10 oe VOL. 15, NO. 1, February 2016

feature

Followup recommendations Part 9Considerations in the elderly post definitive cancer therapyby Malcolm Brigden, MDCM, FRCPC, FACP, and Lodovico Balducci MD, FACP

Malcolm Brigden, MDCM, FRCPC, FACP, is Medical Director of the Jack ady Cancer Center in Lethbridge, alberta, Clinical associate Professor of Medicine at the university of Calgary and associate adjunct Professor at the university of Lethbridge, alberta, Canada. Email: Malcolm.brigden@albertahealthservices.ca

Lodovico Balducci, MD, FACP, is Senior adult Oncologist, Senior adult Oncology Program, H Lee Moffitt Cancer Center and research Institute, Tampa, Florida, uSa. Email: balducci@Moffitt.uSF.edu

ABstRACt

In North America, two-thirds of all malignancies occur in the elderly. Fully 80% of prostate cancers, 74% of colon cancers and 72% of pancreatic cancers are in peo-

ple over age 65.1,2,3 Unfortunately, these absolute num-bers are increasing alongside the aging demographics of Western societies. Emphasis on treatment in the elderly has recently moved away from chronologic age, toward an individualized approach integrating tools for assessing fitness and quality of life, patient treatment preferences

and shared decision-making.3,4,5 It also seems logical that followup considerations in the elderly post definitive can-cer therapy should be similarly individualized. As there exist virtually no data from randomized controlled trials in this area, this article, like earlier articles in this series, takes a literature-based approach and emphasizes practi-cal recommendations.

Keywords: cancer care, cancer follow-up in the elderly, cancer survivorship

IntRoDuCtIonThere is limited evidence-based scientific literature available to support the practice of geriatric oncology.3,4,5 Almost all cancer treatments have been preferentially tested in younger cohorts of patients. However, the specialty of geriatric oncology is no longer simply a palliative field, as a healthy active life is now enjoyed by a significant number of older individuals.3,5

An initial difficulty appears in attempting to define elderly

individuals based simply on chronologic age. People per-form at surprisingly different levels in every age group: a hale British 100-year-old recently completed a marathon in record time!3 As the general health and nutrition of the population has improved (coupled with increased exercise and decreased smoking), we hear that “75 is the new 65.” Some gerontologists now define 4 elderly age groups: the young old (65 to 74), the older old (75 to 85), the oldest old (age >85) and the centenarians.1,2,3 However, simple chron-ologic classification does not take into account true biologic age, the presence of comorbid conditions, or a variety of other relevant factors.2,3,4 Increasingly with the elderly cancer patient, attention has focused on comprehensive geriatric assessment, quality of life, shared decision-making and patient-centred care, with carefully tailored individualized treatment programs.5 This article first reviews treatment algorithms used in elderly cancer patients, then extends the rationale to appropriate followup of these patients after definitive therapy.

tuMouR BIoLogy AnD CAnCeR tReAtMent In eLDeRLy PAtIentsWhile there are some documented differences in tumour behaviour between elderly and younger cancer patients (e.g. more hormone receptor positivity, as well as indolent course, with older breast cancer patients; more aggressive course with some lymphomas in the elderly), recent studies have tended to show that, generally, the behaviour of common solid malig-nancies appears to be no more aggressive in older patients.1,2,4

Regarding patient-related factors, however, studies of various organ systems measured at age 50 suggest an approx-imate 50% physiologic functional deterioration from age 30.1,2,4 Such an erosion of physiologic reserve with aging may be subtle, leaving baseline organ function status relatively unchanged, so that compromise only becomes evident during periods of stress, such as when undergoing cancer therapy.2,4 The progressive restriction in the functional reserve of mul-tiple organ systems associated with aging may also affect

Oncology Exchange would like to dedicate this article to Dr. Lodovico Balducci, Program Leader of the Senior adult Oncology Program at the H. Lee Moffitt Cancer Center, university of South Florida College of Medicine, in Tampa, Florida. Dr. balducci is truly the grandfather of geriatric oncology as an area of subspecialty interest.

Over 4 decades, he has authored over 300 articles on the subject of geriatric oncology, including 5 monographs. He has received numerous awards, including the first bJ Kennedy award from aSCO in 2007 for excellence in geriatric oncology. Dr. balducci produced the definitive Textbook of Geriatric Oncology, which fittingly includes a self-portrait of the elderly Leonardo da Vinci on the cover. Now in his 70s, Dr. balducci is still active as a clinician and member of numerous oncology boards and editorial committees, as well as editor-in-Chief of Cancer Control: Journal of the Moffitt Cancer Center.

oe VOL. 15, NO. 1, February 2016 11

the pharmacokinetics and pharmacodynamics of cancer chemotherapy drugs. The volume of distribution of hydro-soluble drugs, individual hepatic drug metabolism, and the reduced renal excretion of medications associated with the predictable degree of glomerular filtration rate (GFR) all represent significant age-related variables.1,2 There is evi-dence for both reduced drug effectiveness in the elderly and possibly increased chemotherapy complications, includ-ing heightened bone marrow suppression, an increase in peripheral and central neuropathy, heightened incidence of mucositis, as well as greater long-term risk for cardiac and bone marrow toxicity (e.g. myelodysplastic syndrome and treatment-induced acute myeloid leukemia).1,2,3 While some of these toxicities may be avoided or minimized by mea-sures such as the selection of particular chemotherapeutic agents, appropriate dosage adjustments for renal excretion, judicious use of hematopoietic growth factors, and close attention to anemia management, advanced age remains associated with increased risk of both short-term and long-term chemotherapy complications.1,2,4 While targeted thera-pies have generally appeared to be safer and gentler than traditional cytotoxic therapy, they may also be responsible for serious or even lethal complications in the elderly.6

tooLs to Assess FItness AnD tReAtMent suItABILIty Chronologic ageWhile chronologic age is easily determined and to a certain extent is predictive of life expectancy, it does not take into account true biologic age or the presence of comorbid conditions. Accordingly, attention has increasingly focused on the other means of predicting overall health, capacity for independent living and performance (see Table 1).3,4,5

Performance statusAlthough easy to perform, traditional oncology measurements such as the Karnofsky score or Eastern Cooperative Oncology Group (ECOG) performance scale are not as effective at predicting either chemotherapy tolerance or response in the elderly.2,4,5 Neither does performance status determination always accurately predict overall life expectancy.

Comorbidity scoringComorbidity score determinations such as the Cumulative Illness Rating Scale (CIRS) have been validated in relation to predicting life expectancy in general geriatric populations.7 However, such scoring may be time-consuming to perform, and the various clinical cutoffs for individual comorbidities have generally not been validated or standardized (see Table 1).4,5

frailty assessmentFrailty implies possibly limited life expectancy and near-exhausted functional reserves. Several simplified geriatric assessments with self-reporting questionnaires are available to assess for frailty, allowing quick and simultaneous assessment of multiple domains. However, most reported studies of frailty assessment have been retrospective, and significant hetero-geneities are evident in the patient populations studied.4,5,7

Comprehensive Geriatric assessmentThe Comprehensive Geriatric Assessment (CGA) is increas-ingly recognized as the Cadillac of overall fitness assessment methodologies and is significantly more inclusive than any

Table 1. Tools/methods available for assessing fitness and treatment suitability in the elderly

Tool/Methodology advantages Disadvantages

Chronologic age May predict life expectancyMay anticipate treatment toxicity

Significant heterogeneityMay not reflect biologic age

Performance status Fast, easy, reproducibleMay predict treatment toxicity

Does not predict life expectancyNot sufficiently inclusive

Comorbidity score May predict life expectancy May predict treatment toxicity

Significant difference in scoring methodologies Comorbidity cutoffs not validated

Frailty screening May predict life expectancy and treatment toxicitySimpler than the CGA

Largely not prospectively validatedMay depend on self-assessment

Comprehensive Geriatric Assessment Most thorough assessment availableHas been prospectively studied

Time-consuming and resource intensiveInterpretation may be complex

CGA=Comprehensive Geriatric Assessment.

Table 2. Comprehensive Geriatric assessment: domains and testing

Domain Tests

Functional status ADL, IADLPerformance statusFalls: Timed Up and Go test (TUG)

Comorbidities CIRS, OARS

Socioeconomic Issues Social support, income, housing, transport

Cognitive function Dementia: MMSE, MoCADepression: Geriatric Depression Scale, HADS

Nutritional status Mini nutritional assessment, BMI, weight loss

Polypharmacy Medication reconciliation, drug interactions

Geriatric syndromes Delirium, incontinence, neglect, FTT, pressure ulcers, osteoporosis, fractures

ADL=Activities of Daily Living; IADL=Instrumental Activities of Daily Living; CIRS=Cumulative Illness Rating Scale; OARS=Older American Resources and Service; MMSE=Mini Mental State Examination; MoCA=Montreal Cognitive Assessment; HADS=Hospital Anxiety and Depression Scale; BMI=Body Mass Index; FTT=Failure to thrive.

feature

12 oe VOL. 15, NO. 1, February 2016

feature

of the tools mentioned above.8,9 Typical components of the CGA are summarized in Table 2. Besides performance status elements (documented as functional status) and comorbidities, the CGA also includes socioeconomic factors, cognitive function, nutritional status, polypharmacy and geriatric syndromes. Functional status is usually quantified using 2 common geriatric scales: activities of daily living (ADL), meaning those activities required to maintain independence in the home, and instrumental activities of daily living (IADL), referring to activities needed to maintain indepen-dence in the community.2

Although the standard CGA determination may be both time- and resource-intensive, this process can be fine-tuned to an individual oncology practice in order to meet specific needs as well as accommodate time constraints.9 Simpler tools have been created (the Groningen Frailty Index, the Vulnerable Elders Survey-13, the Timed Up and Go, etc.) for the purpose of quickly screening older patients with cancer for frailty.3,7,9 In followup, a more comprehensive CGA can be undertaken if one of the screening tools points to potential problems.7 In one evaluation of the utility of CGA involv-ing 161 elderly patients receiving first-line cancer therapy in an outpatient setting, 49% had a treatment change based on CGA results. Thirty-four received a less-intensive treatment regimen, while 45 were given more-intensive treatments after the assessment.5

QuALIty oF LIFeLoss of independence is perhaps the most feared complication of aging. Accordingly, preservation of functional indepen-dence should be given the same priority as prolongation of survival and symptom control in the management of elderly cancer patients.3 There is much debate around quality-of-life issues in the older patient with cancer. For instance, is an individual patient better off enjoying his or her remaining life, or is the aim to increase life expectancy despite the threat of morbidity and mortality that may accompany curative or palliative cancer chemotherapy?10

Such choices are often easier with potentially curative therapy, but there is always the risk of trading “quantity”

for “quality” of life.3,11 Interestingly, studies have shown that older people are not more likely to refuse cancer treatment than younger individuals. Another recent investigation found that individuals over 65 were less likely than 55- to 65-year-olds to question decisions regarding which therapies might be best for them.10 It has also been shown that anxiety and depression are possibly less prevalent in older patients, pre-sumably because this group is more likely to have confront-ed their own individual mortality.1,10

InFoRMeD DeCIsIon-MAkIngHistorically, a paternalistic approach was taken in deciding the management of older oncology patients. Indeed, many patients feel overwhelmed by the cancer diagnosis, and thus put their trust in whatever their physician decides.3,5 A more modern approach uses the CGA to come to an objective understanding of an individual patient’s functional age in order to personalize care. By evaluating the key domains predictive of morbidity and mortality risk, this type of assess-ment can also help predict risk for chemotherapy toxicity.5,8 Other tools are available to facilitate prediction of likely remaining life expectancy based on current age and CGA dimensions (see Table 3).11 The multidisciplinary oncology team’s unique knowledge of the natural history of the par-ticular tumour is also invaluable. Recent studies suggest that when all of these pertinent variables are assembled during an individual patient conference, older cancer patients are not necessarily more likely to refuse cancer treatment than their younger counterparts.10 In addition, while all age groups are concerned about cancer treatment side effects, it appears that elderly individuals may actually be less likely to conclude that treatment might be worse than the disease itself.10,12

In the end, the decision regarding therapy for advanced cancer represents a balance between the potential benefits and likelihood of adverse effects. An experienced multidisciplinary oncology team can contribute valuable information about anticipated disease-free survival and the natural history of

Table 3. Canadian statistics of projected remaining years of life based on sex, current age and smoking status

Female Male

age Smoker Nonsmoker Smoker Nonsmoker

65 19 21 15 18

70 16 17 12 15

75 13 14 10 12

80 10 11 8 10

85 7 7 5 6

90 4 4 3 4

95 2 2 2 2

FiGure 1. individualized decision treatment model for the elderly

GFI=Groningen Frailty Index; TUG=Timed Up and Go test; VES-13=Vulnerable Elders Survey 13.

Individual elderly patient with cancer

Frailty assessment (Comprehensive geriatric assessment, GFI, VES-13, TUG)

Quality-of-life considerations/assessment

Appropriate patient participation in shared decision-making based on CGA results and assessment of life expectancy versus tumour-specific survival

Specific recommendations/decisions based on all factors

Finalized individual cancer treatment plan

oe VOL. 15, NO. 1, February 2016 13

the individual tumour. Use of a chemotherapy risk assessment scale for elderly patients can further help discussions with patients and their families.13 A final decision regarding the treatment of cancer in an individual elderly patient represents a complex process, which is summarized in Figure 1.

DeveLoPIng A FoLLowuP PRotoCoL Post DeFInItIve CAnCeR theRAPy A number of generalizations in relation to cancer followup are apparent and may be summarized as follows:12,14,15,16,17

• For most solid tumours, post-treatment surveillance

Table 4: Followup protocol for elderly cancer patients post definitive therapy

Tumour type rationale (providing the patient may consider surgery, chemotherapy or radiation therapy)

Possible followup schedules

Breast • Clinical outcome with recurrent disease may be better when patients are relatively asymptomatic; but no meta-analysis data suggests that intensive surveillance strategies improve outcomes or survival

• Some studies have shown considerable psychological support from regular followup

• Survival benefit has been documented from the detection of new primaries in the contralateral breast

• Appropriate patient education to report any signs suggestive of recurrence

• History and physical every 4 to 6 months for a minimum of 3 to 5 years

• Mammography annually

• Baseline and periodic monitoring of bone density if on aromatase inhibitor therapy

• No evidence to support routine imaging or laboratory testing

Lung • True local recurrence in non-small cell lung cancer occurs in 10% to 20%; only 1% to 4% are amenable to re-surgery, with a survival of <10 %

• Metachronous tumours in 1% to 3%; 50% are operable, 5% survival <20%

• No study has shown that early detection of asymptomatic recurrences post definitive therapy increases survival

• Appropriate patient education to report any signs suggestive of recurrence

• History and physical at regular intervals

• No evidence to support routine imaging or laboratory testing

Colorectal • 2007 Cochrane review of post-therapy followup showed risk reduction of 9% with overall 5-year survival benefit

• Carcinoembryonic antigen (CEA) determination had highest rate of detection of asymptomatic recurrence, followed by computerized tomography (CT) scan

• Patients with asymptomatic recurrence are more likely to be eligible for potentially curative resection

• Appropriate patient education to report any signs suggestive of recurrence

• First colonoscopy within 1 year of original followup; subsequent followup as per guidelines

• CEA every 3 months for 3 to 5 years

• Annual CT of chest, abdomen and pelvis for 3 years

Prostate • Retrospective data support increased survival with salvage therapies initiated at first prostate-specific antigen (PSA) relapse

• Regular followup visits have been documented to improve impotence, incontinence and quality of life

• Appropriate patient education to report any signs suggestive of recurrence

• PSA every 6 to 12 months for minimum 5 years, plus or minus digital rectal exam

Lymphoma • Prospective data largely lacking, but for diffuse large cell lymphoma and Hodgkin’s disease, early treatment of asymptomatic relapse may be curative

• Most recurrences are detected by patients between regularly scheduled appointments

• Appropriate patient education to report any signs suggestive of recurrence

• History and physical at regular intervals

• If earlier chest or axillary radiation, appropriate breast screening and annual thyroid-stimulating hormone (TSH)

• No evidence to support routine imaging or laboratory testing

Generic template

• Many solid tumours (80% to 90%) recur within the first 2 to 3 years after definitive therapy

• Most recurrences are detected by patients between regularly scheduled appointments

• The vast majority of solid tumours are incurable at the time of metastatic presentation

• Generalists can perform post-treatment followup with equal success and acceptance to specialists

• Appropriate patient education to report any signs suggestive of recurrence

• Physical examination every 3 to 6 months for a minimum of 3 years

• No evidence to support routine imaging or laboratory testing

strategies have evolved haphazardly, largely without the benefit of randomized clinical trials.

• Although insurance companies typically take 5 years without relapse as cure, the majority of solid tumours (80% to 90%) that recur will do so within 2 or 3 years of definitive therapy.

• 70% to 90% of cancer recurrences are discovered by patients themselves between regularly scheduled followup visits.

• The vast majority of solid tumours are incurable at the time of metastatic presentation.

• For many solid tumours, there is little evidence that

feature

14 oe VOL. 15, NO. 1, February 2016

feature

FiGure 2. individualized decision followup model for the elderlycommencing treatment in the early asymptomatic state of recurrence, as opposed to initiating treatment at the time of symptomatic recurrence, prolongs survival or otherwise improves clinical outcome.

• Some investigations (notably randomized trial evidence in ovarian cancer) have documented adverse psychologic effects with the performance of routine diagnostic testing for potential detection of recurrence.

• Recent studies have suggested that generalists, including nurse practitioners, can perform post-treatment followup with equal success and patient acceptance when compared to specialists.

Despite the somewhat daunting realities stated above, it is still possible to make the case in certain tumour types for a defined followup protocol based on evidence, patient factors and the natural history of these diseases (see Table 4).12,15,16,17 Taking the generalizations above into account, it would seem reasonable to attempt to formulate an individualized followup algorithm for elderly patients post definitive can-cer therapy utilizing the same considerations involved with developing appropriate treatment plans (see Figure 2). A logical starting point would be the individual patient’s pro-jected cancer-free survival based on age and comorbidities, coupled with the natural history of the particular cancer. This information should lead to a decision as to whether a tailored followup program might be better than a simple wait-and-see approach. Clearly, to benefit from a tailored followup program, the patient’s hypothetical survival should probably not be shorter than the likely tumour recurrence timeframe.

For patients satisfying the above criteria, next steps would involve obtaining an up-to-date CGA, considering quality-of-life factors, and undertaking a comprehensive team-based shared decisionmaking process. Some elderly individuals may, at this point, decide against followup altogether. However, for those who are willing and are likely to benefit, either one of the literature-based tumour-site-specific proposed followup schedules, or in the case of cancer sites for which these are not available, a generic template can be employed.

ConCLusIonsThe comprehensive management of cancer in older individ-uals represents an increasingly common problem. In this population, evidence-based studies and randomized investi-gations are virtually nonexistent. While there is some literature relating to the rational formulation of individualized cancer treatment programs for the elderly, almost nothing has been published in relation to followup post definitive cancer therapy. Based on age-related survival data, the natural history of individual cancers, the CGA assessment, quality-of-life and shared decision-making, the general clinical algorithm proposed in this article may help to provide an appropriate followup framework for these patients.

References1. Brigden ML. Cancer therapy in the elderly - some practical considerations.

BC Med Jour 1999;41:436-42.2. Carreca I, Balducci Ll. Cancer chemotherapy in the older cancer patient. Urologic

Oncology: Seminars and Original Investigations 2009;27:633-42.3. Swaminathan V, Audisio RA . Ecancer 6: 243 / DOI: 10.3332/ecancer.2012.243 4. Hurria A, Siccion EP. Assessing the ‘fit’ older patient for chemotherapy. Oncology

(Williston Park, N.Y.) 2014;28:594,596,598-9.5. Klepin HD, Rodin M, Hurria A. Treating older adults with cancer: geriatric

perspectives. Am Soc Clin Oncol Educ Book 2015;35:e544-52. 6. Agostara B1, Carruba G, Usset A. The management of cancer in the elderly:

targeted therapies in oncology. Immun Ageing 2008;30:5-16.7. Parmelee PA, Thuras PD, Katz IR, et al. Validation of the Cumulative Illness Rating

Scale in a geriatric residential population. J Am Geriatr Soc 1995;43:130-7.8. Caillet P, Canoui-Poitrine F, Vouriot J et al. Comprehensive geriatric assessment

in the decision-making process in elderly patients with cancer: ELCAPA study. J Clin Oncol 2011;29:3636-42.

9. Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol 2015;26:288-300.

10. Bagcchi S. Older people not likely to refuse cancer treatment. Published Online: 27 August 2015 DOl: http://dx.doi.org/ 10.1016/Sl470-2045(15)00273-9.

11. Standard Life Mortality Table accessed at https://advisors.standardlife.ca/en/pdf/reference/4984.pdf.

12. Rose PW , Watson E . What is the value of routine follow-up after diagnosis and treatment of cancer? Br J Gen Pract 2009;59:482-3.

13. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 2012;118:3377-86.

14. Brigden ML. Evidence-based follow-up testing of treated cancer patients - What does the literature support? Annals RCPSC 1999;32:281-90.

15. Shah M, Denlinger CS. Optimal post-treatment surveillance in cancer survivors: is more really better? Oncology (Williston Park, N.Y.) 2015; 29:230-40.

16. Furman MJ, Lambert LA, Sullivan ME, et al. Rational follow-up after curative cancer resection. J Clin Oncol 2013;31:1130-3.

17. Wilbur J. Surveillance of the adult cancer survivor. Am Fam Physician 2015;91:29-36.

Historic projected survival based on age and

comorbidities

Natural history of individual patient’s

cancer

Older patient post definitive cancer therapy

Appropriate individual followup plan

Up-to-date comprehensive geriatric assessment

Individual quality-of-life considerations

Patient shared decision-making process

Tumour type specific Generic