, however, and such symptoms
of relaxation-induced anxiety may be used therapeutically if individuals can learn to relax
during these experiences and thus facilitate greater coping in stressful life situations when
they arise (e.g. [Smith, Woolfolk and Lehrer]).301,302 In any case, only about 4% of clients
seen by psychologists have treatment terminated due to side-effects of relaxation.303
Additionally, relaxation-induced anxiety, abreaction and other adverse effects occur less
frequently in PMR than in autogenic training, PMR + guided imagery, or meditation (e.g.
[Heide and Borkovec, Norton et al, Grigsby, Pitman et al]).304-307 Nevertheless, relaxation
techniques should be used with caution or are best avoided in cancer patients with (a
history of) psychosis (e.g. schizophrenia) or post-traumatic stress disorder.308,309
Additionally, autogenic training and PMR is best avoided in patients with poorly-controlled
cardiovascular disease as tensing muscles may cause heart rate and blood pressure
fluctuations via the Valsalva response.309-311
Turning to efficacy, a meta-analysis of 15 RCTs involving patients undertaking acute non-
surgical cancer treatment (chemotherapy, radiotherapy, bone marrow transplantation,
hyperthermia) revealed that relaxation exerted significant positive effects on nausea, pain,
physiological arousal (blood pressure, heart rate), anxiety, depression and hostility.6 A
more recent meta-analysis of 25 controlled trials and observational studies also found
reasonably strong evidence for the efficacy of relaxation-based interventions in reducing
cancer pain,7 while recent systematic reviews derived some support that relaxation reduced
pain,8 nausea and vomiting9 and anticipatory nausea and vomiting,10 respectively.
2.2.2 Meditation
Meditation is an ancient Eastern practice that has been popularly adopted worldwide. It
involves training the mind to focus on breathing or a specific object/image in an effort to
free it of all thought (concentrative meditation), or to focus on sensations experienced in the
present moment in a non-judgmental and accepting manner to establish a stable, non-
reactive awareness to the physical or psychological symptoms associated with them
(mindfulness meditation).312 Most meditation practices were developed within a religious
or spiritual context and the ultimate goal is to achieve some form of spiritual/personal
growth or transcendental experience and find a system of values and philosophy of life,
266
whereas many approaches in behavioural medicine (e.g. relaxation, biofeedback) are
designed as treatments for particular disorders.313,314 There are many forms of meditation
(e.g. Sahaja yoga meditation, Vipassana meditation), but the two most researched practices
are mindfulness and transcendental meditation [involves a silent word or phrase (a mantra)
being repeated in order to calm (and ultimately transcend) the ordinary flow of internal
mental dialogue].315
Meditation is generally safe and serious adverse events are rare, but it is not without side-
effects. Common adverse effects include relaxation-induced anxiety and panic, restlessness,
frustration, paradoxical increases in tension, depersonalisation or derealisation (which can
recur after meditation), antisocial behaviour and flattened affect.304,316-319 Other adverse
effects during and after meditation may include reduced motivation in life, boredom,
difficulty in returning to normal everyday life after meditation retreats, pain, impaired
reality testing, confusion and disorientation, feeling “spaced out”, depression, increased
negativity, being more judgmental, a sense of ineptitude, greater awareness of one’s own
poor self-esteem or unfortunate life circumstances, feelings of guilt or defencelessness,
uncomfortable kinaesthetic sensations, mild dissociation, hallucinations, psychotic
episodes, grandiosity, elation, destructive behaviour, suicidal ideation or attempts, recovery
of repressed memories, and feeling addicted to meditation.316,318-325
A number of these side-effects, however, are not only expected to be temporary and
transient, but are considered integral to meditation by some proponents (e.g. it is part of the
process of observing both positive and negative experiences in a non-judgmental manner,
which is a core aspect of mindfulness).326 The ability of meditation instructors to handle
such experiences is likely to be important in determining whether they become valuable
learning opportunities or, alternatively, adverse events.326 In any case, most studies
reporting safety concerns about meditation have involved transcendental or Vipassana
meditation and most side-effects have been observed in longer-term retreats (e.g. 10 days)
and/or intensive meditation (e.g. 3 hour sessions), which are not formally recommended for
“novice” patients of some meditation practices such as mindfulness.325,326 Moreover, only
7.4% of long-term meditators in one study reported severe adverse effects.316 Nevertheless,
meditation practices (transcendental or Vipassana meditation, in particular) should be used
with caution or are best avoided in cancer patients with (a history of) psychosis (e.g.
267
schizophrenia), schizoid or schizotypal personality disorder, bipolar disorder, dissociative
states, or hypochondrial and somatisation disorders.325-327 Additionally, meditation is
contraindicated in patients experiencing physical exhaustion caused by fasting and sleep
reduction during longer-term, unguided and intensive meditation.325
Mindfulness-based stress reduction (MBSR) is the most studied meditation technique
among cancer patients and combines mindfulness meditation with Hatha yoga. A meta-
analysis of 3 RCTs and 7 observational studies suggested that MBSR may improve breast
cancer patients’ psychological adjustment to illness (i.e. ameliorating anxiety, stress,
fatigue, general mood and sleep disturbance), but found less convincing evidence to support
improvement of physical health.12 Additional larger RCTs involving other cancer
populations were recommended to validate these results. Similar conclusions were also
drawn in recent systematic reviews involving cancer patients using MBSR or mindfulness
meditation alone.8,13,14
2.2.3 Hypnotherapy
Hypnotherapy is a psychological approach that induces a state of aroused consciousness in
which suggestions are made to an individual to facilitate behaviour change or symptom
relief. An induction procedure, often involving relaxation/imagery techniques, is used prior
to suggestion. The efficacy of hypnotherapy is associated with an individual’s level of
suggestibility, particularly in achieving long-term symptom relief.15 Hypnotherapy is
generally safe when administered by qualified practitioners, but some individuals might
experience transitory side-effects during or after hypnosis.328-331 These adverse effects
include headaches, drowsiness, confusion, dizziness, or nausea and, less frequently, anxiety
or panic;328 they occur in 5% to 31% of individuals who undertake hypnotherapy.330
Serious adverse events are rare and typically involve exacerbation of psychological
symptoms (e.g. abreaction in post-traumatic stress disorder; induction of “false memories”
in psychologically vulnerable individuals), which is usually caused by the misapplication of
hypnotherapeutic techniques or poor clinical practice (e.g. not preparing patients
sufficiently).330 Nevertheless, the World Health Organization and others caution against the
use of hypnotherapy in individuals with (a history of) psychosis, personality disorders or
organic psychiatric conditions.309
268
Hypnotherapy has been used to manage a variety of symptoms in cancer patients, including
nausea and vomiting, chronic pain, acute procedural or peri-/postoperative pain and
anxiety. A meta-analysis of 6 RCTs (one in adults, five in children) has suggested that
hypnotherapy is effective in reducing anticipatory and chemotherapy-induced nausea and
vomiting in paediatric patients alone.16 Further RCTs involving larger samples in children
were recommended, as were more RCTs for adult cancer patients given their paucity in the
literature. A US National Institutes of Health Technology Assessment Panel17 concluded
that there was strong evidence that hypnotherapy alleviated chronic pain, including cancer-
related pain. Similarly, a systematic review examining 6 RCTs suggested that much support
exists for the use of hypnotherapy in cancer pain management.18 Furthermore, a more
recent systematic review found that hypnotherapy improved cancer pain without exception
in a small number of controlled and observational studies,8 although further large RCTs are
required to confirm this positive trend. Finally, systematic reviews of RCTs and
observational studies have demonstrated that hypnotherapy is a potentially valuable
treatment for acute procedural pain and distress in adult and paediatric cancer patients,19,20
although limitations of the studies identified (e.g. non-reporting of the method of
randomisation, outcome measures used may not be clinically-relevant) suggest that further
RCTs should be performed.
2.2.4 Yoga
Yoga is a series of practices that incorporate eight disciplines, including physical poses and
postures, breath control and meditation, with the goal of uniting the mind, body and spirit
for improved physical/mental health and self-awareness. There are many types of yoga,
with Hatha yoga (a gentle form most commonly practiced in Western countries) and
Tibetan yoga being the most studied in recent years. Yoga has been be well-tolerated in
studies and no serious adverse effects [e.g. ligament/joint damage from overstretching;
nerve/vertebral disc damage, stroke or blood vessel blockage due to (prolonged) postures;
eye damage and blurred vision, including worsened glaucoma, caused by increased
intraocular pressure with headstands]332 have been reported in cancer and other chronic
disease populations, possibly owing to the use of gentle poses and stretching that could be
performed even by patients with functional limitations.123 Nevertheless, complications may
arise in certain circumstances, thus yoga should be avoided or used in a gentler, modified
form under the guidance of an experienced instructor by individuals with balance problems;
269
uncontrolled hypertension, symptomatic anaemia, postural hypotension or
lightheadedness/dizziness; fever, systemic infection or significant thrombocytopenia;
certain eye conditions, including glaucoma and retinal detachment; severe osteoporosis,
vertebral damage or cervical spondylosis; fragile or atherosclerotic neck arteries or a risk of
blood clots; artificial joints or prosthetic devices (e.g. infusaport, colostomy bag, stents);
pregnancy; and psychosis.333
Two systematic reviews of RCTs and observational studies provide preliminary support for
the efficacy of yoga interventions in cancer patients and survivors.21,22 Positive effects were
reported for a range of outcomes including sleep quality, mood, stress and overall QoL, but
several methodological limitations prompted recommendations that further RCTs be
performed employing larger samples, male and female non-breast cancer patients and yoga
interventions targeting specific cancer symptoms or problems.
2.2.5 Tai chi
Sometimes referred to as “moving meditation”, tai chi is derived from TCM and
incorporates slow movements and postures (similar to aerobic exercise), controlled
breathing and meditation. Tai chi appears to be generally safe and no serious adverse
effects have been reported in cancer and other chronic disease populations.23-25 The most
common reported side-effects of tai chi, albeit rare, are sore muscles, sprains and electrical
sensations.334 As with any form of exercise, individuals must be aware of their physical
limitations. Therefore tai chi should be should be used with caution or avoided in patients
with severe osteoporosis, joint problems, acute back pain, sprains or fractures, or whose
physical functioning otherwise precludes certain exercises. Additionally, straining
downward or holding low postures is contraindicated in patients with inguinal hernia;
artificial joints or prosthetic devices (e.g. infusaport, colostomy bag, stents); pregnancy; or
those recovering from abdominal surgery.334
Tai chi has been used by cancer patients to improve QoL, mood, flexibility, and balance.24
Two systematic reviews of controlled studies in supportive breast cancer care, however,
have found insufficient evidence for the positive impact of tai chi on physical or
psychological outcomes and QoL in patients.23,24 Given the small sample sizes and poor
quality of the studies identified, further large RCTs involving breast and other cancer
270
populations are required. Additionally, tai chi should be compared to more conventional
forms of exercise to determine whether it confers additional benefits to patients.
2.2.6 Music therapy
Music therapy is designed to facilitate communication and achieve therapeutic goals
through the creative use of music. Using music alone or in combination with
relaxation/imagery techniques, music therapists help individuals engage with different
aspects of live or recorded music (i.e. via passive listening, singing, writing lyrics, or
playing instruments). Many cancer centres worldwide (including Australia) offer music
therapy, thus it is one of the few creative therapies that have been subjected to scientific
evaluation. A recent meta-analysis of 183 studies across 11 medical specialties (with a
heavy emphasis on cancer patients) revealed that music therapy resulted in significant
improvements in pain, well-being, mood, and nausea and vomiting.26 Although the results
suggest that music therapy is useful in an oncology setting, many of the studies used small
samples and few were RCTs. More large RCTs are required, preferably comparing music
therapy to relaxation/imagery techniques in an effort to determine whether music therapy
per se is effective in improving the QoL of cancer patients. In the interim, however, music
therapy could be supported for use in cancer patients given that few (if any) adverse events
are associated with it.
2.2.7 Support groups
Support groups enable patients at any stage of their cancer experience to gain emotional
support from others with similar experiences (and to reciprocate in kind) by sharing
information, experiences and feelings in a caring environment. One of the main aims is to
enhance the patient’s individual coping resources. Cancer support groups include a variety
of different approaches (e.g. psychotherapy, psychoeducation, cognitive-behavioural
therapy), types (e.g. face-to-face, telephone or internet support) and settings (e.g.
community centres or hospitals, the patient’s home) encompassing health professional-led
support groups and self-help groups.
A meta-analysis of 20 RCTs has suggested that participation in professional-led support
groups results in significant improvements in cancer patients’ emotional well-being
(depression, anxiety), adjustment to illness, QoL and marital satisfaction, but not survival.27
271
Similarly, a more recent systematic review of 32 RCTs and 12 descriptive studies revealed
that professional-led support groups produced positive effects in psychosocial functioning
(less social isolation, felt more understood and hopeful) and morale and other QoL
dimensions, but not survival.28 Despite these positive findings, a number of caveats were
highlighted in each review including the overrepresentation of women with breast cancer
(usually during survivorship rather than active disease) and the lack of community trials in
the support group literature. Consequently, further RCTs examining professionally-led
cancer support groups must be performed involving patients with different types of cancer
and disease stages, preferably with a greater focus on men (particularly with prostate cancer
given the prevalence of sexual problems) and facilitation of support groups in community
settings (rather than within clinical trials where optimal resources are often available).
Benefit from peer/volunteer support programmes, however, is less apparent for cancer
patients. A systematic review of 16 controlled trials and 26 descriptive studies indicated a
high level of satisfaction with individual/group peer support programmes, but mixed
evidence for psychosocial benefit.29 A systematic review of 10 controlled trials and 10
descriptive studies also found high satisfaction among participants in individual volunteer
support programmes, but very limited evidence for psychosocial benefit given the lack of
RCTs performed. As with professional-led support groups, more large RCTs involving
patients with different types of cancer and disease stages are required to examine
peer/volunteer support programmes, and preferably with a greater focus on men given the
positive bias toward women with breast cancer in existing studies. Furthermore, levels of
psychosocial adjustment and motivation to seek support should be screened prior to
programme participation as patients with low levels may gain limited benefit from such
programmes. Finally, different modes of peer/volunteer support (e.g. individual/group face-
to-face, group internet, individual telephone) need to be compared to determine the best
methods for offering such programmes to cancer patients.
2.2.8 Spirituality, religion and prayer
Spirituality and religion are overlapping concepts that involve a search for the sacred, in
which individuals seek to discover, hold on to, and, when necessary, transform whatever
they hold sacred in their lives.30 Spirituality differs from religion in that religion is a search
272
for significance in ways related to the sacred31 and, in instances of popular usage, places
spirituality within the context of beliefs, values and practices of an organised institution.32,33
Religion and spirituality may be utilised by cancer patients in adjusting to and coping with
cancer. They may serve many functions in long-term adjustment to cancer, including
maintaining self-esteem; providing hope, psychological comfort and strength; and giving
one a sense of meaning and purpose.34,35 A systematic review of 7 longitudinal and 10
cross-sectional studies found some evidence for improved adjustment to illness or reduced
distress of religious/spiritual coping with cancer, but could not draw any firm conclusions
due to serious methodological problems in many studies (e.g. poor conceptualisation and/or
measurement of religious/spiritual coping; inadequate control of confounding variables,
such as disease site/stage/treatment and perceived social support).36 A more recent review
of 4 longitudinal and 36 cross-sectional studies drew similar conclusions regarding
spirituality and emotional well-being in cancer patients.37 Further sizable longitudinal
studies are required that compare spirituality and/or religion (across faiths) as primary
endpoints to other coping strategies (e.g. social support) in specific cancer populations, and
adequately control for potential confounding variables.
Researchers have argued that prayer can be separated from religion in the same way that
related activities such as meditation have (e.g. [Rossiter-Thornton]).38 Private or personal
prayer also needs to be distinguished from intercessory prayer in which a prayer is made on
behalf of someone else, either in their presence or from afar and with or without their
knowledge and approval.39,40 A systematic review of 7 prospective cohort studies, 14 cross-
sectional studies and 3 qualitative studies involving hospitalised populations (including
cancer patients) found a positive association between private prayer and emotional well-
being (anxiety, depression), optimism and functioning, respectively, in patients with
religious faith who engage in regular devoted prayer, and some evidence that prayer out of
desperation (e.g. in response to pain, poor prognosis or postoperative trauma) in the
absence of faith is associated with poorer emotional well-being and functioning.40
Nevertheless, these observations were based on correlational studies and others (involving
mostly Christian samples) that were considerably flawed by the impossibility of including a
true control group (i.e. participation in prayer cannot be manipulated); thus, more rigorous
studies focusing on a range of religious/non-religious coping strategies including faith- and
273
non-faith-based private prayer across different religions are required in cancer patients and,
where possible, must include adequate control for possible confounding variables.
Studies examining the effects of intercessory prayer on well-being in cancer patients are
virtually non-existent. A double-blind RCT of 999 cancer patients found that those
receiving distant intercessory prayer by a Christian prayer chain showed significantly
greater improvement in spiritual and emotional well-being, peace and faith (and,
counterintuitively, a significantly greater decline in meaning over time) compared to
controls, although effect sizes were small in each case.41 Again, whilst interesting, such
studies are considerably flawed by the impossibility of including a true control group (i.e.
intercessors outside the research study cannot be prevented from praying for patients in the
control group; nor can control patients be prevented from believing that they have been
allocated to the prayer group).42 Nonetheless, more rigorous studies involving triple-blind
designs (i.e. participants themselves being unaware that they are part of a study) and a
range of coping strategies including different types of intercessory prayer across faiths (e.g.
distant vs non-distant, daily vs less frequent, long vs short duration, group vs individual
prayer) are required and, where possible, must include adequate control for potential
confounding variables.
More controversial, however, is the research examining the use of religion, spirituality or
intercessory prayer to reduce the risk of cancer incidence or mortality, or improve survival.
Reviews have revealed little evidence that religion or spirituality positively affect cancer
progression or mortality,43,44 with the authors in the first review highlighting that any
association observed might be confounded by cancer patients being more likely to become
spiritual/religious following diagnosis.43 Additionally, a systematic review of 17
epidemiological studies (including a subgroup analysis of 11 studies adjusted for
demographic and lifestyle factors) revealed no significant reduction in cancer risk among
members of Christian communities compared to the general population, and concluded that
healthy lifestyle was the most important mediating factor in explaining any correlation
observed between religious membership and cancer risk.45 Finally, two meta-analyses of
randomised trials involving medical populations (including leukaemia patients) have found
insufficient evidence that distant intercessory prayer has beneficial effects on clinical
outcomes (health, mortality, hospital re-admission).39,46 Whilst seeing no health risks to
274
patients or others from distant intercessory prayer and not trying to persuade believers to
discontinue the practice as part of their faith, the authors in each case questioned the value
of further trials in preference to studies examining the effects of prayer that can be
conceptualised in scientific terms.
2.3 Biologically-based practices
Biologically-based practices involve supplementing a person’s normal diet with additional
extracts, nutrients, herbs and/or certain foods. Examples include, but are not restricted to,
nutritional supplements, herbal and other plant-based preparations (botanicals), animal-
derived extracts, vitamins, minerals, fatty acids, amino acids, proteins, prebiotics and
probiotics (live bacteria often found in whole grains, yoghurt and functional foods), whole
diet therapies, functional foods, and other so-called natural therapies (e.g. shark cartilage
for cancer treatment).47
2.3.1 Nutritional supplements (dietary supplements, food supplements)
Nutritional supplements serve to augment the daily diet with nutrients in instances where
people’s daily intake is insufficient, or they consider their diet requires supplementation.
Nutrients in these products may include vitamins, minerals, herbs or other plant-based
substances (botanicals), amino acids, fatty acids, and substances such as enzymes.
Nutritional supplements may take the form of extracts or concentrates and are marketed in
many guises, including tablets/capsules, liquids, or powders.
2.3.1.1 Antioxidants
Free radicals are unstable molecules produced when the body breaks down food, or is
exposed to environmental influences (e.g. tobacco smoke, radiation). While free radicals
are essential for various biological functions including the removal of damaged cells, they
are also highly reactive and can damage healthy cells via oxidation. Excessive free radicals
may play a role in the development and progression of certain diseases, such as cancer,
cardiovascular disease and liver disease (e.g. [Ames et al]).48 Antioxidants neutralise free
radicals and may protect cells in the body from damage caused by oxidative stress (e.g.
[Wilcox et al]).49 Broadly, antioxidants take the form of nutrients [e.g. vitamins C (ascorbic
acid) and E (alpha-tocopherol); minerals such as selenium and zinc] and non-nutrients (e.g.
phytochemicals such as lycopene, beta-carotene and indole-3-carbinol; zoochemicals in red
275
meat and fish products). Whilst present in food and beverages, they are commonly taken as
nutritional supplements (capsules/tablets, powders). Antioxidant supplements are available
individually or in combination with other antioxidants, vitamins, or vitamins and minerals
as part of multivitamins.
Cancer patients use antioxidants to relieve treatment side-effects (predominantly from
chemotherapy and radiotherapy), for cancer treatment and prevention, and to improve
general health and QoL. The benefits and risks of using antioxidants during cancer
treatment are controversial. Proponents argue that antioxidants are beneficial to patients
undergoing treatment because they enhance the efficacy of chemotherapy, as well as
alleviate treatment toxicity and thus allow patients to tolerate full courses of chemotherapy
and/or radiotherapy with fewer interruptions and dose reductions.50 Others are concerned
that antioxidants may not only reduce the efficacy of some chemotherapy agents and
radiotherapy, but may protect cancer cells as well as healthy cells from oxidative
damage.51,52
In relation to treatment toxicity, a recent systematic review of 33 RCTs found that
concurrent use of antioxidants with chemotherapy resulted in reduced toxicity in the
majority of studies, and that patients in 5 studies completed more full doses of
chemotherapy or had fewer dose reductions when receiving antioxidants than control
patients.53 Similarly, another review suggested that antioxidants may mitigate the adverse
effects of radiotherapy,54 while a meta-analysis of 14 RCTs showed that amifostine
(synthetic antioxidant) significantly reduced the side-effects of radiotherapy.55 In contrast,
however, a systematic review of 22 controlled trials and observational studies involving
breast cancer patients found insufficient evidence that individual antioxidant supplements
reduced toxicity during conventional breast cancer treatment.56 Other systematic reviews
have also revealed insufficient evidence that selenium supplementation alleviates
chemotherapy- or radiotherapy-induced toxicity or postoperative side-effects in cancer
patients,57 or that selenium or lycopene supplementation relieves symptoms in prostate
cancer patients.58,59 Similarly, a systematic review of 6 controlled trials found inconclusive
evidence that coenzyme Q10 (synthetic antioxidant) reduced chemotherapy-induced
toxicity.60 Poor quality and small samples were problematic with some studies in all the
systematic reviews discussed, however, thus large, well-designed RCTs are warranted.
276
The formation of free radicals is the primary mechanism of radiotherapy and many
chemotherapy drugs in destroying cancer cells. Such chemotherapy drugs include
anthracyclines (e.g. doxorubicin, epirubicin), alkylating agents (e.g. cyclophosphamide,
ifosfamide), platinum-containing complexes (e.g. cisplatin, carboplatin), podophyllotoxin
derivatives (e.g. etoposide), camptothecins (e.g. irinotecan), and cytotoxic antiobiotics (e.g.
bleomycin).61,62 Antioxidant supplementation could improve treatment response and
survival by helping patients tolerate full doses of these chemotherapy drugs with
uninterrupted treatment schedules. However, they could also hinder the cytotoxic
mechanisms of chemotherapy by scavenging free radicals produced by the drugs.
One systematic review of 21 randomised trials and 31 observational studies of antioxidants
and chemotherapy observed such great diversity across studies (study design, cancer
diagnoses, chemotherapy regimens, type/dose/schedule of antioxidant supplementation)
that definitive conclusions could not be made about the efficacy and safety of antioxidant
supplementation.63 Similarly, a systematic review of 22 controlled trials and observational
studies could not draw any conclusions regarding the effects of antioxidants during breast
cancer treatment (chemotherapy, radiotherapy and/or hormonal therapy) on tumour
response, survival or recurrence;56 nor could the authors in a systematic review of lycopene
supplementation in prostate cancer patients.59 Another review of 44 randomised trials,
however, went further and concluded that concurrent use of antioxidants with
chemotherapy and/or radiotherapy should be discouraged due to the possibility of tumour
protection and reduced survival, despite limited evidence of these negative outcomes during
radiotherapy and limited evidence that some antioxidant supplements may actually enhance
the efficacy of chemotherapy.61 In contrast, a systematic review found that the great
majority of 19 RCTs demonstrated either statistically significant or non-significantly
greater survival and/or treatment response for concurrent use of antioxidants with free
radical-generating chemotherapy, in patients with predominantly advanced or recurrent
cancer.62 Additionally, no evidence was found that antioxidant supplementation reduced the
efficacy of chemotherapy. Nevertheless, the authors concluded that the number of small,
statistically underpowered studies and diversity of cancer diagnoses and chemotherapy
treatments limits any clear conclusions being made about the potential benefits of
277
antioxidant supplementation during chemotherapy, and recommended that large, well-
designed studies be performed.
More unequivocal, though, were the results of three meta-analyses. One meta-analysis of 7
RCTs (with no evidence of heterogeneity) found that amifostine (synthetic antioxidant) had
no effect on tumour response in locally advanced non-small cell lung cancer patients
treated with radiotherapy ± chemotherapy.64 Another meta-analysis and systematic review
of 38 studies found no support that vitamin E or C supplementation helped treat or prevent
cancer.65 The third meta-analysis of 10 unblinded RCTs (with no evidence of
heterogeneity), however, demonstrated consistent positive effects on 1-year survival across
melatonin dose and diagnosis for advanced solid tumour patients receiving melatonin alone
or combined with cancer treatment.66
In summary, many of the studies (including the RCTs) examining the effects of
antioxidants during cancer treatment on tumour response, survival or recurrence have
employed insufficient sample sizes based on estimates of the primary endpoints of toxicity
rather than local tumour control. Moreover, variable doses and protocols of antioxidants,
chemotherapy and/or radiotherapy have been used and only short-term follow-up has
occurred. Large, well-designed RCTs should measure both the benefits and toxicities of
specific antioxidants (defined by dose and schedule) used concurrently with different
chemotherapy and/or radiotherapy protocols and cancer populations. Furthermore, studies
should measure short- and long-term tumour control and toxicities, as well as long-term
survival and recurrence rates. Finally, RCTs need to employ multiple arms to evaluate
multiple regimens simultaneously, given the large number of antioxidants and
combinations thereof.67
Turning to chemoprevention, several recent meta-analytic and systematic reviews have
produced disappointing results. A meta-analysis of 22 RCTs indicated that there is no
evidence for the primary or secondary prevention of cancer through use of antioxidant
supplements.68 Another meta-analytic and systematic review of 12 RCTs (predominantly
high quality) revealed that antioxidant supplementation did not significantly reduce total
cancer incidence or mortality or any site-specific cancer incidence in primary prevention.69
Similarly, meta-analytic and systematic reviews do not support the supplementation of
antioxidants (vitamins A, C, E; selenium; beta-carotene) alone or in combination to prevent
278
colorectal cancer70 or gastrointestinal cancers;71 vitamin C or E individually to prevent
cancer overall;65,69,72,73 or vitamin C or E, folate or beta-carotene individually to prevent
lung cancer.74,75 Perhaps the only exceptions to these discouraging results are that vitamin E
and selenium may have preventative effects for prostate cancer and gastrointestinal cancers
or cancer in men, respectively, although confirmation is required in further RCTs.69,71,72
Despite the lack of clinical trial data, antioxidants in foods are generally considered safe
and few studies of antioxidant supplements have reported adverse effects. Common minor
adverse effects include mild diarrhoea and gastrointestinal upset for vitamin C,76 and
carotenodermia (yellowish discolouration of the skin) following heavy, chronic intake of
beta-carotene.71 However, the research does point to some potential concerns. For example,
high-dose beta-carotene appears to increase lung cancer incidence and cancer mortality
among smokers;69,77 antioxidant supplementation may increase the risk of bladder cancer;68
and high vitamin E supplementation may increase bleeding in individuals with drug-
induced vitamin K deficiency.76,78 Possible contraindications therefore include coagulation
disorders and surgery, as well as use of anticoagulants (e.g. warfarin) and antiplatelet
medications (e.g. aspirin). Given the lack of human clinical trials, particularly those
providing long-term safety data, concurrent antioxidant supplementation during cancer
treatment is not recommended without the guidance of the oncology treatment team.
2.3.1.2 Omega-3 fatty acids (n-3 polyunsaturated fatty acids)
Omega-3 fatty acids [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-
linolenic acid (ALA)] influence many physiological functions, including fertility, cell
division, angiogenesis, apoptosis and immune cell function, thus suggesting they may
protect against cancer or alter the response to cancer treatment.79,80 Omega-3 fatty acids are
found naturally in fish, fish oil, vegetable oils (mainly canola and soybean), walnuts, wheat
germ, and other foods. They are also available as nutritional supplements in fish oil
preparations in both capsule and liquid form. EPA and, to a lesser extent, DHA have
demonstrated anti-cancer and anticachectic effects in human studies.81-84
Omega-3 fatty acids have been used to prevent cancer, as well as to decrease weight loss,
promote weight gain and increase survival in cancer patients with cachexia.84 A meta-
analytic and systematic review of 38 studies, involving 20 different prospective cohorts
279
across 7 countries with different demographics, revealed that data across 11 different types
of cancer suggested that nutritional supplementation with omega-3 fatty acids is unlikely to
prevent cancer.85 Additionally, a recent meta-analysis of 5 prospective studies found a weak
protective association between high dietary ALA intake (1.5g/day) and prostate cancer
risk.86 In contrast, two other recent meta-analyses of prospective and case-control studies
revealed that high intake or blood level of ALA (but not EPA or DHA intake) is weakly
associated with an increased risk of prostate cancer.87,88 Heterogeneity across identified
studies and/or publication bias in these meta-analyses necessitates clarification of these
inconsistent results in further in vitro and epidemiological studies.
Many advanced cancer patients develop cachexia and treatment of associated weight loss
and other symptoms has proven difficult. More recently, novel approaches have included
the use of fish oils containing EPA and DHA. A Cochrane meta-analytic review of 5 RCTs
found insufficient data to establish whether oral EPA was better than placebo in improving
symptoms associated with cachexia in advanced cancer patients.84 Similarly, a meta-
analytic and systematic review of 19 studies demonstrated no effect of omega-3 fatty acids
on weight loss, nutritional status, postoperative complications, mortality or length of
hospital stay after surgery for upper gastrointestinal cancers.85 A more recent systematic
review of 17 clinical trials and prospective studies, however, suggested that dietary or
supplemental intake of omega-3 fatty acids (EPA and/or DHA; 1.5g/day) for prolonged
periods (8 weeks) by advanced cancer patients is associated with improved clinical
(nutritional status, tolerance, survival, hospital stays), biological and QoL outcomes.83
Given the paucity of RCTs and the frequent employment of small samples and
supplementation of omega-3 fatty acids with other supportive treatments (e.g.
corticosteroids, appetite stimulants such as megestrol acetate), further large RCTs are
required to determine whether EPA or DHA supplementation alone or in combination with
each other or other supportive treatments is beneficial for cachexia in specific cancer
populations.
Generally, omega-3 fatty acids are well-tolerated and cause few adverse effects in low to
moderate doses. Gastrointestinal symptoms (e.g. diarrhoea, heartburn, bloating, nausea) are
the most common side-effects. In pancreatic cancer patients, the dosage tolerated was
limited by a sensation of fullness, cramping abdominal pain, diarrhoea and nausea.82
280
Omega-3 fatty acids are thought to increase the risk of bleeding, but clinical trials have
shown that high doses do not affect coagulation and platelet function following major
surgery or when concurrently administered with anticoagulant/antiplatelet medications such
as warfarin, and aspirin (e.g. [Carayol et al, Simon et al]).86,87 Nonetheless, it may be
prudent to avoid high-dose fish oil intake or supplementation in patients with coagulation
disorders or at high risk to haemorrhagic stroke, and discontinue use 4-7 days prior to
surgery.89 Finally, excessive fish consumption may result in adverse effects due to toxic
levels of mercury and other contaminants, although this does not apply to fish oil
supplements.89
2.3.1.3 Shark cartilage and AE-941 (Neovastat)
Shark cartilage use by cancer patients became popular in the 1980s after several poor
quality studies claiming “miracle” cancer cures were reported by the US media,90 many of
which were generated by a single manufacturer (Lane Labs-USA, producer of BeneFin).
Use of shark cartilage in cancer patients originally stemmed from and has been perpetuated
by the popular belief that sharks do not develop cancer because of the high proportion of
cartilage in their body (about 6% by body weight).91 Scientifically, this has been shown to
be untrue (several tumours in sharks have subsequently been detailed in a review article).92
Primarily extracted from the backbone and head of the spiny dogfish shark (Squalus
acanthias) and hammerhead shark (Sphyrna lewini),93,94 shark cartilage is frequently
promoted as a nutritional supplement for the alternative treatment of diseases including
cancer, arthritis, osteoporosis and pain. The major compounds in shark cartilage are
proteoglycans and glycosaminoglycans (large molecules made of protein and
carbohydrate), protein and calcium salts.94 Shark cartilage preparations are administered
orally (tablets/capsules, powdered liquid), topically, subcutaneously by injection, or used
rectally or intravaginally as an enema/suppository.94 Shark cartilage preparations are not
standardised and there is no generally accepted recommended dosage or duration for
administration. Preparations may contain varying amounts of shark cartilage (e.g. liquid
shark cartilage preparations reportedly contain over 99% water and less than 1% protein;
excessive binding agents and fillers may be added to powdered shark cartilage during
processing, including collagen, gelatin, talc, magnesium stearate and silica), which may not
have any biological activity and can affect the safety of their use.94,95 The only standardised
281
source of shark cartilage is Neovastat (AE-941, manufactured by AEterna Zentaris), a
matrix metalloproteinase inhibitor that has been specifically developed as a highly purified
liquid shark cartilage extract for evaluation in clinical drug trials.
While some preclinical studies of shark cartilage and preliminary clinical studies of
Neovastat have demonstrated anti-angiogenic and anti-cancer properties,96 and it has been
observed that cartilage lacks blood vessels and that human cancer rarely invades
cartilage,97,98 no controlled study has demonstrated that crude cartilage extracts are
beneficial in the treatment of cancer in humans (or animals).99-102 In a double-blind RCT of
83 incurable breast and colorectal carcinoma patients (with good performance status and
organ function), no differences in overall survival or QoL were observed between patients
receiving standard conventional care (including chemotherapy for some patients) +
powdered liquid shark cartilage extract (BeneFin nutritional supplement, 3-4 times daily
until unacceptable toxicity developed) versus standard conventional care + placebo.101
These results mirrored those of a previous uncontrolled phase I/II trial involving 60
advanced cancer patients.103
Larger RCTs involving the use of Neovastat in cancer patients have been similarly
disappointing. In a double-blind RCT of 305 metastatic renal cell carcinoma patients
refractory to immunotherapy, no survival advantage was observed in patients treated with
Neovastat versus placebo.104 More recently, a comprehensive double-blind RCT of 379
locally advanced non-small cell lung cancer patients (newly-diagnosed, unresectable and
previously untreated) found no differences in overall survival, tumour response rates, time
to disease progression and progression-free survival between patients receiving
chemoradiation + Neovastat (120ml orally, twice daily until disease progression or
unacceptable toxicity developed) versus chemoradiation + placebo.102 It was concluded that
the results do not support the use of shark cartilage-derived products for lung cancer
patients, and has prompted the pharmaceutical manufacturer of Neovastat to cease clinical
development. Given the lack of available evidence and the expense associated with shark
cartilage products, it is difficult to recommend shark cartilage even as a complementary
therapy to conventional anticancer treatments. Certainly, it is not recommended as an
alternative therapy to conventional anticancer treatments.
282
A limited number of published studies suggest that shark cartilage is well-tolerated in most
people (including advanced cancer patients) at doses administered in clinical trials, even in
the long-term (over 4 years with Neovastat).94,101,102,105,106 Additionally, drug interactions
with shark cartilage have not been reported.94 The most common adverse effects reported
are gastrointestinal symptoms (nausea, vomiting, stomach upset, constipation, diarrhoea,
flatulence) and taste alteration.94,103,105
Very limited evidence suggests that shark cartilage may result in lower blood sugar levels
in diabetics or hepatitis,105,107 thus caution is advised in patients with diabetes,
hypoglycaemia or liver disease and in those taking medications, herbs, or nutritional
supplements that affect blood sugar levels or liver function. Additionally, some shark
cartilage products may contain high calcium content; while hypercalcaemia is not
contraindicated,103 use is best avoided with calcium supplements and medications (e.g.
calcitriol, thiazide diuretics, antacids) that elevate blood calcium levels. Consistent with
warning labels on some products due to the anti-angiogenic effects of shark cartilage, use is
also best avoided in surgical patients (potential for slow wound healing) and pregnant or
breast-feeding women (potential teratogenic effects).94 Finally, excessive shark cartilage
consumption may result in adverse effects due to toxic levels of mercury, cadmium and
other contaminants.94,108 In short, the available evidence does not indicate great safety
concerns regarding shark cartilage use; however, a systematic long-term safety study of
shark cartilage nutritional supplements (as performed for Neovastat) would be advisable
given the standardisation and contamination issues reported.
2.3.1.4 Laetrile and amygdalin (Vitamin B17)
Laetrile has been popularly used by cancer patients worldwide since the 1970s in the hope
that it might cure or slow the growth of cancer. The term “laetrile” is an amalgam of
laevorotatory and mandelonitrile, which is used to describe a purified form of amygdalin
(cyanogenic glycoside plant compound).109 Amygdalin is found in the stones of many fruits
(primarily apricots); nuts (e.g. almonds, cashews); many plants belonging to the Rosaceae
family, such as Prunus persica (peach), Prunus armeniaca (apricot), Prunus amygdalus
(almond) and Prunus amygdalus var. amara (bitter almond); and the bark of Prunus
Africana (pygeum; often mistaken as bitter almond).3,110 Laetrile may be taken as an oral
supplement (dubbed vitamin B17, although not a real vitamin), or injected intravenously,
283
intraperitoneally or intramuscularly. Laetrile is commonly given intravenously over a
period of time and then orally as maintenance therapy. While laetrile and amygdalin are
often used interchangeably, they are not quite the same. The intravenous form of laetrile
(D-mandelonitrile-beta-glucuronide) is a US patented semi-synthetic derivative of
amygdalin, while laetrile produced in Mexico (D-mandelonitrile-beta-gentiobioside) is
usually amygdalin naturally produced from crushed apricot stones.
Laetrile/amygdalin is typically used as an adjunct to conventional anticancer treatments or
in combination with other alternative therapies, such as metabolic therapy (e.g. combining
diet, enzymes and vitamins), dietary intake of fruit seeds (apricot, peach, bitter almond),
diet therapy, nutritional supplements, urine therapy and beta-glucuronidase injections.111 In
vitro studies suggest that amygdalin has anti-cancer properties (e.g. [Fukuda et al, Syrigos
et al]),109,112 but no RCTs have been performed of amygdalin or laetrile in humans.3 A
limited uncontrolled phase II trial, performed by the US National Cancer Institute in 1982,
found that 95 of 178 (53%) mixed, non-metastatic cancer patients experienced disease
progression and only 1 patient exhibited a partial tumour response (lasting 10 weeks)
following 21 days of intravenous laetrile + oral maintenance therapy combined with
metabolic therapy (pancreatic enzymes, high vitamin doses, dietary changes employed by
metabolic practitioners).111 Furthermore, all remaining patients experienced disease
progression within 7 months post-treatment, and no significant difference in survival was
observed compared to historical controls who had inactive or no treatment.
Better evidence, however, is offered by a systematic review of 36 studies (25 case reports, 6
best case series of case reports, 3 non-consecutive case series, 2 consecutive case series)
involving 352 cancer patients treated with laetrile/amygdalin.110 Despite the likelihood of
positive bias in case reports, only 3.1% of patients reportedly had a complete response and
9.4% had a partial response (although some of these patients may have received
conventional treatments and no detailed follow-up information was reported for complete
response patients), while 36.4% exhibited disease progression; symptomatic benefits were
also reported in 22.9% of cases. The authors concluded that the claim that laetrile has
beneficial effects for cancer patients is not supported by sound clinical evidence, although
well-designed RCTs could be considered given several limitations of the review (i.e. poor
quality and methodological/clinical heterogeneity of identified studies, paucity of data).
284
Possible adverse effects of laetrile/amygdalin are of particular concern, given the belief that
cyanide produced when it is broken down is what kills cancer cells. In the aforementioned
systematic review, 14.4% of patients experienced adverse reactions consisting mainly of
nausea, vomiting, headache, fever and abdominal pain.110 Other adverse effects include
dizziness, acute cognitive disorientation, dermatitis, bluish discolouration of the skin (due
to oxygen deprivation in the blood), hypotension, neuropathy, hepatotoxicity, and
coma.111,113,114 Adverse events are usually associated with intravenous administration of
laetrile, but have been observed in patients receiving laetrile orally, intramuscularly, or as
enemas.110
The most important concern with toxicity, however, involves several reports of cyanide
poisoning (including deaths) from use of laetrile/amygdalin by cancer patients in North
America in the 1970s and 80s, which prompted the US to ban its use and other countries
(including Australia, UK and other European nations) to require special permission from
governing health regulatory agencies to import it from Mexico and other countries. The risk
of cyanide poisoning associated with laetrile/amygdalin appears high; it is elevated by
concurrent dietary intake of fruit seeds (apricot, bitter almond, peach, apple) and raw
almonds (containing beta-glucosidase that combines with laetrile/amygdalin to produce
cyanide) or megadoses of vitamin C (reducing body stores of cysteine, an amino acid that
facilitates the detoxification of cyanide), as well as in individuals who have a genetically
predisposed, diminished capacity to detoxify cyanide.110,111,115 Adverse events could also be
related to overdosing or problems relating to product standardisation and labelling. Studies
indicate that adulteration, contamination of laetrile/amygdalin preparations (e.g. by
bacteria) and mislabelling in Mexico (the world’s largest supplier) are not uncommon.116,117
In summary, the evidence that laetrile/amygdalin does more good than harm is weak and it
would, therefore, be prudent to advise cancer patients to avoid use outside clinical trial
settings.
2.3.2 Chinese herbal medicine
Chinese herbal medicine (CHM) is a key part of TCM and is used to normalise imbalanced
energy that runs through invisible meridians in the body. CHM includes any mixture of
herbs (mainly plant-based, but may include minerals or animal extracts) and decoction
(liquid extraction of boiled herbs), which may take the form of tablets/capsules, powders,
285
tonics, lotions and pastes. There are a number of issues associated with the safety and
quality of CHMs, including herb-drug interactions [via induction or inhibition of enzyme
systems (e.g. cytochrome P450) or by affecting efflux proteins (e.g. P-glycoprotein)],
resulting in reduced efficacy or increased toxicity of chemotherapy and prescription
medications; direct (pharmacological) or indirect (e.g. free radical-mediated) toxicities;
allergic responses; contamination with heavy metals, pesticides, micro-organisms or other
impurities; deliberate substitution or adulteration with prescription or non-prescription
drugs (e.g. corticosteroids, hormones, salicylates, antihistamines, caffeine); and microbial
reactivation of virii or disease (e.g. hepatitis B or C, herpes simplex, varicella zoster,
tuberculosis).118 The safety and quality of CHMs are regulated by the Therapeutic Goods
Administration (TGA) in Australia, but limitations of The Therapeutic Goods Act 1989 do
not subject individual practitioners to the standards that companies selling CHMs are
required to meet.119 Consequently, practitioners can import raw herbs that may not meet the
TGA standards and legally dispense them over the counter without registering with the
TGA.
2.3.2.1 Astragalus (Astragalus membranaceus, Astragalus mongolicus, Astragalus
propinquus, Radix astragali)
Astragalus is usually combined with other Chinese herbs, particularly as part of an
immune-enhancing herbal regimen known in TCM as Fu Zheng therapy. It is typically
administered as a dried root, a powder or in a decoction, although may be given by
intraperitoneal injection also. Human and in vitro studies have demonstrated the
immunostimulatory properties of astragalus polysaccharides and triterpinoid saponins in
both healthy individuals and cancer patients (e.g. by stimulating macrophage and natural
killer cell activity, and inhibiting T-helper cell type 2 cytokines), as well as anti-cancer
activity.121,347-353
Astragalus is primarily used by cancer patients to boost immunological function, reduce
chemotherapy toxicity and increase survival (via use as an adjunct to conventional
anticancer treatment). In China, astragalus-based Chinese herbs (e.g. Jin Fu Kang)
combined with platinum-based chemotherapy is a standard treatment for non-small cell
lung cancer. A meta-analysis of 34 Chinese RCTs found evidence that astragalus-based
herbal medicine (oral Jin Fu Kang, Aidi injection, other preparations) may enhance the
286
treatment outcomes (improved survival, tumour response and performance status) and
reduce the toxicity (leukopenia, haemoglobin toxicity) of standard platinum-based
chemotherapy for advanced non-small cell lung cancer patients.120 Similarly, a more recent
meta-analysis and systematic review of 45 RCTs revealed that oral astragalus-based herbal
medicine enhanced complete/partial tumour response, survival rates and symptom control
(abdominal pain, fatigue, appetite loss), and reduced the risk of disease progression (for
astragalus alone also) in unresectable liver cancer patients receiving transcatheter arterial
chemoembolization.354 Another systematic review of 14 Chinese RCTs suggested that Aidi
injection improved the tumour response and QoL of non-small cell lung cancer patients
receiving chemotherapy involving vinorelbine and cisplatin injections or cobalt-60 (but not
etoposide or paclitaxel combined with cisplatin injections).355 Finally, a Cochrane meta-
analytic review of 4 RCTs involving colorectal patients suggested that astragalus (huang qi)
compound decoctions as an adjunct to chemotherapy may decrease chemotherapy toxicity
(nausea and vomiting, leukopenia) and stimulate immunocompetent cells.121 The authors in
each review, however, concluded that more large, rigorous RCTs were needed to confirm
these benefits given the poor quality of the studies examined (e.g. selection bias, small
sample size, lack of blinding and use of true randomisation procedures),120,121,354,355 not to
mention the heterogeneity in astragalus preparations (e.g. single herb vs combined herbal
preparations, oral administration vs injection, dosage) and clinical characteristics (e.g.
disease stage) also observed across studies.
Astragalus is generally considered safe, with no serious adverse events or drug interactions
reported to date in cancer and other populations.120-123,356 Attributing specific adverse
events or drug interactions to astragalus is difficult, however, given that it is predominantly
used in combined herbal preparations. Nevertheless, side-effects of oral astragalus-based
preparations have been reported in two phase II studies involving incurable cancer patients
receiving standard care (including chemotherapy and/or radiotherapy) and incurable non-
small lung cancer patients undergoing adjuvant chemotherapy with paclitaxel,
respectively.356,357 Most predominant were grade 3 lymphopenia, grade 3/4
hyperglycaemia and grade 1/2 gastrointestinal symptoms (e.g. diarrhoea, dyspepsia).356,357
Additionally, direct ingestion of certain toxic astragalus plants (locoweed) containing
swainsonine or selenium may cause neurological symptoms, some of which are
irreversible.358,359 Finally, due to its immunostimulatory properties, possible
287
contraindications of astragalus include autoimmune diseases (e.g. multiple sclerosis, lupus,
rheumatoid arthritis) and organ transplant, and use of medications that suppress the immune
system including chemotherapy agents such as cyclophosphamide, immunosuppressants
(e.g. cyclosporine, tacrolimus) and corticosteroids.359,360 Overall, more rigorous studies are
required to investigate the safety of astragalus.
2.3.2.2 Ginseng (Panax ginseng, Panax quinquefolium, Eleutherococcus senticosus,
Angelica sinensis)
Ginseng is primarily used by cancer patients to boost immunological function, reduce
physical and emotional stress, inhibit cancer growth, and ameliorate fatigue and
menopausal symptoms. While the immunostimulatory properties of ginseng (and its
ginsenosides) have in recent reviews124-126 suggested its use as an adjuvant or
immunotherapeutic agent, to enhance immunological function and improve QoL in cancer
patients during chemotherapy and radiotherapy, RCTs are yet to be performed to confirm
these benefits.
Ginseng is associated with a relatively low incidence of adverse events, with reports being
attributed to adulterated or contaminated preparations.122,127 Common side-effects of
ginseng include insomnia if taken in the evening, and agitation/overstimulation if
excessively used.122 Possible contraindications of Asian ginseng (Panax ginseng) and
American ginseng (Panax quinquefolium) include hypertension, diabetes, coagulation
disorders and surgery,122,128 and use of anticoagulants (e.g. warfarin) or antiplatelet
medications (aspirin), phenelzine (monoamine oxidase inhibitor antidepressant),
hypoglycaemics, oestrogens, corticosteroids or alcohol.118,127,128,203 Possible
contraindications of Siberian ginseng/eleuthero (Eleutherococcus senticosus) include
cardiovascular disease129 and use of digoxin (heart medication) and antihypertensive
medications.118 Finally, ginseng, particularly dong quai/female ginseng (Angelica sinensis),
has oestrogenic effects and may interfere with the treatment of hormone-sensitive
conditions, such as breast cancer (e.g. hormonal therapy) and pregnancy.130
2.3.2.3 Ginger (Zingiber officinale)
Ginger may be used by cancer patients to alleviate postoperative and chemotherapy-
induced nausea and vomiting, as well as gastrointestinal symptoms including diarrhoea. A
288
meta-analysis of 5 RCTs demonstrated that a fixed dose of ≥1g of ginger is more effective
than placebo in reducing acute postoperative nausea and vomiting.131 Studies examining the
efficacy of ginger for chemotherapy-induced nausea and vomiting, however, have produced
mixed results and are still in their infancy.132-136 More RCTs comparing ginger to current
antiemetics are required.
Ginger causes few adverse effects when taken in small doses. Gastrointestinal symptoms
(e.g. heartburn, bloating, flatulence) are the most common side-effects. Additionally, ginger
inhibits thromboxane synthase (platelet enzyme) and platelet aggregation, thus the risk of
bleeding is increased in individuals taking anticoagulant/antiplatelet medications (e.g.
warfarin, aspirin), those with coagulation disorders and surgical patients.128
2.3.2.4 Lingzhi/Reishi mushroom (Ganoderma lucidum, Ganoderma tsugae)
Lingzhi is a traditional medicinal mushroom that has been used extensively in cancer
treatment in Asia. Lingzhi polysaccharides have demonstrated anti-cancer and
immunostimulatory properties.137 Reviews of preliminary clinical data suggest that Lingzhi
extracts or powders may have some potential in cancer treatment, but more rigorous RCTs
are required to establish its efficacy and safety as an adjuvant or standalone treatment.137,138
Adverse effects from medicinal mushrooms are rare. Dry throat and nose and
gastrointestinal symptoms are the most common side-effects of Lingzhi. Caution is
warranted, however, as Lingzhi causes platelet inhibition, thus the risk of bleeding is
increased in individuals taking anticoagulant/antiplatelet drugs (e.g. warfarin, aspirin),
those with coagulation disorders and surgical patients.139 Additionally, Lingzhi can increase
antioxidant capacity and may interact with chemotherapy agents that rely on free radicals
[i.e. anthracyclines (e.g. doxorubicin, epirubicin), alkylating agents (e.g.
cyclophosphamide, ifosfamide), platinum-containing complexes (e.g. cisplatin,
carboplatin), podophyllotoxin derivatives (e.g. etoposide), camptothecins (e.g. irinotecan),
cytotoxic antiobiotics (e.g. bleomycin)].140
2.3.2.5 Green tea (Camellia sinensis, Thea sinensis)
Green tea and its extracts have a long history of use as a traditional cancer treatment in
Asian cultures. Polyphenols in green tea known as catechins, particularly epigallocatechin
gallate (EGCG), have demonstrated anti-cancer, antioxidant and chemopreventive
289
properties.141 The US Food and Drug Administration (FDA) in a review of studies
concluded that there is no supportive evidence for green tea decreasing the risk of gastric,
lung, colorectal, oesophageal, pancreatic, ovarian and combined cancers, but weak
evidence for decreased risk in breast and prostate cancer.142 Similarly, more recent
systematic reviews have suggested that green tea may reduce cancer risk and slow or
prevent progression in cancer patients, but found the overall evidence to be
inconclusive143,144 and counselled that use of green tea alone to treat cancer may be ill-
advised given its limited cytotoxic effects.144 Given the paucity of observational studies and
RCTs and heterogeneity of existing studies, further large prospective cohort studies and
clinical trials are warranted and should involve standardised preparations of green tea in
various populations and control for lifestyle factors and other confounding variables.
Green tea is generally safe when consumed in moderate amounts (3-9 cups per day).
Excessive consumption (5-6 litres per day) may cause gastrointestinal and central nervous
system disturbances (e.g. nausea, insomnia, irritability, frequent urination, cardiac
arrhythmia), however, predominantly as a result of the caffeine content rather than the
tannin content of green tea.145,146 Possible contraindications include known
allergy/hypersensitivity to caffeine or tannin (in food such as fruit, nuts and chocolate, and
beverages such as coffee, teas, fruit juices, wine and beer), pregnancy, breast-feeding and
heart conditions, and use of verapamil (antihypertensive/antiarrhythmic). Additionally,
EGCG and other polyphenols in green tea are potent blockers of boronic acid-based
proteasome inhibitors and can reduce the efficacy of bortezomib during chemotherapy for
multiple myeloma and mantle cell lymphoma.147
2.3.2.6 Ginkgo (Ginkgo biloba, EGb 761)
Ginkgo is one of the most popular herbal medicines worldwide; it is used for a wide range
of conditions including cardiovascular disease, stress, neurodegenerative diseases such as
Alzheimer’s, cognitive impairment including memory loss and psychiatric disorders such
as schizophrenia, as well as cancer. Ginkgo is contained in the leaves and seeds of the
ginkgo tree and is available as a standardised extract (EGb 761), thus may be taken orally
or, in rare cases, intravenously. Amongst others, the flavonoids and the terpenoids
(gingkolides, bilobalide) of ginkgo have been reported to have anti-cancer, antioxidant,
290
cardioprotective, antiplatelet, stress-alleviating, cognitive-improving and sexually-
enhancing effects.346 RCTs are yet to confirm these benefits in cancer patients, however.
Ginkgo has been associated with adverse effects in recent years. Side-effects of excessive
consumption include headache, gastrointestinal disturbances (e.g. nausea, diarrhoea),
dizziness, palpitations, convulsions (due to 4-methoxypyridoxine in ginkgo seeds), allergic
skin reactions (by handling ginkgo seeds), and anaphylaxis-like reactions (intravenous
administration only).346 Ginkgo enhances anticoagulant/antiplatelet activity and increases
the risk of bleeding, thus possible contraindications include coagulation disorders and
surgery and use of anticoagulant/antiplatelet medications (e.g. warfarin, aspirin) and non-
steroidal anti-inflammatory drugs (e.g. ibuprofen).128,203,346 Other possible contraindications
include seizure disorders, and use of anticonvulsants/antiepileptics (e.g. phenytoin, valproic
acid) in individuals with seizure disorders and other drugs metabolised by the cytochrome
P450 C219 enzyme, such as omeprazole (proton pump inhibitor for gastrointestinal
disorders).141,203
2.3.3 Western herbal medicine
Western herbal medicine (WHM) includes any mixture of herbs that are primarily native to
Europe, which may take the form of tablets/capsules, infusions (teas), concentrated liquid
extracts (requiring dilution) and lotions. WHMs share the same safety and quality issues
associated with TCMs.
2.3.3.1 St. John’s wort (Hypericum perforatum)
St. John’s wort (SJW) is well-known for its antidepressant activity. Cancer patients often
use SJW to reduce depression and anxiety. While a Cochrane meta-analytic review of 29
RCTs suggests that SJW has similar efficacy to standard prescription antidepressants and
fewer side-effects,148 multiple herb-drug interactions preclude safe use in cancer patients
and other populations. In fact, SJW is the most implicated herbal product in herb-drug
interactions reported in the literature to date.149 Human studies suggest that SJW can
interact with medicines by affecting drug metabolism (via induction of cytochrome P450
enzymes, particularly cytochrome P450 3A4, and P-glycoprotein) or levels of
neurotransmitters (primarily serotonin).141,203 Consequently, SJW is contraindicated with
the use of opioids, anaesthetics (e.g. fentanyl and propofol), benzodiazepines (e.g.
291
midazolam) and anticoagulants (e.g. warfarin) in surgical patients, and opioid use for
cancer pain in (palliative) patients (e.g. morphine, fentanyl).128,203
SJW taken in combination with other antidepressants (e.g. selective serotonin reuptake
inhibitors such as sertraline; serotonin and noradrenaline reuptake inhibitors such as
venlafaxine; tricyclics such as amitryptiline; monoamine oxidase inhibitors such as
phenelzine) by cancer patients may result in reduced efficacy of the antidepressants or
serotonin syndrome [cognitive, autonomic and somatic effects ranging from mild
symptoms (e.g. hypervigilance, agitation, muscle twitching) to severe symptoms (e.g.
tachycardia and hypertension that may lead to shock and death)].149,203 Additionally, SJW
can reduce the efficacy of imatinib during chemotherapy for chronic myeloid leukaemia,
gastrointestinal stromal tumours and other malignancies, while having the same effect
accompanied by greater myelosuppression in advanced colorectal and lung cancer patients
receiving irinotecan.150,203 Finally, other contraindications of SJW include cardiovascular
drugs (e.g. digoxin; beta-blockers such as talinilol; antihyperlipidemic drugs, such as
simvastatin, for high cholesterol), immunosuppressants (e.g. cyclosporine, tacrolimus),
anxiolytics (e.g. buspirone), anticonvulsants (e.g. mephenytoin), antimigraine drugs (e.g.
triptans such as eletriptan), antiretrovirals (e.g. protease inhibitors such as indinavir; non-
nucleoside reverse transcriptase inhibitors such as nevirapine), anti-addiction medications
(e.g. buproprion for smoking cessation), muscle relaxants (e.g. chlorzoxazone), respiratory
drugs (e.g. antihistamines such as fexofenadine), hypoglycaemics (e.g. gliclazide),
antimicrobial drugs (e.g. antibiotics such as erythromycin), drugs acting on the GI tract
(e.g. antidiarrhoeal drugs such as loperamide, antacids such as omeprazole), and oral
contraceptives (e.g. ethinyl estradiol/norethindrone).149,151,203
2.3.3.2 Garlic (Allium sativum)
Garlic has had a long history of use worldwide for general health, as well as a variety of
conditions including infections and cancer. Garlic can be eaten raw or cooked, may be dried
or powdered and used in tablets/capsules, or take the form of oils and liquid extracts.
Amongst others, garlic has been reported to have antimicrobial, antithrombotic, immune-
enhancing, and anti-cancer/chemopreventive effects.152-155 A meta-analysis of 18
observational studies suggested that high consumption of raw and/or cooked garlic (but not
garlic supplements) may be associated with reduced risk of colorectal and gastric cancers,
292
although a review of intervention studies was recommended given that many of the studies
identified did not control for dietary differences.156 A more recent meta-analysis of 2 small
RCTs and 8 observational studies also found an inverse relationship between high garlic
intake and colorectal cancer risk despite great heterogeneity of measures of intake and lack
of control for dietary differences in the studies examined.157 Additionally, a recent large
RCT found that long-term garlic supplementation has no beneficial effects on the incidence
of gastric cancer or the prevalence of precancerous gastric lesions.158 Given the paucity of
RCTs and the heterogeneity and small samples of existing studies, further large prospective
cohort studies and RCTs are needed and should determine the minimum intake of garlic
necessary to exert protective effects for different cancers and control for lifestyle factors
and other confounding variables.
Garlic appears to be generally safe, but may cause mild to severe gastrointestinal symptoms
(stomach upset, heartburn, bloating) and allergic reactions (e.g. contact dermatitis, garlic
burns and anaphylaxis resulting in possible death with topical or oral use).159 Consequently,
oral garlic should be avoided by patients with stomach and duodenal ulcers. Human clinical
trials using well-established probe drugs have demonstrated that oral garlic inhibits
cytochrome P450 2E1 enzymes (but not 1A2, 3A4 or 2D6 enzymes),160,161 which may
reduce the efficacy of chemotherapy involving dacarbazine (metastatic melanoma,
Hodgkin’s lymphoma and other malignancies) and that of certain other drugs (e.g.
anaesthetics, paracetamol).168,203 Garlic may also reduce the efficacy of antiretrovirals (e.g.
saquinavir, ritonavir).162 Finally, due to its anticoagulant properties, garlic should be
avoided by patients undergoing surgery and should be used with caution by those taking
anticoagulant/antiplatelet medications (e.g. warfarin, fluindione, aspirin).163
2.3.3.3 Kava (Piper methysticum)
Kava, a psychoactive substance, is derived from the pepper plant and has been traditionally
consumed as a beverage in cultural practices of Pacific countries. It has gained popularity
in Western countries in recent years as a medicinal herb because of its anxiolytic, stress-
relieving and sedative properties.164 The roots and rhizomes of kava are used to prepare
beverages, extracts, tablets/capsules, and topical solutions. Complementary medicine
practitioners commonly prescribe kava for anxiety, sleep disorders and menopausal
symptoms. A recent Cochrane meta-analytic review of 7 RCTs suggests that kava extract is
293
a safe, effective treatment for anxiety in the short-term (1-24 weeks) compared to placebo,
but more rigorous studies are required to clarify uncertainties about long-term efficacy and
safety.165
Possible adverse effects of kava are of concern. Chronic and/or heavy use (300-400g per
week) may cause appetite loss leading to malnutrition and weight loss, shortness of breath,
skin conditions (e.g. dry, scaly skin; yellow or white ulcer-like lesions known as kani or
kava dermopathy), blood and metabolic abnormalities, loss of muscle control
(ataxia/dystonia), and pulmonary hypertension.166 The most important concern with
toxicity, however, involves several reports of hepatotoxicity (including those resulting in
death and liver transplants) from use of concentrated kava extracts (but not beverages) in
Europe and North America, which prompted several European countries to ban its use in
2002 and other countries (including Australia and the US) to issue health warnings to
healthcare professionals and consumers. Although a highly probable causal association was
established in few reported cases per se,167 use of kava extracts are best avoided in cancer
patients with (a history of) liver disease, or those receiving hepatotoxic drugs including
chemotherapy agents such as cyclophosphamide, camptothecins (e.g. irinotecan), taxanes
(e.g. paclitaxel), vinca alkaloids (e.g. vinorelbine) and EGFR-TK inhibitors (e.g. erlotinib
for non-small cell lung, pancreatic and other cancers).168 Additionally, due to the possibility
that kava may potentiate the sedative effect of anaesthetics, benzodiazepines (e.g.
alprazolam) and barbiturates [via gamma-aminobutyric acid (GABA) neurotransmission], it
is recommended that patients discontinue use at least 24 hours prior to surgery.128 Finally,
human studies have shown that kava extract may inhibit cytochrome P450 2E1 and 1A2
(but not 3A4) enzymes,169-171 and thus precipitate herb-drug interactions with substances
metabolised by those enzymes (e.g. anaesthetics, antidepressants, antipsychotics,
anticoagulants, alcohol).203 Similar inhibitory effects have also been observed on dopamine,
thus reducing the efficacy of medications such as levodopa (anti-Parkinsonian drug).203
2.3.3.4 Valerian (Valeriana officinalis)
Valerian, although native to Europe and Asia, grows in most parts of the world and has a
long history of use as a sedative for sleep disturbance. The roots and rhizomes of valerian
can be prepared to make supplements including capsules/tablets and liquid extracts, as well
as infusions (teas). Short-term use (≤ 4-6 weeks) of valerian in recommended doses is
294
generally well-tolerated. Common side-effects include central nervous system (e.g.
headache, nervousness, dizziness) and gastrointestinal symptoms (notably diarrhoea, but
also nausea, heartburn and epigastric pain).172 As with conventional sleep medications,
chronic use of valerian (≥ 2-4 months) may result in insomnia, as well as withdrawal effects
(e.g. delirium, tachycardia) if also used heavily.173
Valerian is associated with few serious adverse effects. Studies suggest the absence of
adverse interactions with alcohol.174,175 Human studies have not found any effects of
valerian on cytochrome P450 enzymes involved in drug metabolism either, thus clinically-
relevant interactions with chemotherapy drugs (and many other medications) are
unlikely.169,176 Like kava, however, the effects of valerian are mediated through GABA
neurotransmission, thus concomitant use of sedatives (benzodiazepines and barbiturates),
hypnotics, anxiolytics and anaesthetics are contraindicated due to possible potentiation
effects.177Additionally, cancer patients planned for surgery should taper use over a period
of weeks rather than cease use abruptly to avoid possible withdrawal symptoms.128,177
Valerian is often used for the treatment of insomnia, fatigue and anxiety/stress, which are
common symptoms experienced by cancer patients. A Cochrane review found only one
small RCT evaluating the treatment of anxiety disorders using valerian and recommended
that more, larger RCTs be performed before drawing any conclusions about its efficacy for
anxiety.178 Evidence for the treatment of insomnia using valerian, however, is mixed. One
systematic review of 29 controlled trials found no significant differences between valerian
pills and placebo, overall, in healthy individuals or individuals with general sleep
disturbance or insomnia.179 A more recent meta-analysis of 18 RCTs, however, found that
valerian resulted in significant improvement on subjective measures of sleep quality, but
the effect was not mirrored in objective sleep measures.172 This not only confirmed
observations made in an earlier meta-analysis,180 but outcomes were maintained in
subgroup analysis of more recent, higher quality RCTs that contained less methodological
heterogeneity and, importantly, controlled for differences in odour between valerian and
placebo. More RCTs assessing different doses of standardised preparations of valerian in
individuals with sleep disturbance and using both subjective and objective measures are
required, as well as studies evaluating the efficacy of valerian in liquid form for sleep
disturbance, none of which exist. Nevertheless, despite the different conclusions regarding
295
efficacy, the reviews were unanimous in finding that valerian is generally safe and rarely
associated with adverse events. Consequently, short-term use of valerian could be
considered for some cancer patients (e.g. non-surgical patients who prefer not to take
conventional sleep medications), particularly given there is no evidence of potential
interactions with chemotherapy agents.
2.3.3.5 Evening primrose oil (Oenothera biennis)
Evening primrose, although native to North America, grows in Europe and parts of the
southern hemisphere. Flowers and seeds are pressed to make evening primrose oil (EPO)
that contains gamma-linolenic acid (GLA), an omega-6 essential fatty acid believed to be
the active ingredient. EPO is commercially available in capsule or liquid form and widely
used to treat menopausal symptoms, premenstrual syndrome and chronic mastalgia (breast
pain associated with menstruation), as well as other problems such as atopic eczema and
rheumatoid arthritis.181
Breast cancer patients may experience symptoms of (premature) menopause (e.g. hot
flashes, night sweats, vaginal dryness) as a result of chemotherapy, which may be
exacerbated by 5 year follow-up hormonal therapy with tamoxifen in patients with
hormone-receptor positive (HR+) tumours.182 Non-hormonal therapies in the form of herbal
medicines such as EPO have become a popular alternative for women (including breast
cancer survivors) for the treatment of menopausal symptoms, particularly since health risks
were cast over prolonged use (> 5 years) of hormone replacement therapy by the Women’s
Health Intervention study published in 2002.183 The menopausal benefits of EPO, however,
have yet to be confirmed in RCTs involving postmenopausal women or breast cancer
patients.184,185 Few studies examining the safety of EPO have been conducted either.
Common adverse effects include headache and gastrointestinal symptoms (e.g. stomach
upset, nausea, mild diarrhoea).186 Limited evidence suggests that EPO may lower the
seizure threshold and increase the risk of seizures in individuals taking phenothiazines (e.g.
fluphenazine).181 Finally, despite the absence of reported herb-drug interactions of EPO, it
may be prudent to monitor use by patients receiving chemotherapy.168
296
2.3.3.6 Black cohosh (Actaea racemosa, Cimicifuga racemosa)
Black cohosh, a member of the buttercup family, was traditionally used by the North
American Indians and in 19th-century America for a variety of conditions ranging from
gynaecological disorders to rheumatism, but has more recently been adopted for use in
Europe and Western countries for the treatment of menopausal symptoms and
dysmenorrhoea. The roots and rhizomes of black cohosh are commonly used fresh or dried
to make infusions (strong teas), capsules, solid extracts used in pills, or liquid extracts.
Like evening primrose oil, black cohosh is used by breast cancer survivors for the treatment
of menopausal symptoms. Alternatively, prostate cancer patients may use black cohosh to
control hot flushes after surgical or medical castration (e.g. hormonal ablation).182
Systematic reviews of RCTs, however, have found inconclusive evidence to support the use
of black cohosh for menopausal symptom relief in peri-/post-menopausal women187-189 and
breast cancer patients.190 Given the general poor quality of existing studies, more rigorous
RCTs of longer duration (> 6 months) are required and should involve standardised
preparations and uniform outcome measures, as well as prostate cancer patients.
Black cohosh appears to be relatively safe189 despite reports that it may be associated with
hepatotoxicity. Approximately 50 cases of hepatotoxicity associated with black cohosh use
have been reported since 2002, including 16 in Australia (of which three required liver
transplants). While this has prompted the application of health warning labels to black
cohosh sold in Australia and the US, recent expert panel reviews191-193 failed to establish a
causal link and suggested that the risk of liver damage with black cohosh use is very low.
Nevertheless, use is best avoided by patients with (a history of) liver disease and caution is
warranted in those receiving hepatotoxic drugs, including chemotherapy agents such as
cyclophosphamide, camptothecins (e.g. irinotecan), taxanes (e.g. paclitaxel), vinca
alkaloids (e.g. vinorelbine) and EGFR-TK inhibitors (e.g. erlotinib for non-small cell lung,
pancreatic and other cancers).
The most important safety concern with black cohosh, however, is the fear that it has
oestrogenic effects and may promote breast or uterine cancer in women. Early studies
suggested an oestrogenic mechanism of action for black cohosh, but this may have been
due to phyto-oestrogen contamination.191,194 More recent in vitro and human studies of
297
unadulterated black cohosh extracts, though, have demonstrated no oestrogenic
activity.190,191 Nevertheless, women with oestrogen-dependent cancers may want to avoid
black cohosh until its long-term effects on breast or uterine tissue are more clearly
established in epidemiological studies. Finally, no herb-drug interactions have been
reported for black cohosh,195 nor does it inhibit the cytochrome P450 3A4 enzyme or P-
glycoprotein in human studies.141 In summary, while the efficacy of black cohosh for
treatment of menopausal symptoms is inconclusive, short-term use (< 6 months) is
relatively safe and may include minor side-effects (e.g. gastrointestinal symptoms such as
stomach upset; headaches, dizziness). Further studies examining the efficacy and safety of
black cohosh in breast, uterine and prostate patients in the longer-term are required.
2.3.3.7 Echinacea (Echinacea purpurea, Echinacea angustifolia, Echinacea pallida)
Echinacea is an immunostimulant that is commonly used by cancer patients to boost their
immune system and prevent or treat upper respiratory tract infections. RCTs are yet to
confirm these benefits in cancer patients, however.122 Safety of echinacea has recently been
reviewed. Short-term use of echinacea is relatively safe, although there is some concern
about allergic reactions including rashes, increased asthma and, in rare cases,
anaphylaxis.122,196 Individuals with asthma or atopy (a genetic tendency towards allergic
reactions) may be more likely to have an allergic reaction when taking echinacea, thus use
is contraindicated.122
Currently, there are no verifiable reports of herb-drug interactions for any echinacea
products,197,198 despite probe studies indicating a low potential for herb-drug interactions
with substances metabolised by the cytochrome P450 1A2 and 3A4 enzymes.199,200
Nevertheless, marked differences in the quality of echinacea preparations could alter the
potential for interactions and is of major concern.168,201,202 Possible contraindications of
echinacea, therefore, include use with chemotherapy agents producing cytochrome P450
3A4 substrates [e.g. cyclophosphamide, camptothecins (e.g. irinotecan), taxanes (e.g.
paclitaxel), vinca alkaloids (e.g. vinorelbine), EGFR-TK inhibitors (e.g. erlotinib for non-
small cell lung, pancreatic and other cancers)], antipsychotics (e.g. clozapine, olanzipine),
tricyclic antidepressants (e.g. amitryptiline), benzodiazepines (e.g. midazolam),
immunosuppressants (e.g. corticosteroids, cyclosporine), antihypertensives/antiarrhythmics
(e.g. verapamil), antihyperlipidemic drugs to reduce high cholesterol (e.g. simvastatin),
298
antimicrobial drugs (e.g. antibiotics such as erythromycin), oral contraceptives (e.g. ethinyl
estradiol/norethindrone) and caffeine.168,199,203
2.3.3.8 Milk thistle (Silybum marianum, Carduus marianum)
Milk thistle is one of the most popular herbal medicines worldwide and is commonly used
for liver disorders. The principal constituent of milk thistle is silymarin, which is a mixture
of flavonolignans (silychristin, silydianin, silybin and others) isolated mainly from the
seeds (fruit) of the plant. The seeds are used to prepare capsules, extracts, and infusions
(strong teas). Evidence suggests that milk thistle has hepatoprotective, anti-cancer, tissue-
regenerative, hypoglycaemic and cardioprotective properties.204,205 Milk thistle is being
increasingly used by cancer patients for liver protection during chemotherapy (e.g.
involving hepatotoxic agents, including docetaxel, gemcitabine, methotrexate, oxaliplatin,
dactinomycin, daunorubicin and imatinib)206 and detoxification between chemotherapy
cycles or after chemotherapy, as well as an adjuvant treatment and chemopreventive agent.
A Cochrane meta-analytic review of 13 RCTs involving alcoholic and/or hepatitis B or C
liver disease patients found significant benefits of milk thistle on mortality or hepatic
complications across low quality trials alone, but not across all trials or high quality trials
alone.207 High quality RCTs on milk thistle in liver disease are required, and should include
patients with chemotherapy-induced hepatotoxicity given the absence of adult studies.
Reviews of preclinical studies suggest that milk thistle extract may have some potential in
protecting the liver against toxins and stimulate the transcription and activity of phase II
detoxification enzymes, but no clinical trials have assessed the detoxification effects of
milk thistle.205,208 Similarly, reviews of preclinical studies and preliminary clinical trials
suggests that milk thistle extract may potentiate the antitumour action of certain
chemotherapy drugs (e.g. doxorubicin, cisplatin) and radiotherapy208 and have
chemopreventive potential (e.g. skin cancer, colorectal cancer),208,209 but rigorous RCTs are
required to establish its efficacy and safety as an adjuvant or chemopreventive treatment.
Reviews have established that chronic use (≤ 41 months) of milk thistle is generally safe
and well-tolerated in recommended doses (oral form standardised to contain 70-80%
silymarin, 420mg daily).207,210,211 Gastrointestinal problems are the most common
complaint, but are infrequent.212 Allergic reactions, ranging from itchiness to eczema and
299
anaphylaxis, are rare. Large doses (> 1.5g/day) may cause diarrhoea, and very high doses
(10-20g/day) can result in asymptomatic hepatotoxicity (hyperbilirubinaemia) in cancer
patients.213 Drug interactions do not appear to be problematic either. Silymarin and silybin
have been shown to inhibit cytochrome P450 enzyme activity.214,215 A review of several
recent in vitro and human studies, however, reported no clinically-relevant effects with
chemotherapy agents (e.g. irinotecan, vincristine) or other drugs (e.g. midazolam, caffeine)
metabolised by the cytochrome P450 and UGT1A1 enzymes, or interference with P-
glycoprotein modulation.204 Nonetheless, these effects may be dose-responsive and require
further study at higher doses.216 It would, therefore, be prudent to monitor milk thistle use
by cancer patients receiving chemotherapy.
2.3.3.9 European mistletoe (Viscum album L.)
Mistletoe has a long tradition of folk remedy use in Europe, but has been used extensively
in recent years in adjuvant cancer treatment or as a standalone alternative therapy, by and
large, in German-speaking countries (Switzerland, Austria, Germany). Its use in cancer
treatment stems from anthroposophic medicine developed in the early 1900s, which
approaches disease as an imbalance in the biological organism and utilises treatment
strategies designed to restore this balance. Anthroposophic doctors believe that regular
injections of mistletoe will inhibit or stop tumour growth and improve QoL in cancer
patients.217 Mistletoe preparations undergo a standardised manufacturing process, but may
also be standardised to include specific amounts of a particular component (e.g. mistletoe
lectin). The stem and leaves of the semi-parasitic mistletoe plant are used to make
commercial preparations (e.g. extracts, pressed sap) that are often administered by
subcutaneous injection (near or directly into the tumour), but may be taken orally,
intravenously or intrapleurally. Currently, there is no generally accepted protocol for
administering mistletoe preparations, but studies indicate that injections given 2-3 times per
week for varying lengths of time are most common with dosage depending on the response
and disease stage of cancer patients.218,219
In vitro studies indicate that mistletoe or its main constituents (lectins, viscotoxins,
polysaccharides, alkaloids) have anti-angiogenic, anti-cancer and immunostimulatory
properties.220 Several systematic reviews over the last decade have examined the efficacy of
mistletoe use in cancer patients with varying results. In 2003, a systematic review of 10
300
RCTs found some benefits of mistletoe extract as adjuvant or standalone treatment for
cancer patients, particularly in relation to QoL, across low quality trials alone; however, no
benefits in terms of QoL, survival and other outcomes were demonstrated in higher quality
trials.221 In contrast, another systematic review in 2003 involving 16 RCTs and 7 quasi-
/non-randomised controlled trials of mistletoe preparations revealed that 12 studies
exhibited significantly positive results on at least one clinically-relevant outcome measure,
7 studies indicated a positive trend on at least one measure, 3 showed no significant results
and 1 demonstrated a negative trend.222 The authors concluded that whilst all studies
exhibited methodological weaknesses, further research was warranted given that a small
number of relatively high quality trials produced positive outcomes. In 2007, a systematic
review of 16 RCTs and 9 non-RCTs involving mistletoe use as adjuvant or standalone
treatment found arguable benefits for cancer survival, but better evidence for the efficacy of
anthroposophic mistletoe preparations in improving QoL and reducing toxicity of
conventional treatments.223 Despite similar observations, a 2008 Cochrane meta-analytic
review of 21 RCTs found weak evidence to support that mistletoe extract improves survival
and QoL or reduces the adverse effects of chemotherapy and radiotherapy, although the
conclusions for QoL were qualified by stating that a small number of higher quality trials
suggested possible benefits for breast cancer patients during chemotherapy.224
Interestingly, the conclusions concerning the efficacy of mistletoe use in cancer patients
drawn from systematic reviews limited to RCTs were more negative. This may reflect the
dubious nature of blinding in RCTs on mistletoe (i.e. some patients may be able to identify
whether they are receiving mistletoe or placebo according to the presence/absence of local
reactions to mistletoe injections)225 and the recruitment problems related to randomisation
in such clinical trials,225,226 as well as the heterogeneity observed across the systematic
reviews (e.g. varying inclusion criteria and study quality ratings; different mistletoe species,
forms of extraction, and route, schedule and dosage of administration).218,221 A more recent
systematic review of 18 RCTs and observational studies sought to minimise these
problems.218 The authors found inconsistent evidence for the efficacy of mistletoe
preparations as adjuvant or standalone treatment in increasing cancer survival and tolerance
to chemotherapy and radiotherapy, but concluded that there was clear evidence for
enhanced QoL and that these benefits were not limited to specific mistletoe preparations or
cancer populations. The latest systematic review (26 RCTs, 10 non-RCTs) has further
301
confirmed the QoL benefits also.219 Nevertheless, given that the majority of existing studies
have significant problems in methodology and/or reporting, further high quality prospective
trials (e.g. involving different dosages, preparations, schedules, cancer sites and disease
stages, treatment durations) are needed to consolidate the efficacy of mistletoe preparations
as a supportive treatment enhancing QoL in cancer patients.
In terms of safety, recent reviews predominantly involving RCTs indicate that mistletoe
preparations are usually well-tolerated and that serious adverse effects are rare (cf.
mistletoe plants and berries, which are poisonous) when used as directed under the
supervision of health professionals.218,224 Depending on the dose, local reactions (e.g.
pruritis, erythema or induration at the injection site) have been observed in 0.9-43% of
cancer patients227 and systemic reactions (e.g. headaches, fever, influenza-like symptoms)
in up to 10% of patients.224 Allergic reactions (e.g. breathing difficulties, anaphylaxis) have
been reported, but are rare (< 1%).227 Also, long-term use of mistletoe extracts may reduce
T-cell function in cancer patients without local reactions, thus use should be suspended
periodically to allow T-cell reactivity to recover.228 Finally, preclinical and human studies
examining possible herb-drug interactions with mistletoe have been lacking,229 with the
existence of only one human study examining interactions with chemotherapy agents
(concomitant use of mistletoe and gemcitabine in advanced cancer patients produced no
clinically-relevant effects).230 Human clinical trials using well-established probe drugs are
required, as well as phase I studies examining possible interactions between mistletoe and
other chemotherapy agents, hormone therapies and immunotherapies, respectively.218 It
would, therefore, be prudent to monitor mistletoe use by cancer patients receiving
chemotherapy and other treatments.
2.4 Manipulative and body-based practices
Manipulative and body-based practices focus primarily on body structures and systems
including bones and joints, soft tissue, and the circulatory and lymphatic systems.231 They
involve manipulation or movement of one or more parts of the body in order to heal the
body and achieve good health. Examples include massage, acupuncture/acupressure,
chiropractic and osteopathic manipulation, tui na, reflexology, and Bowen therapy. There is
considerable variation in the level of formal training and approaches taken by practitioners
both across and within modalities (e.g. chiropractic and osteopathic manipulation primarily
302
involve rapid movements, whereas massage therapy involves slower application of force).
Despite this heterogeneity, manipulative and body-based practices share some common
principles (e.g. the human body is self-regulating, parts of the body are interdependent) and
features (e.g. therapies tend to be tailored to the specific needs of patients).
2.4.1 Massage therapy
Massage therapy involves the systematic manipulation of soft tissues of the body. There are
many types of therapeutic massage, with most cultures having developed their own
variations (e.g. Swedish massage, aromatherapy, shiatsu, reflexology, acupressure). The
common goal of most massage techniques is to promote relaxation and general well-being.
Overall, therapeutic massage administered by trained practitioners is very safe. Two
reviews, one focusing on cancer patients, found few reported adverse events.232,233 Most
adverse effects involved massage administered by laypeople and techniques other than
Swedish massage (e.g. bleeding ranging from minor bruising to internal haemorrhaging in
patients with coagulation disorders and/or those using anticoagulant/antiplatelet
medications; bone fractures in at-risk patients including those with osteoporosis and
metastatic cancer in the bones; increased pain and infection in surgical patients with open
wounds and patients with skin afflictions, such as radiation dermatitis, or prosthetic devices
such as colostomy bags; oxidation, bacterial contamination or accidental overdose of
aromatherapy essential oils due to incorrect storage and handling).233,361 While there is no
evidence that massage therapy can spread cancer, applying direct pressure over known
tumours is best avoided. Reduced pressure and/or avoidance of direct or deep tissue
massage is also advisable for cancer patients with coagulation disorders (and those using
anticoagulant/antiplatelet medications, such as warfarin and aspirin), bone metastases or
severe osteoporosis, open wounds or radiation dermatitis, and prosthetic devices (e.g.
infusaport, colostomy bag, stents).233 Finally, caution is advised with use of aromatherapy
essential oils in cancer patients with renal or liver disorders, and direct application should
be avoided in those with wounds, skin conditions or allergies to essential oils.361
Cancer patients have increasingly employed massage therapy for symptom control. A
Cochrane meta-analytic review of 8 RCTs found limited evidence for short-term benefits of
massage/aromatherapy on anxiety in cancer patients, but inconclusive results for other
symptoms.234 More recent systematic reviews of RCTs and observational studies have also
303
suggested that massage may alleviate anxiety, as well as other symptoms such as pain,
nausea, depression and stress.233,235-237 However, in light of the methodological limitations
of the studies examined, the authors of these reviews collectively recommended that larger
RCTs involving more clinically homogeneous samples, standardised massage doses and
protocols, and more appropriate measurement intervals including longer follow-up periods
be performed to develop a consensus on the most suitable type of massage therapy to offer
different cancer patients. Nevertheless, massage therapy should be supported for use by
patients in the interim, given the promising evidence for symptom control and that it is
associated with few adverse effects.
2.4.2 Acupuncture
Acupuncture, a key aspect of TCM, is a family of procedures that involves the application
of needles, pressure, heat and other treatments to the skin at particular sites called
acupuncture points for therapeutic purposes. Acupuncture performed by competent and
experienced practitioners is safe. Large studies have shown that major adverse events such
as pneumothorax are extremely rare, and that local bleeding and needling pain, the most
common minor adverse effects, occur in a very small minority of individuals (< 0.1%
overall).238-240
Acupuncture is predominantly used in supportive and palliative care for cancer patients,
and has been utilised in the management of a diverse range of symptoms. Clinical trials
have produced mixed results, however. Systematic reviews revealed that there is no
convincing evidence that acupuncture alleviates cancer pain241,242 or hot flushes in breast
and prostate cancer patients,243,244 although further randomised controlled trials (RCTs)
were recommended given the paucity of rigorous controlled studies in the cancer literature.
In contrast, a Cochrane meta-analytic review of 11 RCTs concluded that acupuncture-point
stimulation (manual acupuncture, electroacupunture, self-/practitioner-administered
acupressure) in combination with antiemetics demonstrated benefit for acute
chemotherapy-induced nausea and/or vomiting and complemented the positive evidence for
postoperative nausea and vomiting.245 Additionally, an exploratory meta-analysis of 11
Chinese non-randomised clinical trials of poor quality found that acupuncture was
associated with an increase in leukocytes during chemotherapy and chemoradiation,
suggesting that acupuncture may be effective in reducing leukopenia in patients
304
undertaking such treatments.246 Finally, several pilot studies suggest that acupuncture may
improve radiation-induced xerostomia in head and neck cancer patients,247-253 although
RCTs are needed to further confirm these encouraging results.
2.4.3 Exercise interventions
There are two broad categories of exercise. Aerobic or cardiorespiratory exercise involves
large muscle groups performing continuous or intermittent physical activity over an
extended period of time, while anabolic or resistance exercise involves performing sets of
repetitive movements against a resistance during which neuromuscular fatigue occurs
within 6-12 repetitions.254 Exercise may be home-based or take the form of highly
structured, supervised interventions. Cancer survivors and patients undergoing treatment
are generally prescribed aerobic and/or resistance exercise of low to moderate intensity and
regular frequency (3-5 times per week) for at least 20 minutes per session.255
Aerobic and resistance exercise appear to be relatively safe in cancer patients during
treatment or survivorship, even in home-based programmes and older or advanced cancer
patients.256,257 Recent meta-analytic and systematic reviews have found that serious adverse
events (e.g. back injury; falls; development or exacerbation of lymphoedema, anaemia or
cachexia) are rare, and that the most common minor adverse effects (e.g. hip/calf pain,
pulled hamstring, shoulder tendonitis) of exercise interventions were no more frequent
compared to control interventions in RCTs.257-260 Some researchers have suggested that
anaemia, lymphoedema and cachexia are contraindications to exercise during cancer
treatment. However, exercise intervention studies that have used these outcomes as primary
endpoints have demonstrated no safety risks, with risk of exacerbated lymphoedema even
being reduced in one study.261-264 Additionally, it has been proposed that values above 20 x
109/L for platelet counts and 1.5 x 109/L for leukocyte counts are safe for patients to engage
in vigorous activity.261 Nevertheless, individuals must be aware of their physical limitations
with any form of exercise, thus exercise interventions should be should be used with
caution or avoided in patients with severe osteoporosis, joint problems, acute back pain,
sprains or fractures, or whose physical functioning otherwise precludes certain exercises.
Additionally, straining downward or holding low postures is contraindicated in patients
with inguinal hernia; artificial joints or prosthetic devices (e.g. infusaport, colostomy bag,
stents); pregnancy; or those recovering from abdominal surgery. Finally, larger studies are
305
required to examine the long-term safety of exercise interventions in cancer patients and
survivors.
Recent attention has focused on the use of physical exercise by cancer patients to
ameliorate fatigue and other symptoms (e.g. cachexia, mood) related to cancer and its
treatment, and improve QoL during treatment and survivorship. A meta-analysis and
systematic review of exercise-based and psychological interventions revealed in a subgroup
analysis of 17 RCTs that there were no significant decreases in cancer-related fatigue
(CRF) during treatment or survivorship for predominantly non-metastatic cancer patients
who completed various exercise-based interventions.265 In contrast, a Cochrane meta-
analytic review of 28 RCTs found a small beneficial effect of exercise in reducing
symptoms of CRF during treatment or survivorship in patients (predominantly diagnosed
with breast cancer) who completed various exercise-based interventions compared to
control interventions.266 The authors recommended that exercise be considered for
inclusion as part of comprehensive multifaceted interventions for CRF. Unfortunately,
while the authors acknowledged several problems with the studies identified (e.g. small
sample sizes, fatigue was not a primary endpoint in many studies and therefore was not
assessed as part of eligibility criteria; clinical heterogeneity in terms of disease site/stage;
type of cancer treatment received; time elapsed in survivorship; and form, mode, intensity,
frequency and duration of exercise), they failed to state what impact they had on their
findings and conclusions.
In an effort to address some of these shortcomings, a more recent meta-analysis of 18 RCTs
examined the effects of different exercise parameters on CRF symptoms experienced
during cancer treatment.267 Overall, exercise produced small significant reductions in CRF
for breast cancer patients and moderate significant reductions in prostate cancer patients.
Supervised aerobic exercise interventions proved more effective in reducing CRF during
breast cancer treatment than home-based programmes, which did not significantly decrease
CRF. Neither home-based programmes or supervised aerobic and resistance exercise
interventions, however, significantly reduced CRF among prostate cancer patients, although
statistical power may have been lacking due to small samples. Insufficient data,
heterogeneity and/or poor reporting prevented evaluation of the long-term effects of
exercise on CRF, the effects of exercise in metastatic cancer patients, and the determination
306
of the most effective parameters for exercise frequency, duration and intensity.
Consequently, more large RCTs are required comparing the different forms of exercise
interventions (aerobic and/or resistance) across settings (home-based, supervised) to other
non-pharmacological interventions for CRF. Clearly defined cancer populations (e.g. early-
stage vs advanced cancer, older vs younger, treated patients vs survivors) extending beyond
breast cancer patients and assessed to have CRF must be targeted and the most effective
exercise prescription parameters (mode, intensity, frequency, duration) must be determined.
Exercise interventions have been examined in relation to clinical and QoL outcomes in
cancer patients extending beyond CRF. A meta-analysis of 16 randomised and 14 non-
randomised trials found that exercise interventions resulted in small positive effects on
clinical and QoL outcomes (physical functioning, symptoms other than fatigue, body
composition, fatigue, mood, overall QoL) during cancer treatment, although larger effects
were generally contributed by poorer quality studies.268 Similarly, a systematic review of 3
RCTs and 5 non-randomised trials found positive effects on QoL and physical outcomes in
metastatic cancer patients, although heterogeneity was problematic and limited the
generalisability of results.269 Also, a Cochrane meta-analytic review of 9 RCTs revealed a
moderate positive effect of exercise interventions on physical functioning during adjuvant
breast cancer treatment (and insufficient evidence for other outcomes, such as fatigue,
mood disturbance, immune function and weight gain), although heterogeneity again was
problematic.270 A more recent meta-analysis of exercise and behavioural interventions
revealed in a subgroup analysis of 17 RCTs that physical exercise produced small positive
effects on fatigue, depression, body image and QoL in breast cancer survivors or patients
receiving treatment.271
Finally, in the most comprehensive evaluation to date, a meta-analysis and systematic
review of 74 RCTs and 8 non-randomised trials (including 66 judged to be of high quality)
showed a large beneficial effect of exercise interventions for cancer survivors on lower and
upper body strength and moderate effects on fatigue and breast cancer-specific concerns.260
Small to moderate positive effects in cancer patients undergoing treatment were observed
for physical activity level, aerobic fitness, muscular strength, functional QoL, anxiety and
self-esteem. Nevertheless, as with the CRF studies above, these positive preliminary results
are compromised by the marked heterogeneity seen in exercise intervention studies
307
involving cancer patients and survivors, as well as other major methodological problems
(i.e. study participants were not recruited based on their need for improvement on the
clinical/QoL outcomes measured, such as impaired physical functioning and poor overall
QoL; few studies compared supervised interventions and home-based programmes or
included populations outside breast cancer). Further large RCTs as prescribed above for
CRF should extend to exercise intervention studies involving other targeted clinical and
QoL outcomes and, perhaps most importantly, focus on cancer patients and survivors in
greatest need for improvement on these targeted outcomes.
2.5 Energy therapies
Energy therapies involve the use of two types of energy fields. Veritable energy fields,
which can be measured, employ mechanical vibrations (e.g. sound) and electromagnetic
forces including visible light, magnetism, monochromatic radiation (e.g. laser beams), and
rays from other parts of the electromagnetic spectrum. Specific, measurable wavelengths
and frequencies are used to treat individuals.272 In contrast, putative energy fields or
biofields are theorised to surround the body and have yet to be scientifically measured.
Biofield therapies are based on the concept that humans are infused with a subtle form of
energy or life force (termed differently in different cultures; for example, qi in TCM, ki in
the Japanese Kampo system, doshas in Ayurvedic medicine, and elsewhere as prana,
etheric energy and other names) that can be manipulated to effect changes in the physical
body and influence health.273,274
2.5.1 Biofield therapies
Biofield therapies refer to techniques which use energy fields that purportedly surround the
human body to stimulate one’s own healing (internal practices; e.g. internal Qigong) or
healing in others (external practices; e.g. external Qigong, therapeutic touch, healing touch,
Reiki, Johrei, polarity therapy). Energy fields are sometimes manoeuvred by manipulating
the body using light touch or placing the hands above the body. The broad goal of biofield
therapies is to heal mental or physical disorders by rebalancing the energy fields in the
body or by drawing upon spiritual energies for such healing. Cancer patients may use them
to improve general well-being and QoL (e.g. pain relief), particularly in palliative and
supportive care settings. Biofield therapies are generally safe when administered by trained
practitioners. Although few (if any) adverse events have been reported for touch therapies
308
(healing touch, therapeutic touch, Reiki),275 use of Reiki is not advised for individuals with
(a history of) psychosis, personality disorders or bipolar disorder.
6.5.1.1 Qigong
Qigong is the most studied biofield therapy among cancer patients and refers to a whole
host of different meditative exercises (sometimes combined with breathing techniques,
imagery and/or vocalisation of sounds) from traditional Chinese medicine used to prevent
or slow disease and maintain health. Medical Qigong, however, has been specifically
developed for the treatment and cure of disease (e.g. hypertension, arthritis, cancer, HIV),
and may be used as an adjunct to conventional medical treatments. Given its utilisation of
meditation, imagery and breathing techniques and dependence on regular practice, Qigong
has many parallels to Western behavioural medicine.
Qigong is generally safe for most individuals when instructed by qualified practitioners and
practiced correctly according to standard moderate principles [i.e. individuals should master
the basic skills and progress gradually, step-by-step; practice with moderation, patience and
intuition; demonstrate dedication and perseverance, but avoid over-meditation (e.g. 3 hour
sessions) and preoccupation with Qigong; and, most importantly, lead a balanced life with
moderation and not neglect the pleasures of life].335-338 Abnormal psychosomatic responses
and culture-bound psychiatric disorders (specific to individuals of Chinese or other Asian
ethnicities, even when living in Western countries) may be induced, however, when Qigong
is practiced inappropriately, excessively and/or unguided, particularly by psychologically
vulnerable individuals.335,337,339 Serious adverse events are rare, but Qigong-induced
psychiatric disorders are becoming more prevalent in China.340 An estimated 5% of people
in China practice Qigong and 5% of these individuals develop psychiatric sequelae,341
albeit briefly (episodes lasting 1-2 months) and never coming to medical attention in most
cases.339,342 Adverse effects range from mild to severe and may include sensory or somatic
disturbances (e.g. headache, dizziness, chest tightness, tachycardia, breathlessness); motor
disturbances (e.g. muscle twitching, tremors, odd limb movements, uncontrolled motor
activity); cognitive impairment (e.g. memory, attention); psychological symptoms (e.g.
anxiety, irritability, hypochondriasis, obsessive thoughts or images, delusions,
visual/auditory hallucinations, disorganised speech, dissociation, altered consciousness,
disorientation, mania, depression, suicidal or bizarre behaviour); and allergic skin
309
reactions.336,339,343-345 Consequently, Qigong (particularly in the absence of a qualified
practitioner) should be used with caution or is best avoided in cancer patients with neurotic
traits or (a history of) psychosis, personality disorders or other psychiatric disorders, and
those who are suggestible or otherwise psychologically vulnerable, or whose physical
functioning precludes certain exercises.335,336 Additionally, patients from Chinese and other
Asian backgrounds should be more closely monitored, given the culture-specific nature of
the Qigong-induced psychiatric disorders reported.
In relation to efficacy, an exploratory review of 21 Chinese studies (mostly controlled)
revealed that cancer patients predominantly treated with internal Qigong and conventional
medical treatment exhibited a consistent tendency for greater improvement on biological
indicators and/or longer survival time than those who received conventional treatment
alone, but concluded that there was much need for replication and improved
methodological quality in future studies.276 A more recent systematic review of 9 controlled
studies involving palliative/supportive care cancer patients, however, was less positive and
concluded that the efficacy of internal Qigong (alone or combined with conventional
medical treatment) in cancer care is not yet supported due to the poor methodological
quality of existing studies, and recommended that large-scale RCTs be performed along
with studies investigating possible scientific mechanisms.277 Finally, a systematic review of
66 RCTs and observational studies examining a variety of practitioner-administered
biofield therapies (external Qigong, therapeutic touch, Reiki, spiritual healing, healing
touch and others) in different medical populations found moderate (level 2) evidence for
their efficacy in reducing acute pain in cancer patients and postoperative and hospitalised
patients, but mixed (level 4) evidence for chronic pain, fatigue, physiological arousal
(heart/respiratory rate, blood pressure) and QoL in cancer patients.278 Again, larger high-
quality studies were advised, and must adequately assess the efficacy and dose-response
effect of particular biofield therapies for symptom control in cancer using disease-specific
measures.
2.5.2 Bioelectromagnetic-based therapies
Bioelectromagnetic-based therapies involve the unconventional use of electromagnetic
fields, such as magnetic, pulsed or alternating-/direct-current fields.273 Examples include
magnetic, millimetre wave, sound energy (vibrational or frequency), and light therapy.
310
2.5.2.1 Microwave (UHF radiowave)/Tronado therapy
Microwave or ultra high frequency (UHF) therapy is designed to treat cancer via exposure
of tumorous tissue to electromagnetic radiation delivered using frequencies ranging
300MHz-3GHz (although super high and extra high frequencies ranging up to 300GHz
have reportedly been utilised also).279 UHF frequencies commonly used include 200-
300MHz, 434MHz, 915MHz and 2450MHz.280 Microwave therapy is generally thought to
exert therapeutic effects via direct or indirect heating of cancer cells, thus thermometry is
typically undertaken at the time of treatment to measure intra-tumour temperature.
Microwave therapy is usually combined with conventional radiotherapy or uncommonly
with infusions of glucose-blocking agents (e.g. cyclophosphamide, cystine disulphide or
penicillamine disulphide), and is often administered 5 days per week over a period of
weeks.280
A systematic review of 58 controlled and uncontrolled studies (mostly poor quality due to
the absence of single or double-blind RCTs and inadequate patient follow-up, and
exhibiting significant clinical heterogeneity), largely comparing microwave therapy and
radiotherapy combined to microwave therapy alone in relation to tumour response and
overall survival, found minimal evidence to support the routine use of microwave therapy
for cancer treatment.280 Additionally, in the same review, a limited clinical audit of the
medical records of 179 cancer patients treated in Western Australia suggested that
microwave therapy + radiotherapy resulted in greater toxicity than radiotherapy alone or
microwave therapy + glucose-blocking agents for patients with bladder or other invasive
cancers. Some of the more common adverse effects associated with microwave therapy
appear to be pain, erythema, fibrosis, necrosis, ulcerations, blisters and thermal burns. Third
degree burns, arterial rupture and development of fistulae have been reported on occasions,
as have deaths (often related to inadvertent heating of blood vessels or infections following
invasive thermometry).280,281 Finally, microwave therapy is contraindicated in individuals
with thalassaemia (an inherited autosomal recessive blood disorder that results in abnormal
production of haemoglobin molecules, thus causing anaemia).
3. Summary Conclusions
Complementary and alternative therapies or CAM, as they are commonly referred to by
patients and clinicians, are much sought after by Australian cancer patients as a means of
311
coping with the physical and emotional impact of their disease and/or treatment.
Irrespective of whether doctors like them or believe in them, patients will use them. If
physicians in the medical profession are to provide cancer patients with the best care and
best advice possible, then they cannot ignore this sign of the times.
The complementary and alternative therapies used by cancer patients are diverse in their
origin, premise (including proposed or actual mechanisms of action), practice, efficacy and
safety. In Australia, complementary and alternative medicines may be categorised by the
TGA as registered (prescribed or non-prescribed medications which meet Australian
standards of quality, safety and efficacy) or listed (low risk products that are not routinely
evaluated with respect to a manufacturer’s claims before marketing, but are subject to a
random audit after listing).362 Listed medicines consist almost entirely of complementary
and alternative medicines, which implies that they are produced according to appropriate
standards for quality and safety but guarantees nothing in regard to their efficacy. Cancer
patients and other members of the public are mostly unaware of such distinctions and may
believe that a CAM listed by the TGA has been assessed as both effective and safe and
approved for such use by the Federal Government. Additionally, many complementary and
alternative therapies have long histories as components of ancient traditional medical
practices, but have only been subjected to rigorous scientific investigation in the last 10-20
years. More research is required to evaluate or confirm the efficacy and safety of many of
these therapies.
Currently, however, there is evidence from high quality clinical trials that some
complementary therapies, used as adjuncts to conventional medical treatments, are
beneficial in reducing disease or treatment symptoms and improving QoL and
psychological functioning (e.g. relaxation). There is evidence of potential harm also.
Nutritional supplements, herbal preparations, and other natural therapies among the
biologically-based practices may pose direct safety risks because of their potential adverse
effects or interactions with conventional anticancer treatments (chemotherapy,
radiotherapy, surgery, hormonal therapies) and other medications. Some should not be used
under any circumstances in cancer patients irrespective of potential benefit (e.g. St. John’s
wort), while others may be beneficial when patients are not undergoing these treatments
and have no other contraindications (e.g. valerian for short-term amelioration of sleep
312
problems in non-surgical cancer patients). Alternative therapies promoted as “cures” in
place of conventional treatments (e.g. shark cartilage) have the potential to cause patients
(and their loved ones) the most harm, however, when they forego evidence-based cancer
treatments that are likely to be more effective.
It is therefore imperative that those involved in the medical care of cancer patients are
equipped with the skills and knowledge to help patients appropriately evaluate
complementary and alternative therapies, in order to receive benefit while avoiding harm.
Additionally, as a consequence of the safety risks associated with CAM use, clinicians are
strongly encouraged to routinely ask patients about complementary and alternative therapy
use.
In conclusion, whether termed complementary medicine or integrative oncology, cancer
physicians in Australia should strongly consider offering evidence-based complementary
therapies (or at least safe forms of them) alongside conventional treatments through their
own cancer services.363 Conceivably, this will influence patients to continue with
mainstream care and help them avoid any potential harm that may occur with autonomous
CAM use. In this way, optimal holistic care will be ensured for cancer patients by clinicians
providing conventional oncology treatment and care.
4. Summary Recommendations
Refer to Tables 2 through 13 that follow for a summary of recommendations regarding the
evidence for the efficacy and safety of popular CAM approaches (mind-body techniques,
biologically-based practices consisting broadly of nutritional supplements and
Chinese/Western herbal medicine, manipulative and body-based practices, energy
therapies) used by cancer patients in Australia and elsewhere.
5. Acknowledgements
I would like to thank Professor Ian Olver (editor), Professor Peter Drummond and Mr Paul
Katris for their comments on early drafts of this chapter. Finally, I would like to thank my
loved ones for the patience they showed during the writing of this chapter.
313
Table 1. Classification of complementary and alternative therapies Therapeutic Approaches
Definition Examples of therapies used for
cancer
Whole medical systems
Encompass complete systems of diagnosis and practice, which have some overlap with the other four therapeutic approaches
Traditional Chinese medicine, homeopathy, naturopathy, Ayurveda
Mind-body techniques
Techniques designed to increase the mind’s capacity and behavioural repertoire of active coping strategies to heal or manage physical and/or psychological symptoms of disease and promote general health and well-being
Practitioner-administered therapies e.g. hypnotherapy, mindfulness-based stress reduction, support groups Self-help strategies e.g. relaxation, guided imagery/ visualisation, meditation, music therapy, art therapy, support groups, yoga, tai chi, spiritual/ religious coping, prayer
Biologically-based practices
Involve supplementing normal dietary intake with additional extracts, nutrients, herbs and/or certain foods
Herbal medicines and other plant-based preparations (botanicals), animal-derived extracts, nutritional supplements, vitamins, minerals, antioxidants, fatty/ amino acids, enzymes, proteins, antineoplastons, whole diet therapy (e.g. macrobiotic diet), prebiotics/probiotics, functional foods, metabolic therapy (e.g. Gerson diet), other “natural” therapies (e.g. shark cartilage)
Manipulative and body-based practices
Involve manipulation or movement of one or more parts of the body in order to heal the body and achieve good health
Massage therapy, aromatherapy, hydrotherapy, acupuncture/ acupressure, exercise interventions, chiropractic and osteopathic manipulation, tui na, reflexology, Bowen therapy
Energy therapies
Involve the unconventional use of putative energy fields or biofields, which purportedly surround the human body and have yet to be scientifically measured; and veritable energy fields, which employ mechanical vibrations (e.g. sound) and electromagnetic fields (e.g. magnetic, pulsed or alternating-/direct-current fields)
Biofield therapies e.g. Qigong, therapeutic touch, healing touch, Reiki, Johrei, polarity therapy Bioelectromagnetic-based therapies e.g. microwave/UHF/Tronado therapy, magnetic therapy, light therapy, sound energy therapy
314
Table 2. Evidence supporting benefit in using whole medical system approaches to prevent/ameliorate cancer symptoms and treatment side-effects
Whole Medical Systems: Recommendations for each intervention approach across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Homeopathy Naturopathy* Traditional Chinese Medicine†
Cancer Treatment/Survival Outcomes Survival ― ― √?
Side-Effect/Symptom Outcomes Chemo Toxicity √? ― ― Radiotherapy Toxicity √? ― ― Chemo-Induced Stomatitis
√? ― ―
Radiation-Induced Dermatitis
√? ― ―
Quality of Life and Psychosocial Outcomes (Overall) QoL ― ― √?
Chemo = chemotherapy; CAM = complementary and alternative medicine; QoL = quality of life √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects * Naturopathy encompasses a wide variety of treatment modalities including dietary and lifestyle changes (e.g. eating more whole and unprocessed foods, abstaining from alcohol and sugar, stress reduction); vitamins, minerals and nutritional supplements; herbal medicine; homeopathy; mind-body techniques (e.g. meditation, yoga, counselling); and manipulative and body-based therapies (e.g. hydrotherapy, physical exercise). Given the overlap of naturopathic remedies with other categories of CAM, recommendations for various individual modalities are made in the tables that follow. † Given the overlap of traditional Chinese medicine with other categories of CAM (e.g. Chinese herbal medicine as part of biologically-based practices, acupuncture as part of energy therapies), recommendations for various individual modalities are made in the tables that follow.
315
Table 3. Potential adverse effects and contraindications of whole medical system approaches in cancer patients Whole Medical
System Indication Adverse Effects and Contraindications
Homeopathy
Chemotherapy or radiotherapy toxicity, chemo-induced stomatitis, radiotherapy-induced dermatitis
Homeopathic medicines prescribed by trained practitioners in low concentrations are probably safe and unlikely to cause serious adverse events, with the main risks being indirect and stemming from inexperienced practitioners (e.g. misdiagnosis) ► Monitor use in all cancer patients receiving chemotherapy and other treatments
Naturopathy*
Various (see individual modalities in the tables that follow)
Naturopathy encompasses a wide variety of treatment modalities including dietary and lifestyle changes (e.g. eating more whole and unprocessed foods, abstaining from alcohol and sugar, stress reduction); vitamins, minerals and nutritional supplements; herbal medicine; homeopathy; mind-body techniques (e.g. meditation, yoga, counselling); and manipulative and body-based therapies (e.g. hydrotherapy, physical exercise). Given the overlap of naturopathic remedies with other categories of CAM, refer to the adverse effects and contraindications for various individual modalities made in the tables that follow. ► Monitor use in all cancer patients receiving chemotherapy and other treatments ► Refer to safety recommendations for various individual modalities made in the tables that follow
Traditional Chinese Medicine
Various (see individual modalities in the tables that follow)
Given the overlap of traditional Chinese medicine with other categories of CAM (e.g. Chinese herbal medicine as part of biologically-based practices, acupuncture as part of energy therapies), refer to the adverse effects and contraindications for various individual modalities made in the tables that follow ► Monitor use in all cancer patients receiving chemotherapy and other treatments ► Refer to safety recommendations for various individual modalities made in the tables that follow
316
Table 4. Evidence supporting benefit in using mind-body interventions to prevent/ameliorate cancer symptoms and treatment side-effects Mind-Body Interventions: Recommendations for each intervention strategy across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Relax- ation
Medit- ation
(MBSR)
Hypno-therapy
Yoga Tai Chi
Music Therapy
Professional-led Support
Groups
Peer/ Volunteer Support Groups
Religious/ Spiritual Coping
Private/ Personal Prayer
Inter-cessory Prayer
Quality of Life and Psychosocial Outcomes Anxiety √ √?* ― ― ― √? √? ― ― √?* or X** ― Depression √ ― ― ― ― ― √? ― ― √?* or X** ― General Mood ― √?* ― √? X?* √? √? ― ― ― ― Stress/Distress ― √?* ― √? ― ― ― ― √? ― ― Hostility √ ― ― ― ― ― ― ― ― ― ― (Overall) Psych. Adjustment
― √?* ― ― √?* ― √? √? √? √?* or X** ―
(Overall) QoL ― ― ― √? X?* √? √? ― ― ― ―
Social Functioning
― ― ― ― ― ― √? ― ― ― ―
Marital Satisfaction
― ― ― ― ― ― √? ― ― ― ―
Cancer Survival/Risk Outcomes Survival Length ― ― ― ― ― ― X ― ― ― ― Cancer Progression
― ― ― ― ― ― ― ― X? ― ―
Mortality ― ― ― ― ― ― ― ― X? ― X?*** Cancer Risk ― ― ― ― ― ― ― ― X§ ― ―
Side-Effect/Symptom Outcomes Nausea √ ― ?? ― ― √? ― ― ― ― ― Vomiting √? ― ?? ― ― √? ― ― ― ― ―
317
Table 4. (Continued) Mind-Body Interventions: Recommendations for each intervention strategy across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Relax- ation
Medit- ation
(MBSR)
Hypno-therapy
Yoga Tai Chi
Music Therapy
Professional-led Support
Groups
Peer/ Volunteer Support Groups
Religious/ Spiritual Coping
Private/ Personal Prayer
Inter-cessory Prayer
Side-Effect/Symptom Outcomes Pain √ ― √? ― √?* √? ― ― ― ― ― Fatigue ― √?* ― ― ― ― ― ― ― ― ― Sleep Disturbance
― √?* ― √? ― ― ― ― ― ― ―
Physical Health/ Functioning
― X?* ― ― X?* ― ― ― ― √?† or X‡ X?║
Physiological Arousal (BP, heart rate)
√ ― ― ― ― ― ― ― ― ― ―
Overall Side-Effects/ Symptoms
― ― ― ― ― ― ― ― ― ― ―
Conditioned Nausea
√ ― ?? ― ― ― ― ― ― ― ―
Conditioned Vomiting
√ ― ?? ― ― ― ― ― ― ― ―
Acute Procedural Pain
― ― √? ― ― √? ― ― ― ― ―
Acute Procedural Distress
― ― √? ― ― √? ― ― ― ― ―
BP = blood pressure; MBSR = mindfulness-based stress reduction or mindfulness meditation; Psych. = psychological; QoL = quality of life; √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects; * breast cancer; † regular personal/private prayer as part of religious faith; ‡ personal/private prayer out of desperation in the absence of religious faith; § Christian religion members per se; ║distant intercessory prayer per se
318
Table 5. Potential adverse effects and contraindications of mind-body interventions in cancer patients Mind-Body Technique
Indication Adverse Effects and Contraindications
Relaxation
Anxiety, depression, hostility, nausea, vomiting, cancer pain, physiological arousal (BP, heart rate), anticipatory/conditioned nausea or vomiting
Relaxation-induced anxiety, intrusive thoughts, sense of losing control, sensory disturbances, muscle cramps and spasms, abreaction and others ► Use relaxation with caution or avoid in patients with (a history of) psychosis or PTSD Heart rate and BP fluctuations (via the Valsalva response due to muscle tensing) ► Avoid autogenic training and PMR in patients with poorly-controlled cardiovascular disease
Meditation
Psychological adjustment to illness, anxiety, general mood, stress/distress, fatigue
Relaxation-induced anxiety, panic, restlessness, frustration, derealisation, depersonalisation, paradoxical tension, antisocial behaviour, flattened affect and others ► Use meditation (esp. transcendental or Vipassana meditation) with caution or avoid in patients with (a history of) psychosis, schizoid or schizotypal personality disorder, bipolar disorder, dissociative states, or hypochondrial and somatisation disorders ► Contraindicated in patients experiencing physical exhaustion caused by fasting and sleep reduction during longer-term, unguided and intensive meditation
Hypnotherapy Cancer pain, acute procedural pain/distress
Headaches, drowsiness, confusion, dizziness, nausea, anxiety, panic, abreaction and others ► Use with caution or avoid in patients with (a history of) psychosis, personality disorders or organic psychiatric conditions
Music Therapy
Cancer pain, anxiety, general mood, nausea, vomiting, QoL, acute procedural pain/distress
No adverse effects have been reported in the health literature (as far as can be ascertained) ► No obvious contraindications
319
Table 5. (Continued) Mind-Body Technique
Indication Adverse Effects and Contraindications
Yoga General mood, stress/distress, sleep disturbance, overall QoL
Ligament/joint damage from overstretching; nerve/vertebral disc damage, stroke or blood vessel blockage due to (prolonged) postures; eye damage and blurred vision, including worsened glaucoma, caused by increased intraocular pressure with headstands ► Avoid or use in a gentler, modified form under guided instruction in patients with balance problems; uncontrolled hypertension, symptomatic anaemia, postural hypotension or lightheadedness/dizziness; fever, systemic infection or significant thrombocytopenia; certain eye conditions, including glaucoma and retinal detachment; severe osteoporosis, vertebral damage or cervical spondylosis; fragile or atherosclerotic neck arteries or a risk of blood clots; artificial joints or prosthetic devices (e.g. infusaport, colostomy bag, stents); pregnancy; and psychosis
Tai Chi Psychological outcomes, cancer pain
Tai chi is considered to be a relatively safe, moderate physical activity, although adverse effects (albeit rare) can occur (e.g. sore muscles, sprains) ► Use with caution or avoid in patients with severe osteoporosis, joint problems, acute back pain, sprains or fractures, or whose physical functioning otherwise precludes certain exercises ► Straining downward or holding low postures should be avoided by patients with inguinal hernia, artificial joints or prosthetic devices (e.g. infusaport, colostomy bag, stents), pregnancy, or those recovering from abdominal surgery
Professional-led Support Groups
Anxiety, depression, general mood, psychological adjustment to illness, QoL, (psycho)social functioning, marital satisfaction
Acute feelings of discomfort, vulnerability or distress may occur in group internet forms of professional-led support groups in instances of technological unfamiliarity (e.g. of computers or online mediums) or technical failure (e.g. disconnection) ► No obvious contraindications (provided contingency plans are put in place should technical problems arise; e.g. using telephones as a back-up if disconnected)
320
Table 5. (Continued) Mind-Body Technique
Indication Adverse Effects and Contraindications
Peer/Volunteer Support Groups
Psychosocial functioning
Acute feelings of discomfort, vulnerability or distress may occur in group internet forms of peer/volunteer support programmes in instances of technological unfamiliarity or technical failure ► No obvious contraindications (provided contingency plans are put in place should technical problems arise; e.g. using telephones as a back-up if disconnected)
Religious/ Spiritual Coping
Stress/distress, psychological adjustment to illness
No adverse effects have been reported in the health literature (as far as can be ascertained) ► No obvious contraindications
Private/ Personal Prayer
Anxiety, depression, psychological adjustment to illness, functional outcomes
Poorer emotional well-being and functioning if prayer is turned to out of desperation in the absence of pre-existing religious faith ► Use prayer with caution or avoid in patients devoid of religious faith prior to diagnosis
Intercessory Prayer
None No adverse effects have been reported in the health literature (as far as can be ascertained) ► No obvious contraindications
BP = blood pressure; esp. = especially; QoL = quality of life
321
Table 6. Evidence supporting benefit in using nutritional supplements to prevent/ameliorate cancer symptoms and treatment side-effects Nutritional Supplements: Recommendations for each supplement across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Anti-
oxidants (Overall)
Selen-ium
(AO)
Lyco-pene (AO)
Coenz-yme Q10
(AO)*
Amifo-stine
(AO)*
Vit. A (AO)
Vit. C (AO)
Vit. E (AO)
Beta-Carot-
ene (AO)
Folate (AO)
Omega-3 Fatty Acids
Shark Cartil-
age
AE-941
(Neo-vastat)
* Lae
tril
e/A
myg
d-al
in
Cancer Treatment/Survival/Risk Outcomes Tumour Response
?? ― X? ― X§ ― X X ― ― ― ― X§ X?
Cancer Progression
― ― √?† ― ― ― ― ― ― ― ― ― ― X?
Survival Length ?? ― ― ― ― ― ― ― ― ― √?# X?# X§,** X? Progression-Free Survival Length
― ― ― ― ― ― ― ― ― ― ― ― X§ ―
Mortality X ― ― ― ― ― ― ― ― ― X‡ ― ― ― Recurrence ?? ― ― ― ― ― ― ― ― ― ― ― ― ―
Cancer Risk X X‡,║ or √?†,‡
― ― ― X‡,║ X X or √?†,‡
X‡,║,¶ X¶ X? ― ― ―
Side-Effect/Symptom Outcomes Chemo Toxicity (Overall)
?? X? ― ?? ― ― ― ― ― ― ― ― ― ―
Radiotherapy Toxicity (Overall)
√? X? X? ― √? ― ― ― ― ― ― ― ― ―
Postoperative Side-Effects (Overall)
― X? ― ― ― ― ― ― ― ― X‡ ― ― ―
Cancer Symptoms
― X? ― ― ― ― ― ― ― ― ― ― ― ??
322
Table 6. (Continued) Nutritional Supplements: Recommendations for each supplement across types of outcome based on meta-analysis and/or systematic review
Type of Outcome
Anti-oxidants (Overall)
Selen-ium
(AO)
Lyco-pene (AO)
Coenz-yme Q10
(AO)*
Amifo-stine
(AO)*
Vit. A (AO)
Vit. C (AO)
Vit. E (AO)
Beta-Carot-
ene (AO)
Folate (AO)
Omega-3 Fatty Acids
Shark Cartil-
age
AE-941
(Neo-vastat)* L
aetr
ile/
Am
ygd-
alin
Side-Effect/Symptom Outcomes Clinical Outcomes
?? ― ― ― ― ― ― ― ― ― √?# ― ― ―
Cachexia ― ― ― ― ― ― ― ― ― ― X‡ or √?#
― ― ―
Nutritional Status
― ― ― ― ― ― ― ― ― ― X‡ or √?#
― ― ―
Weight Loss ― ― ― ― ― ― ― ― ― ― X‡ ― ― ― Pain ― ― √?† ― ― ― ― ― ― ― ― ― ― ― Urinary Tract Symptoms
― ― √?† ― ― ― ― ― ― ― ― ― ― ―
Quality of Life and Psychosocial Outcomes (Overall) QoL ― ― ― ― ― ― ― ― ― ― √?# X?# ― ― AO = antioxidant; Chemo = chemotherapy; QoL = quality of life; Vit. = vitamin √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects * synthetic nutritional supplement; † prostate cancer; ‡ (upper) gastrointestinal cancer; § locally advanced non-small cell lung cancer; ║ colorectal cancer; ¶ lung cancer; # advanced cancer; ** metastatic renal cell carcinoma
323
Table 7. Potential adverse effects, drug interactions and contraindications of nutritional supplements in cancer patients Nutritional Supplement
Indication Adverse Effects, Drug Interactions and Contraindications
Antioxidants
Radiotherapy toxicity overall (general antioxidants, amifostine alone); pain, urinary tract symptoms and cancer progression in prostate cancer (lycopene only); cancer prevention in prostate or GI cancer (selenium or vitamin E only)
Mild diarrhoea and GI upset (vitamin C); yellowish discolouration of the skin (heavy, chronic beta-carotene intake); increased risk of bleeding in individuals with drug-induced vitamin K deficiency (high vitamin E intake); increased lung cancer incidence and cancer mortality in general among smokers (high-dose beta-carotene); possible increased risk of bladder cancer (antioxidant supplementation in general) ► Avoid in all surgical patients, patients undergoing chemotherapy and other cancer treatments (except under the guidance of the treatment team), and those with coagulation disorders ► Avoid use with anticoagulants (e.g. warfarin) and antiplatelet medications (e.g. aspirin)
Omega-3 Fatty Acids
Cachexia, nutritional status, survival, other clinical outcomes (tolerance, hospital stays) and QoL in advanced cancer
GI symptoms (e.g. diarrhoea, heartburn, bloating or pain, nausea), small increased risk of bleeding ► Avoid high-dose fish oil or supplementation in all surgical patients, cancer patients with coagulation disorders, and those at high risk to haemorrhagic stroke Adverse effects related to toxic levels of mercury and other contaminants in fish (excessive fish consumption only) ► Use high dietary intake of fish with caution in all cancer patients
324
Table 7. (Continued) Nutritional Supplement
Indication Adverse Effects, Drug Interactions and Contraindications
Laetrile/ Amygdalin
None
Nausea, vomiting, headache, fever, abdominal pain, dizziness, acute cognitive disorientation, dermatitis, bluish discolouration of the skin (due to oxygen deprivation in the blood), hypotension, neuropathy, hepatotoxicity, coma, infection or disease (e.g. hepatitis B or C, herpes simplex, varicella zoster, tuberculosis) [due to contamination by bacteria and other impurities], cyanide poisoning, death ► Avoid in all cancer patients (except in clinical trials of laetrile/amygdalin) ► Avoid in patients who have a genetically predisposed, diminished capacity to detoxify cyanide ► Avoid use with dietary intake of fruit seeds (apricot, bitter almond, peach apple) and raw almonds, or megadoses of vitamin C (due to elevated risk of cyanide poisoning and related death)
Shark Cartilage and AE-941 (Neovastat)
None
GI symptoms (e.g. nausea, vomiting, stomach upset, constipation, diarrhoea, flatulence); taste alterations; increased blood calcium levels (due to the high calcium content of some shark cartilage preparations); potential for slow wound healing and teratogenic effects (due to the anti-angiogenic effects of shark cartilage) ► Avoid in all surgical patients and pregnant or breast-feeding women ► Avoid use with calcium supplements and medications (e.g. calicitriol, thiazide diuretics, antacids) Small risk of decreased blood sugar levels; adverse effects related to toxic levels of mercury, cadmium and other contaminants (excessive shark cartilage consumption only) ► Use with caution in all cancer patients, particularly those with diabetes, hypoglycaemia or liver disease ► Use with caution when combining with medications, herbs or nutritional supplements that affect blood sugar levels or liver function
GI = gastrointestinal; QoL = quality of life
325
Table 8. Evidence supporting benefit in using Chinese or Western herbal medicines to prevent/ameliorate cancer symptoms and treatment side-effects Herbal Medicines: Recommendations for each herbal medicine across types of outcome based on meta-analysis and/or systematic review
Type of Outcome
Astra-galus*
Gin-seng*
Gin-ger*
Ling-zhi/
Reishi Mush-room*
Green Tea*
Gin-kgo*
St. John’s Wort†
Gar-lic†
Kava† Valer-ian†
EPO† Black Coh-osh†
Echin-acea†
Milk Thistle†
Euro-pean Mistle-toe†
Cancer Treatment/Survival/Risk Outcomes Tumour Response
√?‡,¶¶ ― ― ?? ― ?? ― ― ― ― ― ― ― ?? ―
Cancer Progression
― ― ― ― ?? ― ― ― ― ― ― ― ― ― ―
Survival Length √?‡,¶¶ ― ― ?? ― ?? ― ― ― ― ― ― ― ?? ?? ║║
Cancer Risk ― ― ― ―
?? or X§,║, ¶,
#, ** or √?‡‡,
§§
― ― √?§,║ ― ― ― ― ― ?? ―
Side-Effect/Symptom Outcomes Chemo Toxicity (Overall)
√?‡,§,¶¶ ― ― ― ― ― ― ― ― ― ― ― ― ― √?║║
Radiotherapy Toxicity (Overall)
― ― ― ― ― ― ― ― ― ― ― ― ― ― √?║║
Clinical Outcomes
― ― ― ― ― ― ― ― ― ― ― ― ― ― ?? ║║
Performance Status
√?‡ ― ― ― ― ― ― ― ― ― ― ― ― ― ―
326
Table 8. (Continued) Herbal Medicines: Recommendations for each herbal medicine across types of outcome based on meta-analysis and/or systematic review
Type of Outcome
Astra-galus*
Gin-seng*
Gin-ger*
Ling-zhi/
Reishi Mush-room*
Green Tea*
Gin-kgo*
St. John’s Wort†
Gar-lic†
Kava† Valer-ian†
EPO† Black Coh-osh†
Echin-acea†
Milk Thistle†
Euro-pean Mistle-toe†
Side-Effect/Symptom Outcomes Acute Postoperative Nausea
― ― √? ― ― ― ― ― ― ― ― ― ― ― ―
Acute Postoperative Vomiting
― ― √? ― ― ― ― ― ― ― ― ― ― ― ―
Chemo-Induced Nausea
√?‡,§ ― ?? ― ― ― ― ― ― ― ― ― ― ― ―
Chemo-Induced Vomiting
√?‡,§ ― ?? ― ― ― ― ― ― ― ― ― ― ― ―
Appetite Loss √?¶¶ ― ― ― ― ― ― ― ― ― ― ― ― ― ― Pain √?¶¶ ― ― ― ― ― ― ― ― ― ― ― ― ― ― Fatigue √?¶¶ ― ― ― ― ― ― ― ― ― ― ― ― ― ― Sleep Disturbance
― ― ― ― ― ― ― ― ― √? ― ― ― ― ―
Cognitive Functioning
― ― ― ― ― ?? ― ― ― ― ― ― ― ― ―
Sexual Functioning
― ― ― ― ― ?? ― ― ― ― ― ― ― ― ―
327
Table 8. (Continued) Herbal Medicines: Recommendations for each herbal medicine across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Astra-galus*
Gin-seng*
Gin-ger*
Ling-zhi/
Reishi Mush-room*
Green Tea*
Gin-kgo*
St. John’s Wort†
Gar-lic†
Kava† Valer-
ian† EPO†
Black Coh-osh†
Echin-acea†
Milk Thistle†
Euro-pean Mistle-toe
Side-Effect/Symptom Outcomes Immunological Function
√?§ ?? ― ?? ― ― ― ― ― ― ― ― ?? ― ―
Leukopenia √?‡,§ ― ― ― ― ― ― ― ― ― ― ― ― ― ― Haemoglobin Toxicity
√?‡ ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Liver Function ― ― ― ― ― ― ― ― ― ― ― ― ― ?? ― Menopausal Symptoms
― ― ― ― ― ― ― ― ― ― ?? ?? ― ― ―
Urinary Tract Symptoms
― ― ― ?? ― ― ― ― ― ― ― ― ― ― ―
URTI ― ― ― ― ― ― ― ― ― ― ― ― ?? ― ― Quality of Life and Psychosocial Outcomes
(Overall) QoL √?‡ ?? ― ― ― ― ― ― ― ― ― ― ― ― √? Anxiety ― ― ― ― ― ― √? ― √? ?? ― ― ― ― ― Stress/Distress ― ― ― ― ― ?? ― ― ― ― ― ― ― ― ― Depression ― ― ― ― ― ― √? ― ― ― ― ― ― ― ― Chemo = chemotherapy; QoL = quality of life; URTI = upper respiratory tract infections √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects * Chinese herbal medicines; † Western herbal medicines; ‡ non-small cell lung cancer patients receiving platinum-based chemotherapy combined with astragalus-based Chinese herbal medicine; § colorectal cancer; ║ gastric cancer; ¶ lung cancer; # oesophageal cancer; ** pancreatic cancer; †† ovarian cancer; ‡‡ breast cancer; §§ prostate cancer; ║║ as adjuvant or standalone treatment; ¶¶ = unresectable liver cancer patients receiving transcatheter arterial chemoembolization combined with astragalus-based Chinese herbal medicine
328
Table 9. Potential adverse effects, herb-drug interactions and contraindications of Chinese and Western herbal medicines in cancer patients Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Astragalus*
Chemo toxicity, QoL, immune function, tumour response, survival (all as an adjunct to chemo for CRC or advanced NSCLC)
No significant interactions reported for astragalus alone, although more safety studies are required Astragalus-based preparations: immunosuppressive chemo (e.g. cyclophosphamide) and medications (e.g immunosuppressants, corticosteroids)
Lymphopenia, hyperglycaemia, GI symptoms (e.g. diarrhoea, dyspepsia) [astragalus-based herbal preparations only] Potentially irreversible neurological symptoms from direct ingestion of certain toxic astragalus plants (locoweed) containing swainsonine or selenium ► Avoid in all surgical patients and cancer patients receiving chemotherapy using immunosuppressive agents such as cyclophosphamide ► Avoid or use with caution in cancer patients with autoimmune disease (e.g. rheumatoid arthritis), and those at risk to haemorrhagic stroke or have had a recent organ transplant ► Avoid or use with caution with medications that suppress the immune system such as cyclophosphamide, immunosuppressants (e.g. cyclosporine) and corticosteroids
Ginseng* None
Asian/American Ginseng: anticoagulants or antiplatelet drugs (e.g. warfarin, aspirin), phenelzine (MAOI), hypoglycaemics, oestrogens, corticosteroids, alcohol Siberian Ginseng/ Eleuthero: digoxin, antihypertensives Female Ginseng/Dong Quai: oestrogens
Insomnia (after evening intake), agitation/overstimulation (high intake)
►Avoid use of ginseng or use with caution in hormone-sensitive cancers (e.g. breast and endometrial cancer) and conditions (e.g. pregnancy) [due to potential stimulation of tumour growth via oestrogenic effects] ►Avoid use of ginseng (esp. female ginseng/dong quai) with oestrogens
► Avoid use of Asian or American ginseng in all surgical patients, cancer patients with coagulation disorders, hypertension or diabetes, and those at risk to haemorrhagic stroke ► Avoid use of Asian or American ginseng with anticoagulant/antiplatelet drugs (e.g. warfarin), phenelzine (MAOI), hypoglycaemics, oestrogens, corticosteroids and alcohol
► Avoid use of Siberian ginseng/eleuthero in cancer patients with cardiovascular disease ► Avoid use of Siberian ginseng/eleuthero with digoxin (cardiac drug) and antihypertensive medications (e.g. verapamil, nifedipine)
►Avoid use of female ginseng/dong quai in hormone-sensitive cancers (e.g. breast and endometrial cancer) and conditions (e.g. pregnancy), or with oestrogens
329
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Ginger* Acute postoperative nausea and/or vomiting
Anticoagulants or antiplatelet medications (e.g. warfarin, aspirin)
GI symptoms (e.g. heartburn, bloating, flatulence), increased risk of bleeding
► Avoid in all surgical patients, cancer patients with coagulation disorders, and those at risk to haemorrhagic stroke ► Avoid use with anticoagulants (e.g. warfarin, heparin) or antiplatelet drugs (e.g. aspirin)
Ginkgo* None
All drugs metabolised by the cytochrome P450 2C19 enzyme (CYP2C19 induction) e.g. anticonvulsants/ antiepileptics, omeprazole NSAIDs, anticoagulants or antiplatelet drugs
Headache, GI symptoms (e.g. GI upset, nausea, diarrhoea), dizziness, palpitations, convulsions, allergic skin reactions, anaphylaxis-like reactions (iv admin. only), increased risk of bleeding Reduced efficacy of drugs metabolised by the CYP2C19 enzyme (e.g. increased risk of seizures and possible death with antiepileptics)
► Avoid in all surgical patients, cancer patients with coagulation or seizure disorders, and those at risk to haemorrhagic stroke
► Avoid use with all drugs metabolised by the cytochrome P450 2C19 enzyme, including anticonvulsants (e.g. phenytoin, valproic acid) and omeprazole (proton pump inhibitor) ► Avoid use with anticoagulant/antiplatelet drugs (e.g. warfarin) and NSAIDs (e.g. ibuprofen)
Lingzhi/ Reishi Mushroom*
None
Chemo agents that rely on free radicals including: anthracyclines (e.g. doxorubicin); alkylating agents (e.g. cyclophosphamide); platinum-containing complexes (e.g. cisplatin); podophyllotoxin derivatives (e.g. etoposide); camptothecins (e.g. irinotecan); cytotoxic antibiotics (e.g. bleomycin)
Antiplatelet/anticoagulants
Dry throat and nose, GI symptoms (e.g. heartburn, bloating, flatulence), increased risk of bleeding ► Avoid in all surgical patients ► Avoid in all cancer patients receiving chemotherapy and other treatments (except under the guidance of the treatment team), and those with coagulation disorders ► Avoid use with anticoagulants (e.g. warfarin, heparin) and antiplatelet medications (e.g. aspirin)
330
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Green Tea* Breast or prostate cancer risk
Boronic acid-based proteasome inhibitors (e.g. bortezomib in chemo for multiple myeloma or mantle cell lymphoma); verapamil; caffeine; tannin (in food such as fruit and nuts, drinks such as coffee, teas, fruit juices, wine/beer)
GI and CNS disturbances (e.g. nausea, insomnia, irritability, frequent urination, cardiac arrhythmia) [high intake of 5-6 litres per day] Reduced efficacy of boronic acid-based proteasome inhibitors (e.g. increased risk of suboptimal tumour response and survival in chemotherapy with bortezomib) ► Avoid in cancer patients receiving chemotherapy using bortezomib (e.g. for multiple myeloma and mantle cell lymphoma), cancer patients with known allergy/hypersensitivity to caffeine or tannin and heart conditions, and pregnant or breast-feeding women ► Avoid use with boronic acid-based proteasome inhibitors (e.g. bortezomib), verapamil (antihypertensive/antiarrhythmic), caffeine and tannin (in food and drinks incl. wine/beer)
Garlic† Colorectal or gastric cancer risk
All drugs metabolised by the cytochrome P450 2E1 enzyme (CYP2E1 inhibition) e.g. dacarbazine in chemo (metastatic melanoma, Hodgkin’s lymphoma, other cancers), anaesthetics, paracetamol Antiretrovirals (e.g. saquinavir), anticoagulants or antiplatelet drugs
Mild to severe GI symptoms (e.g. stomach upset, heartburn, bloating) and allergic reactions (e.g. contact dermatitis, garlic burns and anaphylaxis resulting in possible death with topical or oral use); increased risk of bleeding Reduced efficacy of chemotherapy with dacarbazine and other drugs metabolised by the CYP2E1 enzyme, and antiretrovirals ► Avoid in all surgical patients ► Avoid in cancer patients receiving chemotherapy using dacarbazine (e.g. metastatic melanoma and Hodgkin’s lymphoma patients) ► Avoid use with all drugs metabolised by the cytochrome P450 2E1 enzyme (e.g. dacarbazine, anaesthetics, paracetamol) and antiretrovirals (e.g. saquinavir) ► Use with caution when combined with anticoagulants (e.g. warfarin, heparin) or antiplatelet medications (e.g. aspirin)
331
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
St. John’s Wort†
Depression, anxiety
All drugs metabolised by cytochrome P450 enzymes and P-glycoprotein (CYP3A4, CYP2E1, CYP2C19 and P-glycoprotein induction) e.g. chemo agents (e.g. imatinib, irinotecan), opioids, anaesthetics, benzodiazepines, anticoagulants, CV/GI tract/respiratory drugs, antiretrovirals, immunosuppressants, anticonvulsants, muscle relaxants, anti-addiction drugs, hypoglycaemics, antimicrobials, oral contraceptives All drugs that enhance neurotransmitter reuptake or signalling (additive effects) e.g. antidepressants, anxiolytics, antimigraine drugs
Headache, nausea, GI discomfort, diarrhoea, dizziness, palpitations, allergic skin reactions, intermenstrual bleeding, pregnancy, serotonin syndrome [cognitive, autonomic and somatic effects − mild (e.g. hypervigilance, agitation, muscle twitching) to severe symptoms (e.g. tachycardia and hypertension that may lead to shock and death)]; increased risk of bleeding; potentiation or reduced efficacy of medications in drug interactions ► Avoid in all surgical patients ► Avoid in all cancer patients receiving chemotherapy (esp. imatinib for chronic myeloid leukaemia, GI stromal tumours and other malignancies; and irinotecan for advanced colorectal and lung cancer patients), and those with coagulation disorders ► Avoid use with all drugs metabolised by the CYP450 enzyme, including opioids (esp. in palliative patients with cancer pain), anaesthetics (e.g. fentanyl, propofol), benzodiazepines (e.g. midazolam), antidepressants (e.g. SSRIs such as sertraline; SNRIs such as venlafaxine; tricyclics such as amitryptiline; MAOIs such as phenelzine), anticoagulants or antiplatelet drugs (e.g. warfarin, aspirin), cardiovascular drugs (e.g. simvastatin for high cholesterol; verapamil for hypertension and arrhythmias; beta-blockers such as talinolol; antianginals such as ivabradine; cardiac inotropic drugs such as digoxin for heart failure), immunosuppressants (e.g. cyclosporine, tacrolimus), antiretrovirals (e.g. protease inhibitors, such as indinavir, and non-nucleoside reverse transcriptase inhibitors, such as nevirapine, widely used for HIV/AIDS), antimigraine drugs (e.g. triptans such as eletriptan), anxiolytics (e.g. buspirone), anticonvulsants (e.g. mephenytoin), anti-addiction medications (e.g. buproprion for smoking cessation), muscle relaxants (e.g. chlorzoxazone), respiratory drugs (e.g. antihistamines such as fexofenadine), hypoglycaemics (e.g. gliclazide), antimicrobial drugs (e.g. antibiotics such as erythromycin), drugs acting on the GI tract (e.g. antidiarrhoeal drugs such as loperamide, omeprazole), and oral contraceptives (e.g. ethinyl estradiol/norethindrone)
332
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Kava† Short-term anxiety (1-24 weeks)
All drugs metabolised by cytochrome P450 2E1 and 1A2 enzymes (CYP2E1 and CYP1A2 inhibition)
e.g. dacarbazine (chemo drug), anaesthetics, muscle relaxants, antidepressants, antipsychotics, anticoagulants, paracetamol, alcohol
All drugs mediated via GABA neurotransmission (additive effects)
e.g. sedatives (benzodiazepines, barbiturates), anaesthetics
Potentially all hepatotoxic drugs, including chemo agents such as dacarbazine, cyclophosphamide, camptothecins, taxanes, vinca alkaloids and EGFR-TK inhibitors
Potentially all dopaminergic drugs (inhibitory effects) e.g. levodopa
Appetite loss, malnutrition, weight loss, shortness of breath, skin conditions (e.g. kava dermopathy; dry, scaly skin), blood and metabolic abnormalities, ataxia, dystonia, pulmonary hypertension [all with chronic and/or high intake of 300-400g per week]; sedative effects; possible hepatotoxicity, liver transplantation and death; increased risk of bleeding; potentiation or reduced efficacy of medications in drug interactions ► Avoid in all surgical patients ► Avoid in cancer patients receiving hepatotoxic chemo, including cyclophosphamide, camptothecins (e.g. irinotecan), taxanes (e.g. paclitaxel), vinca alkaloids (e.g. vinorelbine) and EGFR-TK inhibitors (e.g. erlotinib for non-small cell lung, pancreatic and other cancers), or dacarbazine (metastatic melanoma, Hodgkin’s lymphoma, other cancers) ► Avoid in cancer patients with (a history of) liver disease or coagulation disorders ► Avoid use with all drugs metabolised by the cytochrome P450 2E1 and 1A2 enzymes, including dacarbazine (chemo drug), anaesthetics (e.g. fentanyl and propofol), muscle relaxants (e.g. chlorzoxazone), antidepressants, antipsychotics (e.g. paroxetine), anticoagulant/antiplatelet medications (e.g. warfarin, aspirin), paracetamol and alcohol ► Avoid use with all drugs mediated via GABA neurotransmission (e.g. anaesthetics, benzodiazepines such as alprazolam, barbiturates, hypnotics, anxiolytics) ► Avoid use or use with caution with all hepatotoxic drugs unrelated to cancer treatment, all drugs that enhance GABA neurotransmission (e.g. anaesthetics; sedatives including benzodiazepines such as alprazolam and barbiturates; hypnotics; anxiolytics), and all dopaminergic drugs (e.g. anti-Parkinsonian drug levodopa)
333
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Valerian† Sleep disturbance
All drugs mediated via GABA neurotransmission (additive effects) e.g. sedatives (benzodiazepines, barbiturates), anaesthetics, hypnotics, anxiolytics
CNS symptoms (e.g. headache, nervousness, dizziness), GI symptoms (e.g. diarrhoea, nausea, heartburn, epigastric pain), insomnia (chronic use ≥ 2-4 months), withdrawal effects (e.g. delirium, tachycardia) [high intake] Potentiation effects of medications involved in drug interactions (e.g. excessive sedation) ► Avoid in all surgical patients ► Avoid use with all drugs mediated via GABA neurotransmission (e.g. anaesthetics, benzodiazepines such as alprazolam, barbiturates, hypnotics, anxiolytics)
Evening Primrose Oil†
None Anticonvulsants (e.g. phenothiazines such as fluphenazine)
Headache, GI symptoms (e.g. stomach upset, nausea, mild diarrhoea), small increased risk of seizures ► Monitor use in all cancer patients receiving chemotherapy and other treatments ► Use with caution in cancer patients with seizure disorders ► Use with caution when combined with anticonvulsants (e.g. phenothiazines such as fluphenazine)
Black Cohosh†
None
Potentially all hepatotoxic drugs, including chemo agents such as dacarbazine, cyclophosphamide, camptothecins, taxanes, vinca alkaloids and EGFR-TK inhibitors
Headache, dizziness, GI symptoms (e.g. stomach upset, nausea), small increased risk of hepatotoxicity ► Avoid in cancer patients receiving hepatotoxic chemotherapy, including cyclophosphamide, camptothecins (e.g. irinotecan), taxanes (e.g. paclitaxel), vinca alkaloids (e.g. vinorelbine) and EGFR-TK inhibitors (e.g. erlotinib for non-small cell lung, pancreatic and other cancers) ► Avoid in cancer patients with (a history of) liver disease, and women with oestrogen-dependent cancers (e.g. breast or uterine cancer) ► Use with caution with all hepatotoxic drugs unrelated to cancer treatment
334
Table 9. (Continued) Herbal
Medicine Indication Herb-Drug Interactions Adverse Effects and Contraindications
Echinacea† None
Potentially all drugs metabolised by cytochrome P450 1A2 and 3A4 enzymes (weak CYP1A2 and CYP3A4 inhibition/induction) e.g. tricyclic antidepressants, antipsychotics, benzodiazepines, CV drugs (antihypertensives, antiarrhythmics, antihyperlipidemics), antimicrobials, immunosuppressants, oral contraceptives, caffeine
Rashes, increased asthmatic episodes, anaphylaxis and related death (rare) Possible potentiation or reduced efficacy of medications in drug interactions ► Avoid in cancer patients receiving chemotherapy metabolised by cytochrome P450 1A2 and 3A4 enzymes, including cyclophosphamide, camptothecins (e.g. irinotecan), taxanes (e.g. paclitaxel), vinca alkaloids (e.g. vinorelbine) and EGFR-TK inhibitors (e.g. erlotinib for non-small cell lung, pancreatic and other cancers) ► Avoid in cancer patients with asthma or atopy (genetic tendency towards allergic reactions) ► Avoid use or use with caution all drugs metabolised by the cytochrome P4501A2 and 3A4 enzymes, including tricyclic antidepressants (e.g. amitryptiline), antipsychotics (e.g. clozapine, olanzipine), benzodiazepines (e.g. midazolam), immunosuppressants (e.g. corticosteroids, cyclosporine), antihypertensives/antiarrhythmics (e.g. verapamil), antihyperlipidemic drugs to reduce high cholesterol (e.g. simvastatin), antimicrobial drugs (e.g. antibiotics such as erythromycin), oral contraceptives (e.g. ethinyl estradiol/norethindrone) and caffeine
Milk Thistle† None
No significant interactions reported, but effects may be dose-responsive (i.e. require high doses)
GI symptoms (e.g. stomach upset, nausea); allergic reactions ranging from itchiness to eczema and anaphylaxis (rare) Diarrhoea (high intake > 1.5g/day) and asymptomatic hepatotoxicity (hyperbilirubinaemia, very high intake of 10-20g/day) in cancer patients per se ► Monitor use in all cancer patients receiving chemotherapy and other treatments
335
Table 9. (Continued)
Herbal Medicine
Indication Herb-Drug Interactions Adverse Effects and Contraindications
European Mistletoe†
Chemotherapy and radiotherapy toxicity, QoL
No significant interactions reported, but studies are lacking
Local reactions (e.g. pruritis, erythema or induration at the injection site), systemic reactions (e.g. headaches, fever, influenza-like symptoms), allergic reactions (e.g. breathing difficulties, anaphylaxis) [rare] Reduced T-cell function in cancer patients without local reactions (chronic use) ► Monitor use in all cancer patients receiving chemotherapy and other treatments
Chemo = chemotherapy; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CRC= colorectal cancer; CV = cardiovascular; CYP = cytochrome P450; EGFR-TK = epidermal growth factor receptor tyrosine-kinase; esp. = especially; GABA = gamma-aminobutyric acid; GI = gastrointestinal; incl. = including, MAOIs = monoamine oxidase inhibitors; NSAIDs = non-steroidal anti-inflammatory drugs; NSCLC = non-small cell lung cancer; QoL = quality of life; SNRIs = serotonin and noradrenaline reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors * Chinese herbal medicines; † Western herbal medicines
336
Table 10. Evidence supporting benefit in using manipulative and body-based interventions to prevent/ameliorate cancer symptoms and treatment side-effects
Manipulative and Body-based Interventions: Recommendations for each intervention strategy across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Massage Therapy Acupuncture Exercise
Interventions Side-Effect/Symptom Outcomes
Clinical Outcomes ??‡‡ ― √? Physical Functioning ― ― √? or √?*,# Physical Activity Level and Aerobic Fitness
― ― √?
Body Composition ― ― √? Body/Muscle Strength ― ― √? or √?** Acute Postoperative Nausea ― √? ― Acute Postoperative Vomiting ― √? ― Acute Chemo-Induced Nausea ― √?‡ ― Acute Chemo-Induced Vomiting ― √?‡ ― Nausea (Overall) √? ― ― Pain √? X? ― Fatigue
?? ― X?*,║,¶ or √?**,††
Immunological Function ― √? ??* Leukopenia ― ?? ― Weight Gain ― ― ??* Body Image ― ― √?*,†† Hot Flushes ― X?*,† ― Radiation-Induced Xerostomia ― √?§ ―
Quality of Life and Psychosocial Outcomes (Overall) QoL ?? ?? √? or √?*,#,†† Anxiety √? or ?‡‡ ― √? Depression √? ― √?*,†† General Mood ??‡‡ ― √? Stress/Distress √? ― ― Anger ?? ― ― Self-Esteem ― ― √? Cancer-Specific Concerns ― ― √?*,††
BP = blood pressure; chemo = chemotherapy; CRF = cancer-related fatigue; QoL = quality of life √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects * breast cancer; † prostate cancer; ‡ acupuncture-point stimulation (manual acupuncture, electroacupunture, self-/practitioner-administered acupressure) + antiemetics; § head and neck cancer; ║ prostate cancer; ¶ supervised + home-based aerobic/resistance interventions overall reduced CRF in breast and prostate patients, but neither supervised intervention alone did so in prostate patients and only supervised aerobic exercise per se did so in breast patients; # metastatic cancer; ** cancer survivors; †† breast cancer survivors ‡‡ aromatherapy per se
337
Table 11. Potential adverse effects and contraindications of manipulative and body-based interventions in cancer patients Manipulative
and Body-Based Practice
Indication Adverse Effects and Contraindications
Massage Therapy
Anxiety, stress/distress, depression, nausea, cancer pain
Bleeding (ranging from minor bruising to internal haemorrhaging), bone fractures, increased pain, infection, and adverse events (e.g. allergic reactions, infection, accidental overdose) due to incorrect storage and handling of aromatherapy essential oils [all rare] ► Reduce pressure and/or avoid direct or deep tissue massage in all surgical patients, esp. those with open wounds ► Avoid direct pressure over known tumours in cancer patients ► Reduce pressure and/or avoid direct or deep tissue massage in cancer patients with bone metastases, radiation dermatitis or prosthetic devices (e.g. infusaport, colostomy bag, stents), and in those with coagulation disorders or severe osteoporosis ► Reduce pressure and/or avoid direct or deep tissue massage with patients using anticoagulants (e.g. warfarin, heparin) or antiplatelet drugs (e.g. aspirin) ► Avoid direct application of aromatherapy essential oils in cancer patients with known allergy/hypersensitivity, wounds or skin conditions, and use with caution in those with renal or liver disease
Acupuncture
Acute postoperative or chemo-induced nausea/vomiting, nausea (in general), immunological function, radiation-induced xerostomia
Local bleeding and needling pain (rare), pneumothorax (extremely rare) ► Monitor use in all cancer patients receiving chemotherapy and other treatments
338
Table 11. (Continued) Manipulative
and Body-Based Practice
Indication Adverse Effects and Contraindications
Exercise Interventions
Physical functioning, physical activity level, aerobic fitness, body composition, body/muscle strength (incl. survivors), fatigue (survivors only), clinical outcomes, QoL (incl. breast cancer survivors); depression, body image and cancer-specific concerns (breast cancer patients and survivors only)
Pain (e.g. hip/calf), pulled muscles (e.g. hamstring), (shoulder) tendonitis; serious adverse events such as back injury, falls and development or exacerbation of lymphoedema, anaemia or cachexia (rare) ► Use with caution or avoid in patients with severe osteoporosis, joint problems, acute back pain, sprains or fractures, or whose physical functioning otherwise precludes certain exercises ► Straining downward or holding low postures should be avoided by patients with inguinal hernia, artificial joints or prosthetic devices (e.g. infusaport, colostomy bag, stents), pregnancy, or those recovering from abdominal surgery
Chemo = chemotherapy; esp. = especially; incl. = including; QoL = quality of life
339
Table 12. Evidence supporting benefit in using energy therapies to prevent/ameliorate cancer symptoms and treatment side-effects
Energy Therapies: Recommendations for each therapeutic strategy across types of outcome based on meta-analysis and/or systematic review
Type of Outcome Biofield
Therapies* Qigong†
Microwave (UHF Radiowave)/Tronado
Therapy‡ Cancer Treatment/Survival/Risk Outcomes
Tumour Response ― ― X?¶
Survival Length ― √?§ or
??║ X?¶
Side-Effect/Symptom Outcomes Radiotherapy Toxicity ― ― X¶,# Clinical Outcomes ― ??║ ― Physiological Arousal (BP, heart/respiratory rate)
?? ― ―
Biological Indicators ― √?§ ― Acute Cancer Pain √? ― ― Chronic Cancer Pain ?? ― ― Acute Postoperative Pain √? ― ― Fatigue ?? ― ―
Quality of Life and Psychosocial Outcomes (Overall) QoL ?? ― ―
UHF = ultra-high frequency frequency; QoL = quality of life √ = highly recommended, strong evidence for beneficial effects; √? = tentatively recommended, mixed evidence for beneficial effects; ?? = neither recommend nor advise against, inconclusive evidence for beneficial effects; X? = tentatively advise against, little evidence for beneficial effects; X = decisively advise against, no evidence for beneficial effects * practitioner-administered biofield therapies (external Qigong, therapeutic touch, Reiki, spiritual healing, healing touch and others); † type of biofield therapy; ‡ type of bioelectromagnetic-based therapy; § predominantly internal Qigong + conventional medical treatment; ║ internal Qigong ± chemotherapy or herbal medicine in palliative/supportive cancer care; ¶ largely microwave therapy + radiotherapy; # bladder or other invasive cancers
340
Table 13. Potential adverse effects and contraindications of energy therapies in cancer patients Energy Therapy Indication Adverse Effects and Contraindications
Biofield Therapies*
Acute cancer or postoperative pain
Few (if any) adverse events have been reported in the health literature for touch therapies (healing touch, therapeutic touch, Reiki) and other external practices (as far as can be ascertained), but appear more likely for internal practices such as internal Qigong (see below) ► Avoid or use Reiki with caution in patients with (a history of) psychosis, personality disorders or bipolar disorder
Qigong†
Biological indicators and survival (as an adjunct to conventional medical treatment)
Mild to severe adverse effects including sensory or somatic disturbances (e.g. headache, dizziness, chest tightness, tachycardia, breathlessness); motor disturbances (e.g. muscle twitching, tremors, odd limb movements, uncontrolled motor activity); cognitive impairment (e.g. memory, attention); psychological symptoms (e.g. anxiety, irritability, hypochondriasis, obsessive thoughts or images, delusions, visual/auditory hallucinations, disorganised speech, dissociation, altered consciousness, disorientation, mania, depression, suicidal or bizarre behaviour); and allergic skin reactions Qigong-induced, culture-bound psychiatric disorders (specific to individuals of Chinese or other Asian ethnicities, even when living in Western countries) [rare] ► Use with caution or avoid (esp. in the absence of a qualified practitioner) in cancer patients with neurotic traits or (a history of) psychosis, personality disorders or other psychiatric disorders, and those who are suggestible or otherwise psychologically vulnerable, or whose physical functioning precludes certain exercises ► Monitor use in cancer patients from Chinese and other Asian backgrounds, given the culture-specific nature of the Qigong-induced psychiatric disorders reported
Microwave (UHF Radiowave)/ Tronado Therapy‡
None
Pain, erythema, fibrosis, necrosis, ulcerations, blisters, thermal burns (all more common); third degree burns, arterial rupture, development of fistulae, death (often related to inadvertent heating of blood vessels or infections following invasive thermometry) [all occasional or rare] ► Avoid in cancer patients with thalassaemia (genetic blood disorder causing anaemia)§
Esp. = especially; UHF = ultra-high frequency frequency; QoL = quality of life * biofield therapies (e.g. Qigong, therapeutic touch, Reiki, spiritual healing, healing touch, Johrei, polarity therapy); † internal qigong, a type of biofield therapy; ‡ type of bioelectromagnetic-based therapy; § an inherited autosomal recessive blood disorder that results in abnormal production of haemoglobin molecules, thus causing anaemia
341
6. References
1. F. Dantas and H. Rampes, Do homeopathic medicines provoke adverse effects? A
systematic review, Br Homeopath J. 89(Suppl 1): S35-S38 (2000).
2. A. Molassiotis, P. Fernandez-Ortega, D. Pud, G. Ozden, J. A. Scott, V. Panteli, A.
Margulies, M. Browall, M. Magri, S. Selvekerova, E. Madsen, L. Milovics, I.
Bruyns, G. Gudmundsdottir, S. Hummerston, A. M. Ahmad, N. Platin, N. Kearney
and E. Patiraki, Use of complementary and alternative medicine in cancer patients: a
European survey, Ann Oncol. 16(4): 655-663 (2005).
3. S. Milazzo, E. Ernst, S. Lejeune and K. Schmidt, Laetrile treatment for cancer,
Cochrane Database Syst Rev. 2: CD005476 (2006).
4. S. Kassab, M. Cummings, S. Berkovitz, R. van Haselen and P. Fisher, Homeopathic
medicines for adverse effects of cancer treatments, Cochrane Database Syst Rev. 2:
CD004845 (2009).
5. R. Wong, C. M. Sagar and S. M. Sagar, Integration of Chinese medicine into
supportive cancer care: a modern role for an ancient tradition, Cancer Treat Rev.
27(4): 235-246 (2001).
6. K. Luebbert, B. Dahme and M. Hasenbring, The effectiveness of relaxation training
in reducing treatment-related symptoms and improving emotional adjustment in
acute non-surgical cancer treatment: a meta-analytical review, Psychooncology.
10(6): 490-502 (2001).
7. E. C. Devine, Meta-analysis of the effect of psychoeducational interventions on pain
in adults with cancer, Oncol Nurs Forum. 30(1): 75-89 (2003).
8. K. L. Kwekkeboom, C. H. Cherwin, J. W. Lee and B. Wanta, Mind-body treatments
for the pain-fatigue-sleep disturbance symptom cluster in persons with cancer, J
Pain Symptom Manage. 39(1): 126-138 (2010).
9. K. Lotfi-Jam, M. Carey, M. Jefford, P. Schofield, C. Charleson and S. Aranda,
Nonpharmacologic strategies for managing common chemotherapy adverse effects:
a systematic review, J Clin Oncol. 26(34): 5618-5629 (2008).
10. C. Figueroa-Moseley, P. Jean-Pierre, J. A. Roscoe, J. L. Ryan, S. Kohli, O. G.
Palesh, E. P. Ryan, J. Carroll and G. R. Morrow, Behavioral interventions in
treating anticipatory nausea and vomiting, J Natl Compr Canc Netw. 5(1): 44-50
(2007).
342
11. J. A. Astin, S. L. Shapiro and G. E. R. Schwartz, Meditation. In: Clinicians’ Rapid
Access Guide to Complementary and Alternative Medicine, ed. D. Novey (Mosby,
St. Louis, 2000).
12. D. Ledesma and H. Kumano, Mindfulness-based stress reduction and cancer: a
meta-analysis, Psychooncology. 18(6): 571-579 (2009).
13. J. E. Smith, J. Richardson, C. Hoffman and K. Pilkington, Mindfulness-based stress
reduction as supportive therapy in cancer care: systematic review, J Adv Nurs.
52(3): 315-327 (2005).
14. M. J. Ott, R. L. Norris and S. M. Bauer-Wu, Mindfulness meditation for oncology
patients: a discussion and critical review, Integr Cancer Ther. 5(2): 98-108 (2006).
15. D. R. Patterson and M. P. Jensen, Hypnosis and clinical pain, Psychol Bull. 129(4):
495-521 (2003).
16. J. Richardson, J. E. Smith, G. McCall, A. Richardson, K. Pilkington and I. Kirsch,
Hypnosis for nausea and vomiting in cancer chemotherapy: a systematic review of
the research evidence, Eur J Cancer Care (Engl). 16(5): 402-412 (2007).
17. National Institutes of Health (NIH) Technology Assessment Panel, Integration of
behavioral and relaxation approaches into the treatment of chronic pain and
insomnia. NIH Technology Assessment Panel on Integration of Behavioral and
Relaxation Approaches into the Treatment of Chronic Pain and Insomnia, JAMA.
276: 313-318 (1996).
18. S. M. Sellick and C. Zaza, Critical review of 5 nonpharmacologic strategies for
managing cancer pain, Cancer Prev Control. 2(1): 7-14 (1998).
19. N. Flory and E. Lang, Practical hypnotic interventions during invasive cancer
diagnosis and treatment, Hematol Oncol Clin North Am. 22(4): 709-725 (2008).
20. J. Richardson, J. E. Smith, G. McCall and K. Pilkington, Hypnosis for procedure-
related pain and distress in pediatric cancer patients: a systematic review of
effectiveness and methodology related to hypnosis interventions, J Pain Symptom
Manage. 31(1): 70-84 (2006).
21. J. E. Bower, A. Woolery, B. Sternlieb and D. Garet, Yoga for cancer patients and
survivors, Cancer Control. 12(3): 165-171 (2005).
22. K. B. Smith and C. F. Pukall CF, An evidence-based review of yoga as a
complementary intervention for patients with cancer, Psychooncology. 18(5): 465-
475 (2009).
343
23. M. S. Lee, M. H. Pittler and E. Ernst, Is tai chi an effective adjunct in cancer care?
A systematic review of controlled clinical trials, Support Care Cancer. 15(6): 597-
601 (2007).
24. M. S. Lee, T. Y. Choi and E. Ernst, Tai chi for breast cancer patients: a systematic
review, Breast Cancer Res Treat. 120(2): 309-316 (2010).
25. G. Y. Yeh, C. Wang, P. M. Wayne and R. Phillips R, Tai chi exercise for patients
with cardiovascular conditions and risk factors: a systematic review, J Cardiopulm
Rehabil Prev. 29(3):152-160 (2009).
26. C. Dileo, Effects of music and music therapy on medical patients: a meta-analysis
of the research and implications for the future, J Soc Integr Oncol. 4(2): 67-70
(2006).
27. A. Zabalegui, S. Sanchez, P. D. Sanchez and C. Juando, Nursing and cancer support
groups, J Adv Nurs. 51(4): 369-381 (2005).
28. B. H. Gottlieb and E. D. Wachala, Cancer support groups: a critical review of
empirical studies, Psychooncology. 16(5): 379-400 (2007).
29. L. M. Hoey, S. C. Ieropoli, V. M. White and M. Jefford, Systematic review of peer-
support programs for people with cancer, Patient Educ Couns. 70(3): 315-337
(2008).
30. K. I. Pargament, The psychology of religion and spirituality? Yes and no. Int J
Psych Religion. 9: 3-16 (1999).
31. K. I. Pargament, The Psychology of Religion and Coping: Theory, Research,
Practice, (Guilford Press, New York, 1997).
32. J. J. Mytko and S. J. Knight, Body, mind and spirit: towards the integration of
religiosity and spirituality in cancer quality of life research, Psychooncology. 8(5):
439-450 (1999).
33. J. A. Belzen, Spirituality, culture and mental health: prospects and risks for
contemporary psychology of religion, J Religion Health. 43: 291-316 (2004).
34. R. Jenkins and K. Pargament, Religion and spirituality as resources for coping with
cancer. J Psychosocial Oncol. 13(1–2): 51-74 (1995).
35. S. C. Johnson and B. Spilka, Coping with breast cancer: the roles of clergy and
faith, J Religion Health. 30: 21-33 (1991).
344
36. I. C. Thuné-Boyle, J. A. Stygall, M. R. Keshtgar and S. P. Newman, Do
religious/spiritual coping strategies affect illness adjustment in patients with cancer?
A systematic review of the literature, Soc Sci Med. 63(1): 151-164 (2006).
37. A. Visser, B. Garssen and A. Vingerhoets, Spirituality and well-being in cancer
patients: a review, Psychooncology. 19(6): 565-572 (2010).
38. J.F. Rossiter-Thornton, Prayer in your practice, Complement Ther Nurs Midwifery.
8(1): 21-28 (2002).
39. K.S. Masters and G. I. Spielmans, Prayer and health: review, meta-analysis and
research agenda, J Behav Med. 30(4): 329-338 (2007).
40. C. Hollywell and J. Walker, Private prayer as a suitable intervention for hospitalised
patients: a critical review of the literature, J Clin Nurs. 18(5): 637-651 (2009).
41. I. N. Olver and H. S. Whitford, A randomized controlled trial of the effect of
intercessory prayer on the spiritual wellbeing and quality of life of patients with
cancer, J Clin Oncol. 27(Suppl): e20708 (2009).
42. K. S. Masters, G. I. Spielmans and J. T. Goodson, Are there demonstrable effects of
distant intercessory prayer? A meta-analytic review, Ann Behav Med. 32(1): 21-26
(2006).
43. L. H. Powell, L. Shahabi and C. E. Thoresen, Religion and spirituality. Linkages to
physical health, Am Psychol. 58(1): 36-52 (2003).
44. M. Stefanek, P. G. McDonald and S. A. Hess, Religion, spirituality and cancer:
current status and methodological challenges, Psychooncology. 14(6): 450-463
(2005).
45. A. Hoff, C. T. Johannessen-Henry, L. Ross, N. C. Hvidt and C. Johansen, Religion
and reduced cancer risk: what is the explanation? A review, Eur J Cancer. 44(17):
2573-2579 (2008).
46. L. Roberts, I. Ahmed, S. Hall and A. Davison, Intercessory prayer for the alleviation
of ill health, Cochrane Database Syst Rev. 15(2): CD000368 (2009).
47. National Center for Complementary and Alternative Medicine (NCCAM),
Biologically based practices: an overview (NCCAM Publication No. D237),
Available at http://www.umbwellness.org/PDF_files/biobasedprac.pdf (accessed 15
June 2010).
48. B. N. Ames, L. S. Gold and W. C. Willett, The causes and prevention of cancer,
Proc Natl Acad Sci USA. 92(12): 5258-5265 (1995).
345
49. J. K. Willcox, S. L. Ash and G. L. Catignani, Antioxidants and prevention of
chronic disease, Crit Rev Food Sci Nutr. 44(4): 275-295 (2004).
50. K. A. Conklin, Cancer chemotherapy and antioxidants, J Nutr. 134(11): 3201S-
3204S (2004).
51. G.M. D'Andrea, Use of antioxidants during chemotherapy and radiotherapy should
be avoided, CA Cancer J Clin. 55(5): 319-321 (2005).
52. H. E. Seifried, S. S. McDonald, D. E. Anderson, P. Greenwald and J. A. Milner,
The antioxidant conundrum in cancer, Cancer Res. 63(15): 4295-4298 (2003).
53. K. I. Block, A. C. Koch, M. N. Mead, P. K. Tothy, R. A. Newman and C.
Gyllenhaal, Impact of antioxidant supplementation on chemotherapeutic toxicity: a
systematic review of the evidence from randomized controlled trials, Int J Cancer.
123(6): 1227-1239 (2008).
54. R. W. Moss, Do antioxidants interfere with radiation therapy for cancer?, Integr
Cancer Ther. 6(3): 281-292 (2007).
55. A. D. Sasse, L. G. Clark, E. C. Sasse and O. A. Clark, Amifostine reduces side
effects and improves complete response rate during radiotherapy: results of a meta-
analysis, Int J Radiat Oncol Biol Phys. 64(3): 784-791 (2006).
56. H. Greenlee, M. D. Gammon, P. E. Abrahamson, M. M. Gaudet, M. B. Terry, D. L.
Hershman, M. Desai, S. L. Teitelbaum, A. I. Neugut and J. S. Jacobson, Prevalence
and predictors of antioxidant supplement use during breast cancer treatment: the
Long Island Breast Cancer Study Project, Cancer. 115(14): 3271-3282 (2009).
57. G. Dennert and M. Horneber, Selenium for alleviating the side effects of
chemotherapy, radiotherapy and surgery in cancer patients, Cochrane Database Syst
Rev. 3: CD005037 (2006).
58. A. Tabassum, R. G. Bristow and V. Venkateswaran, Ingestion of selenium and
other antioxidants during prostate cancer radiotherapy: a good thing?, Cancer Treat
Rev. 36(3): 230-234 (2010).
59. F. Haseen, M. M. Cantwell, J. M. O'Sullivan and L. J. Murray, Is there a benefit
from lycopene supplementation in men with prostate cancer? A systematic review,
Prostate Cancer Prostatic Dis. 12(4): 325-332 (2009).
60. L. Roffe, K. Schmidt and E. Ernst, Efficacy of coenzyme Q10 for improved
tolerability of cancer treatments: a systematic review, J Clin Oncol. 22(21): 4418-
4424 (2004).
346
61. B. D. Lawenda, K. M. Kelly, E. J. Ladas, S. M. Sagar, A. Vickers and J. B.
Blumberg, Should supplemental antioxidant administration be avoided during
chemotherapy and radiation therapy?, J Natl Cancer Inst. 100(11): 773-783 (2008).
62. K. I. Block, A. C. Koch, M. N. Mead, P. K. Tothy, R. A. Newman and C.
Gyllenhaal, Impact of antioxidant supplementation on chemotherapeutic efficacy: a
systematic review of the evidence from randomized controlled trials, Cancer Treat
Rev. 33(5): 407-418 (2007).
63. E. J. Ladas, J. S. Jacobson, D. D. Kennedy, K. Teel, A. Fleischauer and K. M.
Kelly, Antioxidants and cancer therapy: a systematic review, J Clin Oncol. 22(3):
517-528 (2004).
64. L. K. Mell, R. Malik, R. Komaki, B. Movsas, R. S. Swann, C. Langer, D.
Antonadou, M. Koukourakis and A. J. Mundt, Effect of amifostine on response
rates in locally advanced non-small-cell lung cancer patients treated on randomized
controlled trials: a meta-analysis, Int J Radiat Oncol Biol Phys. 68(1): 111-118
(2007).
65. I. D. Coulter, M. L. Hardy, S. C. Morton, L. G. Hilton, W. Tu, D. Valentine and P.
G. Shekelle, Antioxidants vitamin C and vitamin e for the prevention and treatment
of cancer, J Gen Intern Med. 21(7): 735-744 (2006).
66. E. Mills, P. Wu, D. Seely and G. Guyatt, Melatonin in the treatment of cancer: a
systematic review of randomized controlled trials and meta-analysis, J Pineal Res.
39(4): 360-366 (2005).
67. S. Sagar, Should patients take or avoid antioxidant supplements during anticancer
therapy? An evidence-based review, Curr Oncol. 12: 44-54 (2005).
68. S. K. Myung, Y. Kim, W. Ju, H. J. Choi and W. K. Bae, Effects of antioxidant
supplements on cancer prevention: meta-analysis of randomized controlled trials,
Ann Oncol. 21(1): 166-179 (2010).
69. A. Bardia, I. M. Tleyjeh, J. R. Cerhan, A. K. Sood, P. J. Limburg, P. J. Erwin and
V. M. Montori, Efficacy of antioxidant supplementation in reducing primary cancer
incidence and mortality: systematic review and meta-analysis, Mayo Clin Proc.
83(1): 23-34 (2008).
347
70. D. Papaioannou, K. Cooper, C. Christopher Carroll, D. Hind, H. Pilgrim, P.
Tappenden and R. F. Logan, Antioxidants in the chemoprevention of colorectal
cancer and colorectal adenomas in the general population: a systematic review and
meta-analysis, Colorectal Dis. DOI: 10.1111/j.1463-1318.2010.02289.x.
71. G. Bjelakovic, D. Nikolova, R. G. Simonetti and C. Gluud, Systematic review:
primary and secondary prevention of gastrointestinal cancers with antioxidant
supplements, Aliment Pharmacol Ther. 28(6): 689-703 (2008).
72. A. Alkhenizan and K. Hafez, The role of vitamin E in the prevention of cancer: a
meta-analysis of randomized controlled trials, Ann Saudi Med. 27(6): 409-414
(2007).
73. D. Q. Pham and R. Plakogiannis, Vitamin E supplementation in cardiovascular
disease and cancer prevention: part 1. Ann Pharmacother. 39(11): 1870-1878
(2005).
74. E. Cho, D. J. Hunter, D. Spiegelman, D. Albanes, W. L. Beeson, P. A. van den
Brandt, G. A. Colditz, D. Feskanich, A. R. Folsom, G. E. Fraser, J. L. Freudenheim,
E. Giovannucci, R. A. Goldbohm, S. Graham, A. B. Miller, T. E. Rohan, T. A.
Sellers, J. Virtamo, W. C. Willett and S. A. Smith-Warner, Intakes of vitamins A, C
and E and folate and multivitamins and lung cancer: a pooled analysis of 8
prospective studies, Int J Cancer. 118(4): 970-978 (2006).
75. L. Gallicchio, K. Boyd, G. Matanoski, X. G. Tao, L. Chen, T. K. Lam, M. Shiels, E.
Hammond, K. A. Robinson, L. E. Caulfield, J. G. Herman, E. Guallar and A. J.
Alberg, Carotenoids and the risk of developing lung cancer: a systematic review,
Am J Clin Nutr. 88(2): 372-383 (2008).
76. J. N. Hathcock, A. Azzi, J. Blumberg, T. Bray, A. Dickinson, B. Frei, I. Jialal, C. S.
Johnston, F. J. Kelly, K. Kraemer, L. Packer, S. Parthasarathy, H. Sies and M. G.
Traber, Vitamins E and C are safe across a broad range of intakes, Am J Clin Nutr.
81(4): 736-745 (2005).
77. World Cancer Research Fund and American Institute for Cancer Research (AICR),
Food, nutrition, physical activity, and the prevention of cancer: a global
perspective (AICR, Washington DC, 2007).
78. A. T. Diplock, Safety of antioxidant vitamins and beta-carotene, Am J Clin Nutr.
62(6 Suppl): 1510S-1516S (1995).
348
79. C. P. R. Avula, R. A. Lawrence, C. A. Jolly and G. Fernandes, Role of n-3
polyunsaturated fatty acids (PUFA) in autoimmunity, inflammation, carcinogenesis,
and apoptosis, Recent-Research-Developments-in-Lipids. 4(2): 303-319 (2000).
80. I. T. Johnson, Anticarcinogenic effects of diet-related apoptosis in the colorectal
mucosa, Food Chem Toxicol. 40(8): 1171-1178 (2002).
81. M. J. Tisdale, Catabolic mediators of cancer cachexia, Curr Opin Support Palliat
Care. 2(4): 256-261 (2008).
82. M. D. Barber, J. A. Ross, A. C. Voss, M. J. Tisdale and K. C. H. Fearon, The effect
of an oral nutritional supplement enriched with fish oil on weight loss in patients
with pancreatic cancer, Br J Cancer. 81(1): 80-86 (1999).
83. R. Colomer, J. M. Moreno-Nogueira, P. P. García-Luna, P. García-Peris, A. García-
de-Lorenzo, A. Zarazaga, L. Quecedo, J. del Llano, L. Usán and C. Casimiro, N-3
fatty acids, cancer and cachexia: a systematic review of the literature, Br J Nutr.
97(5): 823-831 (2007).
84. A. Dewey, C. Baughan, T. Dean, B. Higgins and I. Johnson, Eicosapentaenoic acid
(EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia,
Cochrane Database Syst Rev. 24(1): CD004597 (2007).
85. C. H. MacLean, S. J. Newberry, W. A. Mojica, P. Khanna, A. M. Issa, M. J.
Suttorp, Y. W. Lim, S. B. Traina, L. Hilton, R. Garland and S. C. Morton, JAMA.
295(4): 403-415 (2006).
86. M. Carayol, P. Grosclaude and C. Delpierre, Prospective studies of dietary alpha-
linolenic acid intake and prostate cancer risk: a meta-analysis, Cancer Causes
Control. 21(3): 347-355 (2010).
87. J. A. Simon, Y. H. Chen and S. Bent, The relation of alpha-linolenic acid to the risk
of prostate cancer: a systematic review and meta-analysis, Am J Clin Nutr. 89(5):
1558S-1564S (2009).
88. I. A. Brouwer, Omega-3 PUFA: good or bad for prostate cancer, Prostaglandins
Leukot Essent Fatty Acids. 79(3-5): 97-99 (2008).
89. H. E. Bays, Safety considerations with omega-3 fatty acid therapy, Am J Cardiol.
99(6A): 35C-43C (2007).
90. J. Mathews, Media feeds frenzy over shark cartilage as cancer treatment, J Natl
Cancer Inst. 85(15): 1190-1191 (1993).
349
91. I. W. Lane and L. Comac, Sharks Don’t Get Cancer. (Avery Publishing, New York,
1992).
92. G. K. Ostrander, K. C. Cheng, J. C. Wolf and M. J. Wolfe Shark cartilage, cancer
and the growing threat of pseudoscience, Cancer Res. 64(23): 8485-8491 (2004).
93. E. Ernst and B. R. Cassileth, How useful are unconventional cancer treatments?,
Eur J Cancer. 35(11): 1608-1613 (1999).
94. Institute of Medicine and National Research Council, Dietary Supplements: A
Framework for Evaluating Safety. (The National Academies Press, Washington DC,
2004), pp. 380-384.
95. S. Holt, Shark cartilage and neutraceutical update, Altern Complement Ther. 1: 414-
416 (1995).
96. D. Gingras, A. Renaud, N. Mousseau and R. Béliveau, Shark cartilage extracts as
antiangiogenic agents: smart drinks or bitter pills?, Cancer Metastasis Rev. 19(1-2):
83-86 (2000).
97. B. U. Pauli, V. A. Memoli and K. E. Kuettner, Regulation of tumor invasion by
cartilage-derived anti-invasion factor in vitro, J Natl Cancer Inst. 67: 65-73 (1981).
98. K. E. Kuettner and B. U. Pauli, Inhibition of tumor invasion by tissue-derived
proteinase inhibitors, Monogr Pathol. 27: 1711-1782 (1986).
99. M. R. Horsman, J. Alsner and J. Overgaard, The effect of shark cartilage extracts on
the growth and metastatic spread of the SCCVII carcinoma, Acta Oncol. 37(5): 441-
445 (1998).
100. J. B. Finkelstein, Sharks do get cancer: few surprises in cartilage research, J
Natl Cancer Inst. 97(21): 1562-1563 (2005).
101. C. L. Loprinzi, R. Levitt, D. L. Barton, J. A. Sloan, P. J. Atherton, D. J.
Smith, S. R. Dakhil, D. F. Moore Jr, J. E. Krook, K. M. Rowland Jr, M. A.
Mazurczak, A. R. Berg, G. P. Kim and North Central Cancer Treatment Group,
Evaluation of shark cartilage in patients with advanced cancer: a North Central
Cancer Treatment Group trial, Cancer. 104(1): 176-182 (2005).
102. C. Lu, J. J. Lee, R. Komaki, R. S. Herbst, L. Feng, W. K. Evans, H. Choy, P.
Desjardins, B. T. Esparaz, M. T. Truong, S. Saxman, J. Kelaghan, A. Bleyer and M.
J. Fisch, Chemoradiotherapy with or without AE-941 in stage III non-small cell
lung cancer: a randomized phase III trial, J Natl Cancer Inst. 102(12): 859-865
(2010).
350
103. D. R. Miller, G. T. Anderson, J. J. Stark, J. L. Granick and D. Richardson,
Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of
advanced cancer, J Clin Oncol. 16(11): 3649-3655 (1998).
104. AEterna Zentaris, AEterna Laboratories reports phase III trial results in renal
cell carcinoma with Neovastat, Available at
http://www.aeternazentaris.com/en/page.php?p=60&q=46 (accessed 22 June 2010).
105. G. Batist, F. Patenaude, P. Champagne, D. Croteau, C. Levinton, C. Hariton,
B. Escudier and E. Dupont, Neovastat (AE-941) in refractory renal cell carcinoma
patients: report of a phase II trial with two dose levels, Ann Oncol. 13(8): 1259-
1263 (2002).
106. D. Gingras, D. Boivin, C. Deckers, S. Gendron, C. Barthomeuf and R.
Béliveau, Neovastat--a novel antiangiogenic drug for cancer therapy, Anticancer
Drugs. 14(2): 91-96 (2003).
107. B. Ashar and E. Vargo, Shark cartilage-induced hepatitis, Ann Intern Med.
125(9): 780-781 (1996).
108. M. Kim, Mercury, cadmium and arsenic contents of calcium dietary
supplements, Food Addit Contam. 21(8): 763-767 (2004).
109. T. Fukuda, H. Ito, T. Mukainaka, H. Tokuda, H. Nishino and T. Yoshida,
Anti-tumor promoting effect of glycosides from Prunus persica seeds, Biol Pharm
Bull. 26(2): 271-273 (2003).
110. S. Milazzo, S. Lejeune and E. Ernst, Laetrile for cancer: a systematic review
of the clinical evidence, Support Care Cancer. 15(6): 583-595 (2007).
111. C. G. Moertel, T. R. Fleming, J. Rubin, L. K. Kvols, G. Sarna, R. Koch, V.
E. Currie, C. W. Young, S. E. Jones and J. P. Davignon, A clinical trial of
amygdalin (Laetrile) in the treatment of human cancer, N Engl J Med. 306(4): 201-
206 (1982).
112. K. N. Syrigos, G. Rowlinson-Busza and A. A. Epenetos, In vitro
cytotoxicity following specific activation of amygdalin by beta-glucosidase
conjugated to a bladder cancer-associated monoclonal antibody, Int J Cancer. 78(6):
712-719 (1998).
113. C. G. Moertel, M. M. Ames, J. S. Kovach, T. P. Moyer, J. R. Rubin and J.
H. Tinker, A pharmacologic and toxicological study of amygdalin, JAMA. 245(6):
591-594 (1981).
351
114. U. P. Kalyanaraman, K. Kalyanaraman, S. A. Cullinan and J. M. McLean,
Neuromyopathy of cyanide intoxication due to "laetrile" (amygdalin). A
clinicopathologic study, Cancer. 51(11): 2126-2133 (1983).
115. J. Bromley, B. G. Hughes, D. C. Leong and N. A. Buckley, Life-threatening
interaction between complementary medicines: cyanide toxicity following ingestion
of amygdalin and vitamin C, Ann Pharmacother. 39(9): 1566-1569 (2005).
116. C. Fenselau, S. Pallante, R. P. Batzinger, W. R. Benson, R. P. Barron, E. B.
Sheinin and M. Maienthal, Mandelonitrile beta-glucuronide: synthesis and
characterization, Science. 198(4317): 625-627 (1977).
117. J. P. Davignon, L. A. Trissel and L. M. Kleinman, Pharmaceutical
assessment of amygdalin (Laetrile) products, Cancer Treat Rep. 62(1): 99-104
(1978).
118. J. Chiu, T. Yau and R. J. Epstein, Complications of traditional
Chinese/herbal medicines (TCM): a guide for perplexed oncologists and other
cancer caregivers, Support Care Cancer. 17(3): 231-240 (2009).
119. G. Q. Li, C. C. Duke and B. D. Roufogalis, The quality and safety of
traditional Chinese medicines. Aust Prescr. 26:128-130 (2003).
120. M. McCulloch, C. See, X. J. Shu, M. Broffman, A. Kramer, W. Y. Fan, J.
Gao, W. Lieb, K. Shieh and J. M. Colford Jr, Astragalus-based Chinese herbs and
platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-
analysis of randomized trials, J Clin Oncol. 24(3): 419-430 (2006).
121. T. Wu, A. J. Munro, L. Guanjian, G. J. Liu, Chinese medical herbs for
chemotherapy side effects in colorectal cancer patients, Cochrane Database Syst
Rev. 1: CD004540 (2005).
122. K. I. Block and M. N. Mead, Immune system effects of echinacea, ginseng,
and astragalus: a review, Integr Cancer Ther. 2(3): 247-267 (2003).
123. M. Zhang, X. Liu, J. Li, L. He and D. Tripathy, Chinese medicinal herbs to
treat the side-effects of chemotherapy in breast cancer patients, Cochrane Database
Syst Rev. 2: CD004921 (2007).
124. Y. S. Chang, E. K. Seo, C. Gyllenhaal and K. I. Block, Panax ginseng: a role
in cancer therapy?, Integr Cancer Ther. 2(1): 13-33 (2003).
352
125. L. Jia, Y, Zhao and X. J. Liang, Current evaluation of the millennium
phytomedicine- ginseng (II): Collected chemical entities, modern pharmacology,
and clinical applications emanated from traditional Chinese medicine, Curr Med
Chem. 16(22): 2924-2942 (2009).
126. P. Wu, J. J. Dugoua, O. Eyawo and E. J. Mills, Traditional Chinese
Medicines in the treatment of hepatocellular cancers: a systematic review and meta-
analysis, J Exp Clin Cancer Res. 28: 112 (2009).
127. J. T. Coon and E. Ernst, Panax ginseng: a systematic review of adverse
effects and drug interactions, Drug Saf. 25(5): 323-344 (2002).
128. N. B. Kumar, K. Allen and H. Bell, Perioperative herbal supplement use in
cancer patients: potential implications and recommendations for presurgical
screening, Cancer Control. 12(3): 149-157 (2005).
129. M. Smith and H. S. Boon, Counseling cancer patients about herbal
medicine, Patient Educ Couns. 38(2): 109-120 (1999).
130. J. Liu, J. E. Burdette, H. Xu, C. Gu, R. B. van Breemen, K. P. Bhat, N.
Booth, A. I. Constantinou, J. M. Pezzuto, H. H. Fong, N. R. Farnsworth and J. L.
Bolton, Evaluation of estrogenic activity of plant extracts for the potential treatment
of menopausal symptoms, J Agric Food Chem. 49(5): 2472-2479 (2001).
131. N. Chaiyakunapruk, N. Kitikannakorn, S. Nathisuwan, K. Leeprakobboon
and C. Leelasettagool, The efficacy of ginger for the prevention of postoperative
nausea and vomiting: a meta-analysis, Am J Obstet Gynecol. 194(1): 95-99 (2006).
132. S. Sontakke, V. Thawani and M. S. Naik, Ginger as an antiemetic in nausea
and vomiting induced by chemotherapy: a randomized, cross-over, double blind
study, Indian J Pharmacol. 35: 32-36 (2003).
133. S. Manusirivithaya, M. Sripramote, S. Tangjitgamol, C. Sheanakul, S.
Leelahakorn, T. Thavaramara and K. Tangcharoenpanich, Antiemetic effect of
ginger in gynecologic oncology patients receiving cisplatin, Int J Gynecol Cancer.
14(6): 1063-1069 (2004).
134. J. T. Hickok, J. A. Roscoe, G. R. Morrow and J. L. Ryan, A phase II/III
randomized, placebo-controlled, double-blind clinical trial of ginger (Zingiber
officinale) for nausea caused by chemotherapy for cancer: a currently accruing
URCC CCOP Cancer Control study, Support Cancer Ther. 4(4): 247-250 (2007).
353
135. J. L. Ryan, C. Heckler, S. R. Dakhil, J. Kirshner, P. J. Flynn, J. T. Hickok
and G. R. Morrow, Ginger for chemotherapy-related nausea in cancer patients: a
URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644
cancer patients, J Clin Oncol. 27(15S): 9511 (2009).
136. S. M. Zick, M. T. Ruffin, J. Lee, D. P. Normolle, R. Siden, S. Alrawi and D.
E. Brenner, Phase II trial of encapsulated ginger as a treatment for chemotherapy-
induced nausea and vomiting, Support Care Cancer. 17(5): 563-572 (2009).
137. A. K. Yang, S. M. He, L. Liu, J. P. Liu, M. Q. Wei and S. F. Zhou, Herbal
interactions with anticancer drugs: mechanistic and clinical considerations, Curr
Med Chem. 17(16): 1635-1678 (2010).
138. J. Mahajna, N. Dotan, B. Z. Zaidman, R. D. Petrova and S. P. Wasser SP,
Pharmacological values of medicinal mushrooms for prostate cancer therapy: the
case of Ganoderma lucidum, Nutr Cancer. 61(1): 16-26 (2009).
139. B. Cassileth, Complementary therapies, herbs, and other OTC agents: Reishi
mushroom, Oncology (Williston Park). 23(8): 728 (2009).
140. S. Wachtel-Galor, B. Tomlinson and I. F. Benzie, Ganoderma lucidum
("Lingzhi"), a Chinese medicinal mushroom: biomarker responses in a controlled
human supplementation study, Br J Nutr. 91(2): 263-269 (2004).
141. S. S. Shord, K. Shah and A. Lukose, Drug-botanical interactions: a review
of the laboratory, animal, and human data for 8 common botanicals, Integr Cancer
Ther. 8(3): 208-227 (2009).
142. Food and Drug Administration (FDA), Letter responding to health claim
petition dated January 27, 2004: green tea and reduced risk of cancer health claim
(docket number 2004Q-0083) (docket number 2004Q-0083), Available at
http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/u
cm072774.htm (accessed 1 May 2010).
143. J. L. Sturgeon, M. Williams and G. van Servellen, Efficacy of green tea in
the prevention of cancers, Nurs Health Sci. 11(4): 436-446 (2009).
144. J. Liu, J. Xing and Y. Fei, Green tea (Camellia sinensis) and cancer
prevention: a systematic review of randomized trials and epidemiological studies,
Chin Med. 3: 12 (2008).
354
145. K. M. Pisters, R. A. Newman, B. Coldman, D. M. Shin, F. R. Khuri, W. K.
Hong, B. S. Glisson and J. S. Lee, Phase I trial of oral green tea extract in adult
patients with solid tumors, J Clin Oncol. 19(6): 1830-1838 (2001).
146. S. A. Laurie, V. A. Miller, S. C. Grant, M. G. Kris and K. K. Ng, Phase I
study of green tea extract in patients with advanced lung cancer, Cancer Chemother
Pharmacol. 55(1): 33-38 (2005).
147. E. B. Golden, P. Y. Lam, A. Kardosh, K. J. Gaffney, E. Cadenas, S. G.
Louie, N. A. Petasis, T. C. Chen and A. H. Schönthal, Green tea polyphenols block
the anticancer effects of bortezomib and other boronic acid-based proteasome
inhibitors, Blood. 113(23): 5927-5937 (2009).
148. K. Linde, M. M. Berner and L. Kriston, St John's wort for major depression,
Cochrane Database Syst Rev, 4: CD000448 (2008).
149. F. Borrelli and A. A. Izzo, Herb-drug interactions with St John's wort
(Hypericum perforatum): an update on clinical observations, AAPSJ. 11(4): 710-727
(2009).
150. M. Kober, K. Pohl and T. Efferth, Molecular mechanisms underlying St.
John's wort drug interactions, Curr Drug Metab. 9(10): 1027-1037 (2008).
151. Therapeutic Goods Administration (TGA), St John's Wort - information
sheet for health care professionals, Available at
http://www.tga.gov.au/docs/html/info.htm (accessed 7 May 2010).
152. G. Goncagul and E. Ayaz, Antimicrobial effect of garlic (Allium sativum),
Recent Pat Antiinfect Drug Discov. 5(1): 91-93 (2010).
153. T. Ariga and T. Seki, Antithrombotic and anticancer effects of garlic-derived
sulfur compounds: a review, Biofactors. 26(2): 93-103 (2006).
154. S. Kasuga, N. Uda, E. Kyo, M. Ushijima, N. Morihara and Y. Itakura,
Pharmacologic activities of aged garlic extract in comparison with other garlic
preparations, J Nutr. 131(3s): 1080S-1084S (2001).
155. M. Iciek, I. Kwiecień and L. Włodek, Biological properties of garlic and
garlic-derived organosulfur compounds, Environ Mol Mutagen. 50(3): 247-265
(2009).
156. A. T. Fleischauer, C. Poole and L. Arab, Garlic consumption and cancer
prevention: meta-analyses of colorectal and stomach cancers, Am J Clin Nutr.
72(4): 1047-1052 (2000).
355
157. S. N. Ngo, D. B. Williams, L. Cobiac and R. J. Head, Does garlic reduce
risk of colorectal cancer? A systematic review, J Nutr. 137(10): 2264-2269 (2007).
158. W. C. You, L. M. Brown, L. Zhang, J. Y. Li, M. L. Jin, Y. S. Chang, J. L.
Ma, K. F. Pan, W. D. Liu, Y. Hu, S. Crystal-Mansour, D. Pee, W. J. Blot, J. F.
Fraumeni Jr, G. W. Xu and M. H. Gail, Randomized double-blind factorial trial of
three treatments to reduce the prevalence of precancerous gastric lesions, J Natl
Cancer Inst. 98(14): 974-983 (2006).
159. F. Borrelli, R. Capasso and A. A. Izzo, Garlic (Allium sativum L.): adverse
effects and drug interactions in humans, Mol Nutr Food Res. 51(11): 1386-1397
(2007).
160. B. J. Gurley, S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry,
Y. Cui and C. Y. Ang, Cytochrome P450 phenotypic ratios for predicting herb-drug
interactions in humans, Clin Pharmacol Ther. 72(3): 276-287 (2002).
161. J. S. Markowitz, C. L. Devane, K. D. Chavin, R. M. Taylor, Y. Ruan and J.
L. Donovan, Effects of garlic (Allium sativum L.) supplementation on cytochrome
P450 2D6 and 3A4 activity in healthy volunteers, Clin Pharmacol Ther. 74(2): 170-
177 (2003).
162. L. S. Lee, A. S. Andrade and C. Flexner, Interactions between natural health
products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects,
Clin Infect Dis. 43(8): 1052-1059 (2006).
163. J. T. Saw, M. B. Bahari, H. H. Ang and Y. H. Lim, Potential drug-herb
interaction with antiplatelet/anticoagulant drugs, Complement Ther Clin Pract.
12(4): 236-241 (2006).
164. Y. N. Singh, Potential for interaction of kava and St. John's wort with drugs,
J Ethnopharmacol. 100(1-2): 108-113 (2005).
165. M. H. Pittler and E. Ernst, Kava extract versus placebo for treating anxiety,
Cochrane Database Syst Rev. 1: CD003383 (2003).
166. J. D. Mathews, M. D. Riley, L. Fejo, E. Munoz, N. R. Milns, I. D. Gardner,
J. R. Powers, E. Ganygulpa and B. J. Gununuwawuy, Effects of the heavy usage of
kava on physical health: summary of a pilot survey in an aboriginal community,
Med J Aust. 148(11): 548-555 (1988).
167. K. I. Block, C. Gyllenhaal and M. N. Mead, Safety and efficacy of herbal
sedatives in cancer care, Integr Cancer Ther. 3(2): 128-148 (2004).
356
168. A. Sparreboom, M. C. Cox, M. R. Acharya and W. D. Figg, Herbal remedies
in the United States: potential adverse interactions with anticancer agents, J Clin
Oncol. 22(12): 2489-2503 (2004).
169. B. J. Gurley, S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry,
I. A. Khan and A. Shah, In vivo effects of goldenseal, kava kava, black cohosh, and
valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes, Clin
Pharmacol Ther. 77(5): 415-426 (2005).
170. B. J. Gurley, A. Swain, M. A. Hubbard, F. Hartsfield, J. Thaden, D. K.
Williams, W. B. Gentry and Y. Tong, Supplementation with goldenseal (Hydrastis
canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A
activity in vivo, Clin Pharmacol Ther. 83(1): 61-69 (2008).
171. S. Russmann, B. H. Lauterburg, Y. Barguil, E. Choblet, P. Cabalion, K.
Rentsch and M. Wenk, Traditional aqueous kava extracts inhibit cytochrome P450
1A2 in humans: protective effect against environmental carcinogens?, Clin
Pharmacol Ther. 77(5): 453-454 (2005).
172. M. I. Fernández-San-Martín, R. Masa-Font, L. Palacios-Soler, P. Sancho-
Gómez, C. Calbó-Caldentey and G. Flores-Mateo, Effectiveness of valerian on
insomnia: a meta-analysis of randomized placebo-controlled trials, Sleep Med.
11(6): 505-511 (2010).
173. H. P. Garges, I. Varia, and P. M. Doraiswamy, Cardiac complications and
delirium associated with valerian root withdrawal, JAMA. 280(18): 1566-1567
(1998).
174. M. Blumenthal, The Complete German Commission E Monographs:
Therapeutic Guide to Herbal Medicines. (American Botanical Council and
Integrative Medicine Communications, Boston, 1998).
175. R. Bos, H. J. Woerdenbag, P. A. G. M. DeSmet and J. J. Scheffer, Valeriana
species. In: Adverse Effects of Herbal Drugs, eds. P. A. G. M. DeSmet, K. Keller,
R. Hansel and R. F. Chandler (Springer, Berlin, 1997), pp. 165-180.
176. J. L. Donovan, C. L. DeVane, K. D. Chavin, J. S. Wang, B. B. Gibson, H. A.
Gefroh and J. S. Markowitz, Multiple night-time doses of valerian (Valeriana
officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6
activity in healthy volunteers, Drug Metab Dispos. 32(12): 1333-1336 (2004).
357
177. D. J. Rowe and A. C. Baker, Perioperative risks and benefits of herbal
supplements in aesthetic surgery, Aesthet Surg J. 29(2): 150-157 (2009).
178. L. S. Miyasaka, A. N. Atallah and B. G. Soares, Valerian for anxiety
disorders, Cochrane Database Syst Rev. 4: CD004515 (2006).
179. D. M. Taibi, C. A. Landis, H. Petry and M. V. Vitiello, A systematic review
of valerian as a sleep aid: safe but not effective, Sleep Med Rev. 11(3): 209-230
(2007).
180. S. Bent, A. Padula, D. Moore, M. Patterson and W. Mehling, Valerian for
sleep: a systematic review and meta-analysis, Am J Med. 119(12): 1005-1112
(2006).
181. B. Bayles and R. Usatine, Evening primrose oil, Am Fam Physician. 80(12):
1405-1408 (2009).
182. K. B. Adelson, C. L. Loprinzi and D. L. Hershman, Treatment of hot flushes
in breast and prostate cancer, Expert Opin Pharmacother. 6(7): 1095-1106 (2005).
183. J. E. Rossouw, G. L. Anderson, R. L. Prentice, A. Z. LaCroix, C.
Kooperberg, M. L. Stefanick, R. D. Jackson, S. A. Beresford, B. V. Howard, K. C.
Johnson, J. M. Kotchen, J. Ockene and Writing Group for the Women's Health
Initiative Investigators, Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the Women's Health Initiative
randomized controlled trial, JAMA. 288(3): 321-333 (2002).
184. D. Cheema, A. Coomarasamy and T. El-Toukhy, Non-hormonal therapy of
post-menopausal vasomotor symptoms: a structured evidence-based review, Arch
Gynecol Obstet. 276(5): 463-469 (2007).
185. E. Rock and A. DeMichele, Nutritional approaches to late toxicities of
adjuvant chemotherapy in breast cancer survivors, J Nutr. 133(11 Suppl 1): 3785S-
3793S (2003).
186. M. M. Seibel, Treating hot flushes without hormone replacement therapy, J
Fam Pract. 52: 291-296 (2003).
187. T. Shams, M. S. Setia, R. Hemmings, J. McCusker, M. Sewitch and A.
Ciampi, Efficacy of black cohosh-containing preparations on menopausal
symptoms: a meta-analysis, Altern Ther Health Med. 16(1): 36-44 (2010).
358
188. C. Palacio, G. Masri, and A. D. Mooradian, Black cohosh for the
management of menopausal symptoms: a systematic review of clinical trials, Drugs
Aging. 26(1): 23-36 (2009).
189. F. Borrelli and E. Ernst, Black cohosh (Cimicifuga racemosa) for
menopausal symptoms: a systematic review of its efficacy, Pharmacol Res. 58(1):
8-14 (2008).
190. R. Walji, H. Boon, E. Guns, D. Oneschuk and J. Younus, Black cohosh
(Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients, Support
Care Cancer. 15(8): 913-921 (2007).
191. G. B. Mahady, Is black cohosh estrogenic?, Nutr Rev. 61(5 Pt 1): 183-186
(2003).
192. European Medicines Agency (EMEA) and Committee on Herbal Medicinal
Products (HMPC), Assessment of case reports connected to herbal medicinal
products containing Cimicifugae racemosae rhizoma (black cohosh, root), Available
at http://www.emea.europa.eu/pdfs/human/hmpc/26925806en.pdf (accessed 19 May
2010).
193. Therapeutic Goods Administration (TGA), Black cohosh (Cimicifuga
racemosa), Available at http://www.tga.gov.au/cm/0705blkcohosh.htm (accessed 19
May 2010).
194. E. J. Kennelly, S. Baggett, P. Nuntanakorn, A. L. Ososki, S. A. Mori, J.
Duke, M. Coleton and F. Kronenberg, Analysis of thirteen populations of black
cohosh for formononetin, Phytomedicine. 9(5): 461-467 (2002).
195. A. Huntley, The safety of black cohosh (Actaea racemosa, Cimicifuga
racemosa), Expert Opin Drug Saf. 3(6): 615-623 (2004).
196. A. L. Huntley, J. Thompson Coon and E. Ernst, The safety of herbal
medicinal products derived from Echinacea species: a systematic review, Drug Saf.
28(5): 387-400 (2005).
197. E. Basch, C. Ulbricht, S. Basch, S. Dalton, E. Ernst, I. Foppa, P. Szapary, N.
Tiffany, C. W. Orlando and M. Vora, An evidence-based systemic review
Echinacea E. angustifolia DC, E. pallida, E. purpurea by the Natural Standard
Research Collaboration, J Herb Pharmacother. 5: 57-88 (2005).
198. C. Freeman and K. Spelman, A critical evaluation of drug interactions with
Echinacea spp, Mol Nutr Food Res. 52(7): 789-798 (2008).
359
199. J. C. Gorski, S. M. Huang, A. Pinto, M. A. Hamman, J. K. Hilligoss, N. A.
Zaheer, M. Desai, M. Miller and S. D. Hall, The effect of echinacea (Echinacea
purpurea root) on cytochrome P450 activity in vivo, Clin Pharmacol Ther. 75(1):
89-100 (2004).
200. B. J. Gurley, S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry,
J. Carrier, I. A. Khan, D. J. Edwards and A. Shah, In vivo assessment of botanical
supplementation on human cytochrome P450 phenotypes: Citrus aurantium,
Echinacea purpurea, milk thistle, and saw palmetto, Clin Pharmacol Ther. 76(5):
428-440 (2004).
201. C. M. Gilroy, J. F. Steiner, T. Byers, H. Shapiro and W. Georgian,
Echinacea and truth in labeling, Arch Intern Med. 163(6): 699-704 (2003).
202. F. Toselli, A. Matthias and E. M. Gillam, Echinacea metabolism and drug
interactions: the case for standardization of a complementary medicine, Life Sci.
85(3-4): 97-106 (2009).
203. A. A. Izzo and E. Ernst, Interactions between herbal medicines and
prescribed drugs: an updated systematic review, Drugs. 69(13): 1777-1798 (2009).
204. C. Tamayo and S. Diamond, Review of clinical trials evaluating safety and
efficacy of milk thistle (Silybum marianum [L.] Gaertn.), Integr Cancer Ther. 6(2):
146-157 (2007).
205. S. M. Sagar, Future directions for research on Silybum marianum for cancer
patients, Integr Cancer Ther. 6(2): 166-173 (2007).
206. J. Floyd, I. Mirza, B. Sachs and M. C. Perry, Hepatotoxicity of
chemotherapy. Semin Oncol. 33: 50-67 (2006).
207. A. Rambaldi, B. P. Jacobs and C. Gluud, Milk thistle for alcoholic and/or
hepatitis B or C virus liver diseases, Cochrane Database Syst Rev. 4: CD003620
(2007).
208. H. Greenlee, K. Abascal, E. Yarnell and E. Ladas, Clinical applications of
Silybum marianum in oncology, Integr Cancer Ther. 6(2): 158-165 (2007).
209. E. J. Ladas and K. M. Kelly, Milk thistle: is there a role for its use as an
adjunct therapy in patients with cancer?, J Altern Complement Med. 9(3): 411-416
(2003).
360
210. B. P. Jacobs, C. Dennehy, G. Ramirez, J. Sapp and V. A. Lawrence, Milk
thistle for the treatment of liver disease: a systematic review and meta-analysis, Am
J Med. 113(6): 506-515 (2002).
211. F. Rainone, Milk thistle, Am Fam Physician. 72(7): 1285-1288 (2005).
212. C. Mulrow, V. Lawrence, B. Jacobs, C. Dennehy, J. Sapp, G. Ramirez, C.
Aguilar, K. Montgomery, L. Morbidoni, J. M. Arterburn, E. Chiquette, M. Harris,
D. Mullins, A. Vickers and K. Flora, Milk thistle: effects on liver disease and
cirrhosis and clinical adverse effects, Evid Rep Technol Assess (Summ). 21: 1-3
(2000).
213. T. W. Flaig, D. L. Gustafson, L. J. Su, J. A. Zirrolli, F. Crighton, G. S.
Harrison, A. S. Pierson, R. Agarwal, and L. M. Glodé, A phase I and
pharmacokinetic study of silybin-phytosome in prostate cancer patients, Invest New
Drugs. 25(2): 139-146 (2007).
214. R. Venkataramanan, V. Ramachandran, B. J. Komoroski, S. Zhang, P. L.
Schiff and S. C. Strom, Milk thistle, a herbal supplement, decreases the activity of
CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte
cultures, Drug Metab Dispos. 28(11): 1270-1273 (2000).
215. R. Zuber, M. Modrianský, Z. Dvorák, P. Rohovský, J. Ulrichová, V.
Simánek and P. Anzenbacher, Effect of silybin and its congeners on human liver
microsomal cytochrome P450 activities, Phytother Res. 16(7): 632-638 (2002).
216. D. J. Kroll, H. S. Shaw and N. H. Oberlies, Milk thistle nomenclature: why
it matters in cancer research and pharmacokinetic studies, Integr Cancer Ther. 6(2):
110-119 (2007).
217. G. S. Kienle, H. Kiene and H. U. Albonico, Anthroposophic Medicine:
Effectiveness, Utility, Costs, Safety. (Schattauer Verlag, Stuttgart, 2006).
218. J. Melzer, F. Iten, K. Hostanska and R. Saller, Efficacy and safety of
mistletoe preparations (Viscum album) for patients with cancer diseases. A
systematic review, Forsch Komplementmed. 16(4): 217-226 (2009).
219. G. S. Kienle and H. Kiene, Influence of Viscum album L (European
mistletoe) extracts on quality of life in cancer patients: a systematic review of
controlled clinical studies, Integr Cancer Ther. 9(2): 142-157 (2010).
361
220. T. Hajto, K. Hostanska, T. Berki, L. Palinkas, F. Boldizsar and P. Nemeth,
Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I):
overview of recent results from in vitro experiments and in vivo animal models, and
their possible relevance for clinical applications, Evid Based Complement Alternat
Med. 2: 59-67 (2005).
221. E. Ernst, K. Schmidt and M. K. Steuer-Vogt, Mistletoe for cancer? A
systematic review of randomised clinical trials, Int J Cancer. 107(2): 262-267
(2003).
222. G. S. Kienle, F. Berrino, A. Büssing, E. Portalupi, S. Rosenzweig and H.
Kiene, Mistletoe in cancer - a systematic review on controlled clinical trials, Eur J
Med Res. 8(3): 109-119 (2003).
223. G. S. Kienle and H. Kiene, Complementary cancer therapy: a systematic
review of prospective clinical trials on anthroposophic mistletoe extracts, Eur J Med
Res. 12(3): 103-119 (2007).
224. M. A. Horneber, G. Bueschel, R. Huber, K. Linde and M. Rostock,
Mistletoe therapy in oncology, Cochrane Database Syst Rev. 2: CD003297 (2008).
225. M. Rostock and R. Huber, Randomized and double-blind studies – demands
and reality as demonstrated by two examples of mistletoe research, Forsch
Komplementarmed Klass Naturheilkd. 11(suppl 1): 18-22 (2004).
226. I. Gerhard, U. Abel, A. Loewe-Mesch, S. Huppmann and J. J. Kuehn,
[Problems of randomized studies in complementary medicine demonstrated in a
study on mistletoe treatment of patients with breast cancer], Forsch
Komplementarmed Klass Naturheilkd. 11: 150-157 (2004).
227. R. Saller, S. Kramer, F. Iten and J. Melzer, Unerwünschte wirkungen der
misteltherapie bei tumorpatienten – eine systematische übersicht. In: Fortschritte in
der Misteltherapie. Aktueller Stand der Forschung und klinische Anwendung, eds.
R. Scheer, R. Bauer, H. Becker, V. Fintelmann, F. Kemper and H. Schilcher (KVC,
Essen, 2005), pp. 367-403.
228. A. Büssing, C. Stumpf, W. Tröger and M. Schietzel, Course of mitogen-
stimulated T lymphocytes in cancer patients treated with Viscum album extracts,
Anticancer Res. 27(4C): 2903-2910 (2007).
362
229. P. J. Mansky, J. Grem, D. B. Wallerstedt, B. P. Monahan and M. Blackman,
Mistletoe and gemcitabine in patients with advanced cancer: a model for the phase I
study of botanicals and botanical-drug interactions in cancer therapy, Integr Cancer
Ther. 2(4): 345-352 (2003).
230. P. J. Mansky, D. B. Wallerstedt, B. P. Monahan, C. Lee, S. Swain, R.
Evande, M. Blackman and J. Grem, Mistletoe extract/gemcitabine combination
treatment: an interim report from the NCCAM/NCI phase I study in patients with
advanced solid tumors, J Clin Oncol. 23: S216 (2005).
231. National Center for Complementary and Alternative Medicine (NCCAM),
Manipulative and body-based practices: an overview (NCCAM Publication No.
D238), Available at http://www.fvpt.com/manipulative.pdf (accessed 15 June
2010).
232. E. Ernst, The safety of massage therapy, Rheumatology (Oxford). 42(9):
1101-1106 (2003).
233. L. Corbin, Safety and efficacy of massage therapy for patients with cancer,
Cancer Control. 12(3): 158-164 (2005).
234. D. Fellowes, K. Barnes and S. Wilkinson, Aromatherapy and massage for
symptom relief in patients with cancer, Cochrane Database Syst Rev. 2: CD002287
(2004).
235. E. Ernst, Massage therapy for cancer palliation and supportive care: a
systematic review of randomised clinical trials, Support Care Cancer. 17(4): 333-
337 (2009).
236. S. Wilkinson, K. Barnes and L. Storey, Massage for symptom relief in
patients with cancer: systematic review, J Adv Nurs. 63(5): 430-439 (2008).
237. S. W. Jane, D. J. Wilkie, B. B. Gallucci and R. D. Beaton, Systematic
review of massage intervention for adult patients with cancer: a methodological
perspective, Cancer Nurs. 31(6): E24-E35 (2008).
238. L. F. Chao, A. L. Zhang, H. E. Liu, M. H. Cheng, H. B. Lam and S. K. Lo,
The efficacy of acupoint stimulation for the management of therapy-related adverse
events in patients with breast cancer: a systematic review, Breast Cancer Res Treat.
118(2): 255-267 (2009).
239. H. MacPherson, K. Thomas, S. Walters and M. Fitter, The York
acupuncture safety study: prospective survey, BMJ. 323(7311): 486-487 (2001).
363
240. D. Melchart, W. Weidenhammer, A. Streng, S. Reitmayr, A. Hoppe, E.
Ernst and K. Linde, Prospective investigation of adverse effects of acupuncture in
97 733 patients, Arch Intern Med. 164(1): 104-105 (2004).
241. H. Lee, K. Schmidt and E. Ernst, Acupuncture for the relief of cancer-
related pain–a systematic review, Eur J Pain. 9(4): 437-444 (2005).
242. K. A. Robb, M. I. Bennett, M. I. Johnson, K. J. Simpson and S. G. Oxberry,
Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults,
Cochrane Database Syst Rev. 3: CD006276 (2008).
243. M. S. Lee, K. H. Kim, S. M. Choi and E. Ernst, Acupuncture for treating hot
flashes in breast cancer patients: a systematic review, Breast Cancer Res Treat.
115(3): 497-503 (2009).
244. M. S. Lee, K. H. Kim, B. C. Shin, S. M. Choi and E. Ernst, Acupuncture for
treating hot flushes in men with prostate cancer: a systematic review, Support Care
Cancer. 17(7): 763-770 (2009).
245. J. M. Ezzo, M. A., Richardson, A. Vickers, C. Allen, S. L. Dibble, B. F.
Issell, L. Lao, M. Pearl, G. Ramirez, J. Roscoe, J. Shen, J. C. Shivnan, K.
Streitberger, I. Treish and G. Zhang, Acupuncture-point stimulation for
chemotherapy-induced nausea or vomiting, Cochrane Database Syst Rev. 2:
CD002285 (2006).
246. W. Lu, D. Hu, E. Dean-Clower, A. Doherty-Gilman, A. T. Legedza, H. Lee,
U. Matulonis and R. S. Rosenthal, Acupuncture for chemotherapy-induced
leukopenia: exploratory meta-analysis of randomized controlled trials, J Soc Integr
Oncol. 5(1): 1-10 (2007).
247. M. Blom, I. Dawidson, J. O. Fernberg, G. Johnson and B. Angmar-Månsson,
Acupuncture treatment of patients with radiation-induced xerostomia, Eur J Cancer
B Oral Oncol. 32B(3): 182-190 (1996).
248. P. A. Johnstone, Y. P. Peng, B. C. May, W. S. Inouye and R. C. Niemtzow,
Acupuncture for pilocarpine-resistant xerostomia following radiotherapy for head
and neck malignancies, Int J Radiat Oncol Biol Phys. 50(2): 353-357 (2001).
249. P. A. Johnstone, R. C. Niemtzow and R. H. Riffenburgh, Acupuncture for
xerostomia: clinical update, Cancer. 94(4): 1151-1156 (2002).
364
250. R. K. Wong, G. W. Jones, S. M. Sagar, A. F. Babjak and T. Whelan, A
phase I-II study in the use of acupuncture-like transcutaneous nerve stimulation in
the treatment of radiation-induced xerostomia in head-and-neck cancer patients
treated with radical radiotherapy, Int J Radiat Oncol Biol Phys. 57(2): 472-480
(2003).
251. J. H. Cho, W. K. Chung, W. Kang, S. M. Choi, C. K. Cho and C. G. Son,
Manual acupuncture improved quality of life in cancer patients with radiation-
induced xerostomia, J Altern Complement Med. 14(5): 523-526 (2008).
252. M. K. Garcia, J. S. Chiang, L. Cohen, M. Liu, J. L. Palmer, D. I. Rosenthal,
Q. Wei, S. Tung, C. Wang, T. Rahlfs and M. S. Chambers, Acupuncture for
radiation-induced xerostomia in patients with cancer: a pilot study, Head Neck.
31(10): 1360-1368 (2009).
253. R. Simcock, L. Fallowfield and V. Jenkins, Group acupuncture to relieve
radiation induced xerostomia: a feasibility study, Acupunct Med. 27(3): 109-113
(2009).
254. R. U. Newton and D. A. Galvão, Exercise in prevention and management of
cancer, Curr Treat Options Oncol. 9(2-3): 135-146 (2008).
255. S. C. Hayes, R. R. Spence, D. A. Galvão and R. U. Newton, Australian
association for exercise and sport science position stand: optimising cancer
outcomes through exercise, J Sci Med Sport. 12: 428-434 (2009).
256. M. C. Morey, D. C. Snyder, R. Sloane, H. J. Cohen, B. Peterson, T. J.
Hartman, P. Miller, D. C. Mitchell and W. Demark-Wahnefried, Effects of home-
based diet and exercise on functional outcomes among older, overweight long-term
cancer survivors: RENEW: a randomized controlled trial, JAMA. 301(18): 1883-
1891 (2009).
257. I. C. De Backer, G. Schep, F. J. Backx, G. Vreugdenhil and H. Kuipers,
Resistance training in cancer survivors: a systematic review, Int J Sports Med.
30(10): 703-712 (2009).
258. M. L. McNeely, K. L Campbell, B. H. Rowe, T. P. Klassen, J. R. Mackey
and K. S. Courneya, Effects of exercise on breast cancer patients and survivors: a
systematic review and meta-analysis, CMAJ. 175(1): 34-41 (2006).
365
259. B. Cheema, C. A. Gaul, K. Lane and F. A. Fiatarone Singh, Progressive
resistance training in breast cancer: a systematic review of clinical trials, Breast
Cancer Res Treat. 109(1): 9-26 (2008).
260. R. M. Speck, K. S. Courneya, L. C. Mâsse, S. Duval and K. H. Schmitz, An
update of controlled physical activity trials in cancer survivors: a systematic review
and meta-analysis, J Cancer Surviv. 4(2): 87-100 (2010).
261. F. Dimeo, R. D. Stieglitz, U. Novelli-Fischer, S. Fetscher, R. Mertelsmann
and J. Keul, Correlation between physical performance and fatigue in cancer
patients, Ann Oncol. 8(12): 1251-1255 (1997).
262. K. S. Courneya, L. W. Jones, C. J. Peddle, C. M. Sellar, T. Reiman, A. A.
Joy, N. Chua, L. Tkachuk and J. R. Mackey, Effects of aerobic exercise training in
anemic cancer patients receiving darbepoetin alfa: a randomized controlled trial,
Oncologist. 13(9): 1012-1020 (2008).
263. S. Hayes, P. S. Davies, T. Parker and J. Bashford, Total energy expenditure
and body composition changes following peripheral blood stem cell transplantation
and participation in an exercise programme, Bone Marrow Transplant. 31: 331-338
(2003).
264. K. H. Schmitz, R. L. Ahmed, A. Troxel, A. Cheville, R. Smith, L. Lewis-
Grant, C. J. Bryan, C. T. Williams-Smith and Q. P. Greene, Weight lifting in
women with breast-cancer-related lymphedema, N Engl J Med. 361: 664-673
(2009).
265. P. B. Jacobsen, K. A. Donovan, S. T. Vadaparampil and B. J. Small,
Systematic review and meta-analysis of psychological and activity-based
interventions for cancer-related fatigue, Health Psychol. 26(6): 660-667 (2007).
266. F. Cramp and J. Daniel, Exercise for the management of cancer-related
fatigue in adults, Cochrane Database Syst Rev. 2: CD006145 (2008).
267. M. J. Velthuis, S. C. Agasi-Idenburg, G. Aufdemkampe and H. M. Wittink,
The effect of physical exercise on cancer-related fatigue during cancer treatment: a
meta-analysis of randomised controlled trials, Clin Oncol (R Coll Radiol). 22(3):
208-221 (2010).
268. V. S. Conn, A. R. Hafdahl, D. C. Porock, R. McDaniel and P. J. Nielsen, A
meta-analysis of exercise interventions among people treated for cancer, Support
Care Cancer. 14(7): 699-712 (2006).
366
269. R. Beaton, W. Pagdin-Friesen, C. Robertson, C. Vigar, H. Watson and S. R.
Harris, Effects of exercise intervention on persons with metastatic cancer: a
systematic review, Physiother Can. 61(3): 141-153 (2009).
270. M. Markes, T. Brockow and K.L. Resch, Exercise for women receiving
adjuvant therapy for breast cancer, Cochrane Database Syst Rev. 4: CD005001
(2006).
271. S. F. Duijts, M. M. Faber, H. S. Oldenburg, M. van Beurden and N. K.
Aaronson, Effectiveness of behavioral techniques and physical exercise on
psychosocial functioning and health-related quality of life in breast cancer patients
and survivors-a meta-analysis, Psychooncology. DOI: 10.1002/pon.1728.
272. C. Vallbona and T. Richards, Evolution of magnetic therapy from alternative
to traditional medicine, Phys Med Rehabil Clin N Am. 10(3): 729-75 (1999).
273. National Center for Complementary and Alternative Medicine (NCCAM),
Energy medicine: an overview (NCCAM Publication No. D235), Available at
http://www.umbwellness.org/PDF_files/energymed.pdf (accessed 15 June 2010).
274. K. J. Hintz, G. L. Yount, I. Kadar, G. Schwartz, R. Hammerschlag and S.
Lin, Bioenergy definitions and research guidelines, Altern Ther Health Med.
9(suppl 3): A13-A30 (2003).
275. P. S. So, Y. Jiang and Y. Qin, Touch therapies for pain relief in adults,
Cochrane Database Syst Rev. 4: CD006535 (2008).
276. K. Chen and R. Yeung, Exploratory studies of Qigong therapy for cancer in
China, Integr Cancer Ther. 1(4): 345-370 (2002).
277. M. S. Lee, K. W. Chen, K. M. Sancier and E. Ernst, Qigong for cancer
treatment: a systematic review of controlled clinical trials, Acta Oncol. 46(6):717-
722 (2007).
278. S. Jain and P. J. Mills, Biofield therapies: helpful or full of hype? A best
evidence synthesis, Int J Behav Med. 17(1): 1-16 (2010).
279. University of New South Wales Department of Physics, The electromagnetic
spectrum, Available at http://www.phys.unsw.edu.au/~jw/EMspectrum.html
(accessed 16 June 2010).
367
280. Review Committee on Microwave Cancer Therapy and National Health and
Medical Research Council, Review of the use of microwave therapy for the
treatment of patients with cancer, Available at
http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/nh67.pdf
(accessed 16 June 2010).
281. P. Wust, J. Gellermann, C. Harder, W. Tilly, B. Rau, S. Dinges, P. Schlag,
V. Budach and R. Felix, Rationale for using invasive thermometry for regional
hyperthermia of pelvic tumors, Int J Radiat Oncol Biol Phys. 41: 1129-1137 (1998).
282. Association of American Medical Colleges, In: Facts and Statistics, ed.
National Institute of Complementary Medicine, Available at
http://www.nicm.edu.au/content/view/65/36/ (accessed 24 June 2010).
283. American Hospital Association, Latest survey shows more hospitals offering
complementary and alternative medicine services, Available at
http://www.aha.org/aha/press-release/2008/080915-pr-cam.html (accessed 25 June
2010).
284. C. Bulsara, A. Ward and D. Joske, Haematological cancer patients:
achieving a sense of empowerment by use of strategies to control illness, J Clin
Nurs. 13(2): 251-258 (2004).
285. R. M. Lowenthal, Integrative oncology in Australia, J Soc Integr Oncol.
4(2): 82-85 (2006).
286. C. D’Cruz, Living with cancer: complementary therapy options, Available at
http://www.cancerwa.asn.au/resources/0806_DCruz.pdf (accessed 15 January
2010).
287. C. O'Callaghan and F. McDermott, Music therapy's relevance in a cancer
hospital researched through a constructivist lens, J Music Ther. 41(2): 151-185
(2004).
288. J. McEwen, What does TGA approval of medicines mean?, Aust Prescriber.
27: 156-158 (2004).
289. M. Angell and J. P. Kassirer, Alternative medicine―the risks of untested
and unregulated remedies, N Engl J Med. 339(12): 839-841 (1998).
290. D. M. Studdert, D. M. Eisenberg, F. H. Miller, D. A. Curto, T. J. Kaptchuk
and T. A. Brennan, Medical malpractice implications of alternative medicine,
JAMA. 280(18): 1610-1615 (1998).
368
291. D. Eisenberg, Advising patients who seek alternative and complementary
medical therapies, Annal Intern Med. 127: 61-69 (1997).
292. M. D. Epstein and R. L. Street, Patient-centered Communication in Cancer
Care: Promoting Healing and Reducing Suffering. (National Cancer Institute,
Bethesda, 2007).
293. H. Burstein, Discussing complementary therapies with cancer patients: what
should we be talking about?, J Clin Oncol. 18: 2501-2504 (2000).
294. C. Zollman and A. Vickers, ABC of complementary medicine:
complementary medicine and the doctor, Br Med J. 319: 1558-1561 (1999).
295. G. Mackenzie, M. Parkinson, A. Lakhani and H. Pannekoek, Issues that
influence patient/physician discussion of complementary therapies, Patient Educ
Couns. 38: 155-159 (1999).
296. M. Frenkel, E. Ben-Arye, C.D. Baldwin and V. Sierpina, Approach to
communicating with patients about the use of nutritional supplements in cancer
care, South Med J. 98: 289-294 (2005).
297. T. E. Steyer, Complementary and alternative medicine: a primer, Fam Pract
Manag. 8(3): 37-42 (2001).
298. P. Schofield, J. Diggens, C. Charleson, R. Marigliani and M. Jefford,
Effectively discussing complementary and alternative medicine in a conventional
oncology setting: communication recommendations for clinicians, Patient Educ
Couns. 79(2): 143-151 (2010).
299. J. D. Edinger and R. Jacobsen, Incidence and significance of relaxation
treatment side effects. Behav Ther. 5: 137-138 (1982).
300. A. A. Lazarus and T. J. Mayne, Relaxation: some limitations, side effects,
and proposed solutions, Psychotherapy. 27: 261-266 (1990).
301. J. C. Smith, Steps toward a cognitive-behavioral model of relaxation,
Biofeedback Self Regul. 13: 307-329 (1988).
302. R. L. Woolfolk and P. M. Lehrer, Principles and Practice of Stress
Management, 2nd ed. (Guilford Press, New York, 1993).
303. J. D. Edinger and R. Jacobsen, Incidence and significance of relaxation
treatment side effects, Behav Therapist. 5: 137-138 (1982).
369
304. F. J. Heide and T. D. Borkovec, Relaxation-induced anxiety: paradoxical
anxiety enhancement due to relaxation training, J Consult Clin Psychol. 51: 171-
182 (1983).
305. G. R. Norton, L. Rhodes, J. Hauch and E. A. Kaprowy, Characteristics of
subjects experiencing relaxation and relaxation-induced anxiety. J Behav Ther Exp
Psychiatry. 16: 211-216 (1985).
306. J. Grigsby, The use of imagery in the treatment of post traumatic stress
disorder, J Nerv Ment Dis. 175: 55-59 (1987).
307. R. Pitman, B. Altman, E. Greenwald, R. Longpre, M. Macklin, R. Poire and
G. Stektee, Psychiatric complications during flooding therapy for post traumatic
stress disorder, J Clin Psychiatry. 52: 17-20 (1991).
308. S. Harding, Relaxation: with or without imagery?, Int J Nurs Pract. 2(3):
160-162 (1996).
309. A. Vickers and C. Zollman, ABC of complementary medicine. Hypnosis
and relaxation therapies, BMJ. 319(7221): 1346-1349 (1999).
310. J. A. Herman, The effect of progressive relaxation on Valsalva response in
healthy adults, Res Nurs Health. 10(3): 171-176 (1987).
311. J. A. Herman, Valsalva response during progressive relaxation: an extension
study, Sch Inq Nurs Pract. 3(3): 217-226 (1989).
312. D. H. Shapiro Jr., Overview: clinical and physiological comparison of
meditation with other self-control strategies, Am J Psychiatry. 139(3): 267-274
(1982).
313. J. A. Astin, S. L. Shapiro, D. M. Eisenberg and K. L. Forys, Mind-body
medicine: state of the science, implications for practice, Mind-Body Med. 16(2):
131-147 (2003).
314. A. Kokoszka, Axiological aspects of comparing psychotherapy and
meditation, Int J Psychosom. 37: 78-81 (1990).
315. C. N. Alexander, P. Robinson, D. W. Orme-Johnson, and R. H. Schneider,
The effects of transcendental meditation compared to other methods of relaxation
and meditation in reducing risk factors, morbidity, and mortality. CIANS-ISBM
Satellite Conference Symposium: Lifestyle changes in the prevention and treatment
of disease (1992, Hannover, Germany), Homeostasis Health Dis. 35: 243-263
(1994).
370
316. D. H. Shapiro Jr., Adverse effects of meditation: A preliminary investigation
of long-term meditators. Int J Psychosom. 39: 62-67 (1992).
317. R. J. Castillo, Depersonalization and meditation, Psychiatry. 53: 158-168
(1990).
318. R. B. Kennedy Jr., Self-induced depersonalization syndrome, Am J
Psychiatry. 133: 1326-1328 (1976).
319. L. S. Otis, Adverse effects of transcendental meditation. In: Meditation:
Classic and Contemporary Perspectives, eds. D. Shapiro and R. Walsh (Aldine
Publishing Co., New York, 1984).
320. A. A. Lazarus, Psychiatric problems precipitated by transcendental
meditation, Psychol Reports. 39: 601-602 (1976).
321. L. S. Otis, The facts on transcendental meditation: III. If well-integrated but
anxious, try TM, Psychol Today. 7: 45-46 (1974).
322. M. D. Epstein and J. D. Lieff, Psychiatric complications of meditation
practice, J Transpers Psychol. 13: 137-147 (1981).
323. J. L. Craven, Meditation and psychotherapy, Canadian J Psychiatry. 34:
648-653 (1989).
324. I. Kutz, J. Z. Borysenko and H. Benson, Meditation and psychotherapy: a
rationale for the integration of dynamic psychotherapy, the relaxation response, and
mindfulness meditation, Am J Psychiatry. 142: 1-8 (1985).
325. H. J. H. Kuijpers, F. M. M. A. van der Heijden, S. Tuinier and W. M. A.
Verhoeven, Meditation-induced psychosis, Psychopathol. 40: 461-464 (2007).
326. Melbourne Academic Mindfulness Interest Group, Mindfulness-based
psychotherapies: a review of conceptual foundations, empirical evidence and
practical considerations, ANZ J Psychiatry. 40: 285-294 (2006).
327. D. H. Shapiro Jr., Examining the content and context of meditation: a
challenge for psychology in the areas of stress management. Psychother Religious
Values. 34(4): 101-135 (1994).
328. F. MacHovec, Hypnosis complications, risk factors, and prevention, Am J
Clin Hypn. 31: 40-49(1988).
329. J. Barber, When hypnosis causes trouble, Int J Clin Exp Hypn. 46: 157-170
(1998).
371
330. S. J. Lynn, D. J. Martin and D. C. Frauman, Does hypnosis pose special
risks for negative effects? A master class commentary, Int J Clin Exp Hypn. 44: 7-
19 (1996).
331. R. A. Page and G. W. Handley, In search of predictors of hypnotic sequelae,
Am J Clin Hypn. 39: 93-96 (1996).
332. American Cancer Society, Yoga, Available at
http://www.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlt
ernativeMedicine/MindBodyandSpirit/yoga (accessed 21 September 2010).
333. P. Oestreicher, Help patients integrate yoga into cancer care, ONS Connect.
23(4): 20-21 (2008).
334. Natural Standard and the Harvard Medical School, Tai chi, Available at
http://www.intelihealth.com/IH/ihtIH/WSIHW000/8513/34968/358867.html
(accessed 5 October 2010).
335. C. Ulbricht, S. Bent, W. Chao, D. Costa, W. Che, D. Lee, R. Liebowitz, H.
Shan, D. Sollars and S. Tanguay-Colucci, An evidence-based review of Qi Gong by
the Natural Standard Research Collaboration, Natural Med J. 2(5): 7-15 (2010).
336. B. Ng, Qigong-induced mental disorders: a review, ANZ J Psychiatry. 33:
197-206 (1999).
337. H. H. Shan, Culture-bound psychiatric disorders associated with Qigong
practice in China, Hong Kong J Psychiatry. 10(3): 12-14 (2000).
338. K. S. Cohen, The Way of Qigong, (Bantam, London, 1997).
339. S. Lee, Cultures in psychiatric nosology: the CCMD-2-R and international
classification of mental disorders, Cult Med Psychiatry. 20: 421-472 (1996).
340. T. L. Zhang and T. H. Xu, Correcting Deviations from the Path of Qigong,
(Publishing House of People's Health, Beijing, 1997).
341. Z. Q. Qian, Treatment and Prevention of Qigong Deviations, (Bai-jia Press,
Shanghai, 1995).
342. M. T. He, Qigong craze. Psychol Health. 12: 33 (1996).
343. H. H. Chan, H. J. Yan, S. H. Xu, M. D. Zhang and B. Fan, A controlled
comparison of hysteria-like episodes induced by Qigong and hysteria with
psychosocial stress, Chinese J Nerv Ment Dis. 18: 156-158 (1992).
344. C. M. Han and W. J. Ji, Qigong induced mental disorders, Chinese Qigong,
1: 37-38 (1997).
372
345. H. Ryu, H. Y. Mo, G. D. Mo, B. M. Choi, C. D. Jun, C. M. Seo, H. M. Kim
and H. T. Chung, Delayed cutaneous hypersensitivity reactions in Qigong (chun do
sun bup) trainees by multitest cell mediated immunity, Am J Chin Med. 23(2): 139-
144 (1995).
346. S. Mahadevan and Y. Park, Multifaceted therapeutic benefits of Ginkgo
biloba L.: chemistry, efficacy, safety, and uses, J Food Sci. 73(1): R14-R19 (2008).
347. Y. H. Zou and X. M. Liu, Effect of astragalus injection combined with
chemotherapy on quality of life in patients with advanced non-small cell lung
cancer, Zhongguo Zhong Xi Yi Jie He Za Zhi. 23(10): 733-735 (2003).
348. H. Wei, R. Sun, W. Xiao, J. Feng, C. Zhen, X. Xu and Z. Tian, Traditional
Chinese medicine Astragalus reverses predominance of Th2 cytokines and their up-
stream transcript factors in lung cancer patients, Oncol Rep. 10(5): 1507-1512
(2003).
349. P. Duan and Z. M. Wang, Clinical study on effect of Astragalus in efficacy
enhancing and toxicity reducing of chemotherapy in patients of malignant tumor,
Zhongguo Zhong Xi Yi Jie He Za Zhi. 22(7): 515-517 (2002).
350. P. Pellegrini, A. M. Berghella, T. Del Beato, S. Cicia, D. Adorno and C. U.
Casciani, Disregulation in TH1 and TH2 subsets of CD4+ T cells in peripheral
blood of colorectal cancer patients and involvement in cancer establishment and
progression, Cancer Immunol Immunother. 42(1): 1-8 (1996).
351. J. Brush, E. Mendenhall, A. Guggenheim, T. Chan, E. Connelly, A.
Soumyanath, R. Buresh, R. Barrett, and H. Zwickey, The effect of Echinacea
purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression
and immune cell activation in humans, Phytother Res. 20(8): 687-695 (2006).
352. H. Zwickey, J. Brush, C. M. Iacullo, E. Connelly, W. L. Gregory, A.
Soumyanath and R. Buresh, The effect of Echinacea purpurea, Astragalus
membranaceus and Glycyrrhizaglabra on CD25 expression in humans: a pilot study,
Phytother Res. 21(11): 1109-1112 (2007).
353. D. T. Chu, J. Lepe-Zuniga, W. L. Wong, R. LaPushin, and G. M. Mavligit,
Fractionated extract of Astragalus membranaceus, a Chinese medicinal herb,
potentiates LAK cell cytotoxicity generated by a low dose of recombinant
interleukin-2, J Clin Lab Immunol. 26(4): 183-187 (1988).
373
354. P. Wu, J. J. Dugoua, O. Eyawo and E. J. Mills, Traditional Chinese
Medicines in the treatment of hepatocellular cancers: a systematic review and meta-
analysis, J Exp Clin Cancer Res. 12(28): 112 (2009).
355. W. H. Ma, K. N. Duan, M. Feng, B. She, Y. Chen and R. M. Zhang, Aidi
Injection as an adjunct therapy for non-small cell lung cancer: a systematic review,
Zhong Xi Yi Jie He Xue Bao. 7: 315-324 (2009).
356. B. R. Cassileth, N. Rizvi, G. Deng, K. S. Yeung, A. Vickers, S. Guillen, D.
Woo, M. Coleton and M. G. Kris, Safety and pharmacokinetic trial of docetaxel
plus an Astragalus-based herbal formula for non-small cell lung cancer patients,
Cancer Chemother Pharmacol. 65(1): 67-71 (2009).
357. J. J. Lee and J. J. Lee, A phase II study of an herbal decoction that includes
Astragali radix for cancer-associated anorexia in patients with advanced cancer,
Integr Cancer Ther. 9(1): 24-31 (2010).
358. Y. Shi, M. Li and F. Xu, A review of the study on swainsonine – toxic
elements of locoweed, Zhong Yao Cai. 22(1): 47-49 (1999).
359. National Center for Complementary and Alternative Medicine (NCCAM),
Astragalus, Available at http://nccam.nih.gov/health/astragalus/D384_Herbs.pdf
(accessed 17 October 2010).
360. L. G. Miller, Herbal medicinals: selected clinical considerations focusing on
known or potential drug-herb interactions, Arch Intern Med. 158: 2200-2211
(1998).
361. W. Maddocks-Jennings and J. M. Wilkinson, Aromatherapy practice in
nursing: literature review, J Adv Nurs. 48(1): 93-103 (2004).
362. J. McEwen, What does TGA approval of medicines mean?, Aust Prescriber.
27: 156-158 (2004).
363. R. M. Lowenthal, Integrative oncology in Australia, J Soc Integr Oncol.
4(2): 82-85 (2006).
374
Appendix D: Complementary and Alternative Medicine Used by Patients with
Cancer– Evidence for Efficacy and Safety (Methodology, Study 2)
Appendix D also contains a detailed methodology of study 2 written using the gold
standard Cochrane review framework, which provides more detail regarding the process
that underpinned the systematic review performed.
375
COMPLEMENTARY AND ALTERNATIVE MEDICINE USED BY PATIENTS
WITH CANCER – EVIDENCE FOR EFFICACY AND SAFETY (STUDY 2)
OBJECTIVES
The primary objective of this systematic review was to evaluate the efficacy and safety of a
range of popular complementary and alternative medicines (CAMs) used by adult cancer
patients in Australia and elsewhere, utilising evidence, where possible, from Cochrane and
other meta-analytic/systematic reviews. Secondary objectives examined whether specific
CAMs can be used with clinical efficacy and safety that is comparable to standard or other
existing interventions (medical or otherwise) for particular symptoms or problems, and
whether some groups of patients benefit or are more prone to harm in response to particular
CAM interventions.
METHODS
Criteria for considering studies for this review
Types of studies
Meta-analytic/systematic ± narrative reviews of randomised controlled trials (RCTs), quasi-
RCTs, epidemiological/population/observational/cohort/case-control studies, and case
series/report studies were utilised where possible. In their absence, individual RCTs of
efficacy were evaluated while all types of studies were considered with respect to potential
safety concerns. Primary research studies, however, were otherwise excluded to prevent
duplication and to ensure that the literature search and review were manageable given the
resources available, unless recent RCTs presented new findings different from those of the
reviews utilised. If recent RCTs using the same dataset appeared in more than one
publication, the results were reported only once.
Types of participants
Studies considered included adult cancer patients (18 years and over) using CAM in
different phases of their cancer experience or trajectory (upon diagnosis, during
conventional treatment, in response to disease progression or recurrence, or during
remission/survivorship), irrespective of gender, diagnosis, histological tumour type, cancer
376
stage, and the intent and type of anticancer treatment received (if undergoing active
conventional treatment). The only other populations considered were healthy volunteers
and non-oncological medical patients in studies examining cancer prevention or safety.
Paediatric, animal and in vitro studies were excluded.
Types of interventions
Pharmacological and non-pharmacological interventions of interest corresponded to the US
National Center for Complementary and Alternative Medicine (NCCAM) / Australian
National Institute of Complementary Medicine (NICM) classifications of CAM, which fall
into 5 categories, whole medical systems, mind-body techniques, biologically-based
practices, manipulative and body-based practices, and energy therapies (Table D1;
NCCAM, 2009; NICM, 2010). Interventions included for review (Table D1) were guided
by those reported by cancer patients in earlier studies in Australia and elsewhere (e.g. Oh et
al., 2010; Pirri, Katris, Trotter, Bayliss, Bennett, & Drummond, 2008; Molassiotis et al.,
2005), as well as those presented in previous comprehensive evidence-based systematic
reviews similar to the one undertaken (e.g. Deng et al., 2009, 2010).
Types of outcome measures
Due to the wide-ranging nature of the present systematic review and the inclusion of
patients in different phases of their cancer experience or trajectory, the review was not
limited to any particular outcome (clinical or otherwise; see Appendix C, Tables 2-13, pp.
312-338 for an indication of the range of outcomes). For purposes of the review, efficacy
was defined as a statistically significant improvement in a clinically-relevant outcome (cf.
NHMRC, 2013). Clinically-relevant outcomes varied depending on the CAM being
considered and the phase of cancer trajectory of study patients. Safety was defined as any
form of direct or indirect harm related to the use of a specific CAM in human studies (see
Pirri, 2011, Tables 3 and 4, pp. 196-200). Risk of direct harm was predominantly concerned
with clinically-relevant outcomes and effects.
377
Table D1. Classification of complementary and alternative therapies evaluated for efficacy and safety Therapeutic Approaches
Definition Therapies used by cancer patients evaluated
for efficacy and/or safety
Whole medical systems
Encompass complete systems of diagnosis and practice, which have some overlap with the other four therapeutic approaches below
Homeopathy, naturopathy, traditional Chinese medicine
Mind-body techniques
Techniques designed to increase the mind’s capacity and behavioural repertoire of active coping strategies to heal or manage physical and/or psychological symptoms of disease and promote general health and well-being
Practitioner-administered therapies Hypnotherapy, mindfulness-based stress reduction, music therapy, support groups
Self-help strategies Relaxation (± imagery techniques), meditation (mindfulness, Vipassana, transcendental), yoga, tai chi, music medicine, support groups, spirituality, religion, intercessory prayer
Biologically-based practices
Involve supplementing normal dietary intake with additional extracts, nutrients, herbs and/or certain foods
Dietary supplements: Antioxidants (vitamins A, C, E; alpha/beta-carotene carotenoids, lycopene, selenium, melatonin, amifostine, coenzyme Q10), omega-3 fatty acids (EPA, DHA, ALA), shark cartilage, laetrile/amygdalin
Chinese herbal medicines: Astragalus and astragalus-based herbs, ginseng and ginseng-based herbs, ginger, Lingzhi/reishi mushroom, green tea, gingko
Western herbal medicines: St. John’s wort, garlic, kava, valerian, evening primrose oil, black cohosh, echninacea, milk thistle, European mistletoe
Manipulative and body-based practices
Involve manipulation or movement of one or more parts of the body in order to heal the body and achieve good health
Massage therapy: therapeutic massage, aromatherapy (isopropyl alcohol, peppermint oil, lavender, orange essential oils)
Acupuncture and acupuncture-point stimulation (simple acupuncture needle insertion, manual acupuncture, electroacupunture, acupuncture injection with herbs, acupoint plaster application, moxibustion, self/practitioner-administered acupressure)
Exercise interventions (aerobic and/or resistance, unsupervised home-based vs supervised institution-based, individual vs group programmes)
Energy therapies
Involve the unconventional use of putative energy fields or biofields, which purportedly surround the human body and have yet to be scientifically measured; and veritable energy fields, which employ mechanical vibrations (e.g. sound) and electromagnetic fields (e.g. magnetic, pulsed or alternating/ direct-current fields)
Biofield therapies Qigong, healing/therapeutic touch, Reiki, Bioelectromagnetic-based therapies Microwave/Tronado therapy
378
Search methods for identification of studies
Electronic searches
The following databases were searched: MEDLINE and EMBASE (via EMBASE.com),
PubMed, PubMed Health, CAM on PubMed, the Cochrane Library, PsycINFO (via
ProQuest), CINAHL (via EBSCOhost), Database of Abstracts of Reviews of Effectiveness
(DARE), and Theses and Dissertations (via ProQuest). Search dates for reviews of efficacy
were limited from January 1997 to October 2010 (and from January 2000 to August 2014
in the post-publication update, in case any relevant reviews were inadvertedly overlooked
in the original systematic review). However, search dates were not limited for safety per se,
or primary research studies of efficacy in the instance where no reviews were found.
A search strategy for each CAM was devised for use with PubMed and adapted for other
databases searched. For example, a search of PubMed for homeopathy (the first CAM in
the present review) used the following search terms (and was extrapolated to PubMed
searches for other CAMs):
1. (“systematic review” OR meta analysis OR “review” OR “pooled analysis” OR
“synthesis” OR “narrative”[Title/Abstract]) AND (homeopath* AND
cancer[Title/Abstract]) for the efficacy of homeopathy among cancer patients
2. (homeopath* AND safe*[Title/Abstract]) OR (homeopath* AND
harm*[Title/Abstract]) OR (homeopath* AND adverse[Title/Abstract]) OR
(homeopath* AND risk*[Title/Abstract]) for the safety of homeopathy
Searches were restricted by date as appropriate, but no search filters were applied to
language (i.e. non-English studies were excluded manually).
Searching other resources
Further publications were manually identified using the bibliographies of articles retrieved
via the electronic searches, and the “cited by other publications” facility of Google Scholar
379
when titles of retrieved articles were entered. Relevant publications were also searched for
on specific websites:
1. CAM-Cancer (http://www.cam-cancer.org/)
2. Memorial Sloan Kettering Cancer Center: About Herbs, Botanicals & Other
Products (https://www.mskcc.org/cancer-care/treatments/symptom-
management/integrative-medicine/herbs/search)
3. U.S. National Cancer Institute: Office of Cancer Complementary and Alternative
Medicine (http://cam.cancer.gov/health_camaz.html)
4. The Society for Integrative Oncology (https://integrativeonc.org/)
5. Cancer Council Australia (http://www.cancer.org.au)
6. National Center for Complementary and Integrative Health (formerly NCCAM;
https://nccih.nih.gov/health/safety/topics.htm)
7. National Health and Medical Research Council (NHMRC)
(http://www.nhmrc.gov.au/)
8. Healthdirect Australia (formerly HealthInsite;
http://www.healthdirect.gov.au/complementary-therapies)
9. Victorian State Government: Better Health Channel
(http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/ct_alternative?open)
10. Therapeutic Goods Administration (http://www.tga.gov.au)
11. U.S. Food and Drug Administration (http://www.fda.gov/)
12. MedlinePlus: Herbs and Supplements
(https://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html)
13. U.S. National Institutes of Health: Office Of Dietary Supplements − Consumer
Fact Sheets (http://ods.od.nih.gov/factsheets/list-all/)
14. Quackwatch: Guide to Quackery, Health Fraud, and Informed Decisions
(http://www.quackwatch.com/)
380
Data collection and analysis
Selection of studies
All citations identified in the literature search were initially screened by the review author
based on the publication title and abstract. Relevant publications were obtained in full-text
and subsequently assessed by two reviewers (CP, PK; see page overleaf).
Consistent with the objectives and criteria outlined for the present systematic review, the
following a priori exclusion criteria were applied to the citations amassed in the literature
search:
1. Duplicate citation.
2. Wrong publication type. CAM efficacy studies that were not reviews (or, as
appropriate, RCTs) were excluded. Paediatric/animal/in vitro studies editorials,
comments, correspondence, and news items relating to efficacy or safety were
excluded. Studies were also excluded if they were not fully-reported (e.g. Cochrane
review, meta-analytic/systematic review or study protocols, conference proceedings,
articles published in abstract form).
3. Wrong intervention. Efficacy studies that did not investigate the effect of the
relevant CAM were excluded, as were those that evaluated complex intervention
packages that happened to include the relevant CAM.
4. Wrong outcomes. Studies that did not include outcomes relevant to the primary
objective of the review were excluded.
5. Study not published in the English language.
Data extraction
Information relevant to the present systematic review of the efficacy and safety of specific
CAMs was routinely collated in accordance with NHMRC standards and levels of evidence
(NHMRC, 2007, 2009). Extracted information included:
1. General study details (citation, review type/study design, level of evidence, country
and setting).
2. Affiliations/sources of funds for each of the included studies.
381
3. Internal and external validity considerations.
4. Number and methodology of studies reviewed, or sample size of study.
5. Participant details, including key demographic and clinical characteristics.
6. Type of intervention/control.
7. Primary, secondary and other outcome variables, objective/subjective measures
used, and study outcome results.
8. Length of any follow-up periods and their outcomes.
9. Limitations noted by the authors or otherwise.
Data was extracted by the review author (CP) and independently verified by a second
reviewer (PK, author 2 of study 1, p.31) working in cancer research and education, with a
special interest in CAM. Any disagreements were resolved by discussion between the
review author and the second reviewer.
Assessment of methodological quality of included reviews and primary studies
Publications were assessed for quality using the brief 10-12 item Critical Appraisal Skills
Programme (CASP) checklists for evaluating reviews and primary studies (RCTs, case-
control studies), which were were developed from guides produced by the Evidence Based
Medicine Working Group published in the Journal of the American Medical Association
(Public Health Resource Unit, 2006a, b, c, d). The CASP checklists examine 3 broad
questions: (i) “Is the study/review valid?”, (ii) “What are the results?”, and (iii) “Are the
results relevant and helpful to clinical practice locally?” (National Collaborating Centre for
Methods and Tools, 2011). Quality assessments were performed by the review author and
checked by the second reviewer.
References
Deng, G. E., Frenkel, M., Cohen, M. L., Cassileth, B. R., Abrams, D. I., Capodice, J. L, . . .
Sagar S, Society for Integrative Oncology. (2009). Evidence-based clinical practice
guidelines for integrative oncology: complementary therapies and botanicals.
Journal of the Society for Integrative Oncology, 7(3), 85-120.
382
Deng, G. E., Rausch, S. M., Jones, L. W., Gulati, A., Kumar, N. B., Greenlee, H., . . .
Cassileth, B. R. (2013). Complementary therapies and integrative medicine in lung
cancer: Diagnosis and management of lung cancer, 3rd ed: American College of
Chest Physicians. Chest, 143(5 Suppl), e420S-e436S.
Molassiotis, A., Fernadez-Ortega, P., Pud, D., Ozden, G., Scott, J. A., Panteli, V., . . .
Patiraki, E. (2005). Use of complementary and alternative medicine in cancer
patients: A European survey. Annals of Oncology, 16(4), 655-663.
National Center for Complementary and Alternative Medicine (2009). CAM basics: What is
CAM? [online document] Retrieved from
http://nccam.nih.gov/health/whatiscam/D347.pdf
National Collaborating Centre for Methods and Tools. (2011). Critical appraisal tools to
make sense of evidence. Retrieved from
http://www.nccmt.ca/registry/view/eng/87.html
National Health and Medical Research Council (Australia). (2007). Standards and
procedures for externally developed guidelines. Retrieved from
http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/nh56.pdf
National Health and Medical Research Council (Australia). (2009). NHMRC additional
levels of evidence and grades for recommendations for developers of guidelines.
Retrieved from
https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_g
rades_evidence_120423.pdf
National Health and Medical Research Council (Australia). (2013). Effectiveness of
homeopathy for clinical conditions: Evaluation of the evidence. Overview report.
Retrieved from https://www.nhmrc.gov.au/your-health/complementary-
medicines/homeopathy-review
National Institute of Complementary Medicine (2010). Understanding complementary
medicine. [online document]. Retrieved from
http://www.nicm.edu.au/content/view/31/35/
Oh, B., Butow, P., Mullan, B., Beale, P., Pavlakis, N., Rosenthal, D., & Clarke, S. (2010).
The use and perceived benefits resulting from the use of complementary and
alternative medicine by cancer patients in Australia. Asia-Pacific Journal of
Clinical Oncology, 6(4), 342-349.
383
Pirri, C., Katris P., Trotter J., Bayliss E., Bennett, R., & Drummond, P (2008). Use of
complementary and alternative therapies by Western Australian cancer patients.
Asia-Pacific Journal of Clinical Oncology, 4(3), 161-169.
Pirri, C. (2011). Integrating complementary and conventional medicine. Cancer Forum,
35(1), 31-39. Retrieved from
http://www.cancerforum.org.au/file/2011/March/Mar_2011_Forum8.pdf
Public Health Resource Unit. (2006a). Critical Appraisal Skills Programme (CASP)
systematic review checklist. Retrieved from http://www.casp-
uk.net/#!checklists/cb36
Public Health Resource Unit. (2006b). Critical Appraisal Skills Programme (CASP)
randomised controlled trial checklist. Retrieved from http://www.casp-
uk.net/#!checklists/cb36
Public Health Resource Unit. (2006c). Critical Appraisal Skills Programme (CASP) cohort
study checklist. Retrieved from http://www.casp-uk.net/#!checklists/cb36
Public Health Resource Unit. (2006d). Critical Appraisal Skills Programme (CASP) case
control checklist. Retrieved from http://www.casp-uk.net/#!checklists/cb36
384
Appendix E: Embracing Complementary and Alternative Medicine (CAM) for All the
Right Reasons (Commentary Article Based on Study 2 – MJA InSight Online
Publication)
Appendix E contains the published work of the manuscript in chapter 3, as it appears in
publication online.
385
386
387
388
Appendix F: Cancer Patients’ Complementary/Alternative Therapy Use in Relation to
Demographics & Clinical Factors (An Alternative Analysis Correcting for Multiple
Comparisons using the Benjamini-Hochberg Procedure – Table A2, Study 1)
Appendix F presents an alternative version of Table 1 contained in the study 1 manuscript
(chapter 2, p39). Table A2 summarises statistical outcomes for the same variables
originally reported in Table 1, but uses a more complex type of statistical analysis that
corrects for the large number of statistical tests (more specifically, chi-square tests)
performed and the potential elevated risk of chance findings (i.e. p-values less than .05
indicating statistically significant outcomes that are not genuine, but rather are the product
of chance).
The more complex statistical analysis (i.e. the Benjamini-Hochberg procedure correcting
for multiple comparisons; Benjamini & Hochberg, 1995) was originally performed to
account for these concerns, but was not reported since it produced outcomes that were no
different to the simplified statistical analysis presented in study 1 (pp.37-39). Consequently,
outcomes of the simplified analysis per se were reported to avoid any unnecessary
confusion among the journal’s wider readership. Nevertheless, the results of the more
complex analysis, using the Benjamini-Hochberg procedure correcting for multiple
comparisons, are now summarised in Table A2 overleaf.
The Benjamini-Hochberg (B-H) procedure corrects for multiple comparisons by adjusting
the false discovery rate. It is an approach similar to the Bonferroni correction for
familywise error, but more powerful (McDonald, 2014). Briefly explained in reference to
Table A2, the p-values derived from the chi-square tests performed for the 15 outcome
variables were assigned a rank (i) from smallest to largest (i.e. 1 to 15, with the smallest p-
value assigned a rank of i = 1, the next smallest a rank of i = 2, and so on). The p-value
derived for each outcome variable was then compared to its B-H critical value, (i/m)Q,
where i is the assigned rank, m is the total number of chi-square tests (m = 15), and Q is the
false discovery rate selected (Q = 0.1, a moderately high false discovery rate, was chosen as
the cost of missing a false negative – i.e. missing a statistically significant outcome – was
considered high; McDonald, 2014).
389
The largest p-value among the chi-square tests performed for which p < B-H critical value,
(i/m)Q, is true was deemed significant (i.e. comorbid medical history, p = .023).
Additionally, all of the p-values smaller than it were also deemed significant, irrespective
of whether they exceeded their B-H critical value (i.e. education, p = .016; age, p = .004;
treatment duration, p = .004).
References
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and
powerful approach to multiple testing. Journal of the Royal Statistical Society, B57,
289-300.
McDonald, J. H. (2014). Handbook of biological statistics (3rd ed). Baltimore: Sparky
House Publishing.
390
Table A2 Cancer patients’ complementary/alternative therapy use in relation to demographics & clinical factors (study 1)§
CAT Users (n=59)
Non‐Users (n=141)
All Patients (N=200) p
Rank (i)
#
B‐H critical value = (i/m)Q
¶
Sex n (row %) n (row %) N [column %] Male 25 (26.3) 70 (73.7) 95 [47.5] Female 34 (32.4) 71 (67.6) 105 [52.5]
.433
7
0.047
Age** n (row %) n (row %) N [column %] 18‐39yrs** 12 (46.2) 14 (53.8) 26 [13.0] 40‐49yrs 14 (37.8) 23 (62.2) 37 [18.5] 50‐59yrs 20 (39.2) 31 (60.8) 51 [25.5] 60‐69yrs** 7 (15.9) 37 (84.1) 44 [22.0] 70yrs and over** 6 (14.3) 36 (85.7) 42 [21.0]
.004** 2 0.013
Marital Status n (row %) n (row %) N [column %] Married / Defacto 46 (32.9) 94 (67.1) 140 [70.0] Divorced / Separated 6 (20.7) 23 (79.3) 29 [14.5] Widowed 2 (12.5) 14 (87.5) 16 [8.0] Single, Never Married 5 (33.3) 10 (66.7) 15 [7.5]
.244 6 0.04
Education†,* n (row %) n (row %) N [column %]
Primary* 2 (10.0) 18 (90.0) 20 [10.2] Secondary 23 (25.3) 68 (74.7) 91 [46.7] Tertiary* 33 (39.3) 51 (60.7) 84 [43.1]
.016* 3 0.02
Residence† n (row %) n (row %) N [column %]
Metropolitan 48 (28.4) 121 (71.6) 169 [84.9] Rural 10 (33.3) 20 (66.7) 30 [15.1]
.742 13 0.087
Health Insurance Status n (row %) n (row %) N [column %] Public 51 (29.8) 120 (70.2) 171 [85.5] Private 8 (27.6) 21 (72.4) 29 [14.5]
.981 14 0.093
Primary Diagnosis n (row %) n (row %) N [column %] Breast 23 (39.7) 35 (60.3) 58 [29.0] Colorectal 11 (19.6) 45 (80.4) 56 [28.0] Other 25 (29.1) 61 (70.9) 86 [43.0]
.064 5 0.03
Comorbid Medical History†,* n (row %) n (row %) N [column %]
None 21 (33.9) 41 (66.1) 62 [32.0]
Single Condition* 19 (41.3) 27 (58.7) 46 [24.0]
Multiple Conditions* 17 (19.8) 69 (80.2) 86 [44.0]
.023* 4 0.028
Psychiatric History† n (row %) n (row %) N [column %]
No Prior History 52 (30.4) 119 (69.6) 171 [88.1] Previous History 5 (21.7) 18 (78.3) 23 [11.9]
.54 10 0.068
Cancer History n (row %) n (row %) N [column %] No Prior History 44 (29.1) 107 (70.9) 151 [75.5] Previous History 15 (30.6) 34 (69.4) 49 [24.5]
.987 15 0.1
Recurrence n (row %) n (row %) N [column %] No 48 (28.4) 121 (71.6) 169 [84.5] Yes 11 (35.5) 20 (64.5) 31 [15.5]
.562 9 0.06
Disease Extent n (row %) n (row %) N [column %] Localised Disease 5 (26.3) 14 (73.7) 19 [9.5]
Locally Advanced 29 (26.6) 80 (73.4) 109 [54.5] Metastatic 25 (34.7) 47 (65.3) 72 [46.0]
.478 8 0.053
Treatment Goal n (row %) n (row %) N [column %] Curative 5 (21.7) 18 (78.3) 23 [11.5]
Adjuvant / Neoadjuvant 31 (30.7) 71 (69.3) 102 [51.0] Palliative 23 (30.4) 52 (69.6) 75 [37.5]
.686 12 0.08
Treatment Received n (row %) n (row %) N [column %] Chemotherapy + Surgery 21 (31.8) 45 (68.2) 66 [33.0] Chemoradiation + Surgery 17 (32.1) 36 (67.9) 53 [26.5] Chemotherapy 10 (21.7) 36 (78.3) 46 [23.0] Chemoradiation 11 (31.4) 24 (68.6) 35 [17.5]
.629 11 0.073
Treatment Duration†,‡,** n (row %) n (row %) N [column %]
0‐6 months** 33 (23.7) 106 (76.3) 139 [74.3] 6‐12 months** 17 (44.7) 21 (55.3) 38 [20.3] > 12 months** 6 (60.0) 4 (40.0) 10 [5.4]
.004** 1 0.068
§Summary of a more complex statistical analysis of Table 1 in study 1 using the Benjamini‐Hochberg (B‐H) procedure. †Patient numbers do not always equal
row/column total due to missing data. ‡Treatment duration excludes any initial surgery received prior to medical oncology presentation.
#i = rank of p‐value.
¶m = total no. of chi‐square tests (15), Q = false discovery rate (0.1). *p<.05, **p<.01 by chi‐square analysis of CAT users vs non‐users via the B‐H procedure.
