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Health problems in childhood cancer survivors: Linkage studies and guideline development

Font-Gonzalez, A.

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Citation for published version (APA):Font-Gonzalez, A. (2016). Health problems in childhood cancer survivors: Linkage studies and guidelinedevelopment.

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Download date: 07 Nov 2020

CHAPTER 7

Guideline Development for Fertility Preservation in Children, Adolescents and Young Adults with Cancer Within the PanCareLIFE Project:

The Methods

Anna Font-Gonzalez, Renée L. Mulder, Erik A.H. Loeffen, Julianne Byrne, Eline van Dulmen-den Broeder, Marry M. van den Heuvel-Eibrink, Melissa M. Hudson, Lisa B. Kenney, Jennifer M. Levine, Karen C. Burns, Jill P. Ginsberg, Julia Inthorn, Jacqueline J. Loonen, Armando Lorenzo, Norbert W. Paul, Gwendolyn P. Quinn, Hanneke M. van Santen, Leontien C.M. Kremer, Wim J.E. Tissing*, Marianne D. van de Wetering*, on behalf of the PanCareLIFE Consortium* Shared last authorship

Manuscript in preparation

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Abstract

Current guidelines for fertility preservation in children, adolescent and young adults (CAYAs) with cancer vary considerably. As evidence-based clinical practice guidelines (CPGs) are essential for uniform and quality care, we have initiated as part of an international European-funded project (PanCareLIFE) the aim to generate harmonized, comprehensive and transparent CPGs for fertility preservation in CAYAs facing potential gonadotoxic therapy. An important aspect of this CPG development within PanCareLIFE is the international collaboration between disciplines involved in the care of CAYAs with cancer.

Herein we describe the key methodological steps for the proposed CPGs, which are adherent to the evidence-based methods of the International Guideline Harmoni-zation Group. As part of the preparatory phase, we convened multidisciplinary panels of international experts resulting in a total of 70 members. In the development phase we have: 1) identified existing CPGs, evaluated their quality and differences in the recommendations; 2) developed clinical questions; and 3) identified available evidence by systematic literature review. We are currently summarizing and appraising the evidence and we will formulate recommendations in the coming year. The final phase will include implementation of the recommendations.

International collaboration and transparent, comprehensive CPGs are essential for optimal and uniform care. CPGs for fertility preservation developed within PanCareLIFE will provide a framework for healthcare professionals caring for CAYAs at risk of fertility impairment.

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Introduction

A significant proportion of children, adolescents and young adults (CAYAs) diagnosed with cancer are at elevated risk for fertility impairment if treatment includes chemotherapy, radiotherapy and/or surgery that adversely impacts reproductive organ function.1-4 CAYA survivors highly value the ability to lead a full reproductive life.5,6 Unfortunately, research supports that patients perceive that they are not adequately counseled about the adverse effects of cancer treatment on reproductive function and options for fertility preservation, and even fewer are referred to specialists for fertility preservation. These deficits lead to disparities in attitudes and practices of fertility preservation.7,8

Our research group has recently shown that recommendations for fertility preservation in CAYAs with cancer vary extensively across existing guidelines and that the guidelines that exist are not always produced with high quality methodology or evidence.9 CAYAs and their health care providers need guidance that provides accurate information regarding treatment-related risks in relation to fertility, including the unique ethical issues that surround fertility preservation and optimal discussion of appropriate methods of communicating fertility options to patients and their families. Clinical practice guidelines (CPGs) promote effective care, communication and collaboration between healthcare providers as well as between healthcare providers and patients. Additionally, CPGs are powerful tools to achieve uniform and high quality care, and can result in a reduction of costs.10,11 A transparent approach in the development of CPGs can benefit both guideline developers and their targeted audiences.12

As part of an international European-funded collaborative research project (PanCareLIFE), in this article we present an overview of the methodology we are using to generate robust, comprehensive and easy-to-use CPGs for fertility preservation in male and female CAYAs diagnosed with cancer.

Clinical practice guidelines within PanCareLIFE

PanCareLIFE, a five years (2013-8) EU Framework 7 Programme in the Health Theme, is one of the large consortia that originated in PanCare (the Pan European Network for Care of Survivors after Childhood and Adolescent Cancers, www.pancare.eu) in order to study chronic health problems after childhood cancer.13 One of the aims of PanCareLIFE is to produce a comprehensive and cohesive set of CPGs for fertility preservation for CAYAs with cancer. Taking into account the complexity of different international healthcare systems, PanCareLIFE will facilitate dissemination of recommendations to appropriate audiences including healthcare providers, survivors and their families.13

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Overall, PanCareLIFE studies the impact of treatment regimes on the long-term health of childhood cancer survivors. The overall aspiration of PanCareLIFE is that survivors of cancer diagnosed before age 25 enjoy the same quality of life and opportunities as their peers who have not had cancer.13,14 PanCareLIFE will also investigate long-term chronic health problems experienced by childhood cancer survivors and their impact on health-related quality of life. Ongoing initiatives involve investigators from 8 European countries who will contribute over 12000 well-characterized research subjects to identify, in observational studies and molecular genetic investigations, genetic and non-genetic risk factors associated to fertility impairment and ototoxicity.

Scope of the guidelines

The CPGs for fertility preservation in CAYAs with cancer within PanCareLIFE will focus on male and female patients diagnosed with cancer up to 25 years old with fertility preservation care. Ten key issues will be addressed in the guideline by four working groups (Table 1).

The first group will focus on risk assessment for fertility preservation in CAYA patients with cancer by considering the following key issues: a) ‘Who should be informed about fertility risk in general?’, b) ‘Who should be referred to a fertility expert to receive fertility preservation (based on individual risk)?’ and c) ‘When should patients be informed about treatment-related fertility risks and options for fertility preservation?’.

The second group will concentrate on fertility preservation methods by addressing a) ‘What fertility preservation method could be used?’, b) ‘When should fertility preservation be initiated?’ and c) ‘What are the logistical aspects in fertility preservation?’.

The third group will focus on topics related to the discussion of fertility preservation, namely a) ‘Who should be involved in the discussion about treatment-related fertility risks and fertility preservation?’, b) ‘Which topics should be included in the discussion on treatment-related fertility risks and fertility preservation?’ and c) ‘What strategies can be used to help overcome barriers (social, legal, ethical, financial, religious, access) to discussing fertility and to support clinicians in having these discussions?’.

The fourth group will consider ethical and legal aspects related to fertility preservation in CAYAs with cancer. Previous CPGs in fertility preservation have not consistently addressed the ethical and legal issues associated with fertility preservation in CAYAs with cancer with a systematic search of the literature.9 The unique aspects of fertility preservation in cancer patients will be considered in this guideline development as a cross-sectional task in all groups. Special issues such as the use

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of investigational fertility preservation methods, posthumous use of cryopreserved tissue, and capacity for decision making in minors will be specifically addressed.15,16

Organization of guideline activities

The guideline development project of PanCareLIFE is directed by a core leadership group of 14 individuals that includes pediatric oncologists, guideline methodologists and epidemiologists. The female and male fertility preservation expert panels are each chaired by two members and a third member serves as a coordinator of group activities. The female and male expert panels, organized into four groups with each assigned a category as outlined above and led by a working group lead, are comprised of 24 and 35 multidisciplinary international experts, respectively. Expert panels represent expertise in pediatric oncology/hematology, gynecology, endocrinology, radiation oncology, reproductive medicine, embryology, psychology, nursing, urology, epidemiology and ethics. Similarly, these experts represent various geographic regions including the countries of Australia, Belgium, Canada, Czech Republic, France, Germany, Italy, The Netherlands, New Zealand, Sweden, Switzerland, Turkey, United Kingdom and United States. Panel experts are representatives of existing guidelines in fertility preservation for CAYAs with cancer published by the Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG),17 Scottish Intercollegiate Guidelines Network (SIGN),18 Fernbach et al 2014,19 American Society of Clinical Oncology (ASCO)20 and the Clinical Oncology Society of Australia (COSA).21

Finally, nine members in total act as advisors for the male and female expert panels. Of these, one member is representative of the PanCareLIFE management team and four others are representatives from the International Guideline Harmonization Group (IGHG) fertility surveillance CPGs.22-24

Guideline development methods

The current guideline development project for fertility preservation within PanCareLIFE uses as a framework the evidence-based methodology that the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) developed to produce CPGs for surveillance of survivors of childhood cancer.25 The IGHG is an international endeavor that was founded in 2010 to establish a common vision and integrated strategy for the surveillance of chronic health problems in childhood, adolescent and young and adult cancer survivors.26 This collaborative effort has published several worldwide, harmonized, evidence-driven surveillance recommendations to decrease discordances between national groups.27,28 This methodology adheres to the Appraisal of Guidelines for Research

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and Evaluation Collaboration and the Standards for Developing Trustworthy Clinical Practice Guidelines of the Institute of Medicine.29,30

The development phase of the current CPGs for fertility preservation in CAYAs with cancer comprises the following steps: 1) identification of existing CPGs, and evaluation of their quality and differences in recommendations; 2) development of clinical questions for each key issue; 3) identification of available evidence by systematic literature review; 4) summarization and appraisal of the evidence; and 5) formulation of recommendations. The final phase includes writing the CPG, an external review, implementation of the recommendations and a plan for updates of the recommendations. A study protocol and timeline was created by the core leadership group with a detailed description and plan for these guideline development steps. These phases are described in more detail below.

Step 1: Identification of existing CPGs and evaluation of quality and differences

The detailed methods used to search for existing CPGs relevant to fertility preservation in CAYAs with cancer have been described elsewhere;9 findings will be summarized here. After using the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II), we observed that approximately one-third of the identified CPGs were found to be of good quality as defined by AGREE II scores of above 60% in any four domains. In two-thirds of the guidelines assessed, the scores did not meet this criteria. Among the considered good quality guidelines, recommendations in fertility preservation for female and male cancer patients exhibited 87.2% and 88.6% of discordance, respectively. It is likely that the lack of available evidence and the low level of existing evidence in the field of fertility preservation for CAYA cancer patients contribute to conflicting recommendations between guidelines and omission of recommendations for certain guideline areas.9

Step 2: Formulation of clinical questions

Having evaluated the existing guidelines, the next step for the core leadership group was to formulate clinical questions based on the discordant areas observed in the high quality CPGs for fertility preservation in CAYAs with cancer. In addition, the areas of concordance that presented a debate in the literature were also used as a starting point for developing clinical questions. In order to have clinical questions that were clear, focused and closely defining the boundaries of the topic that the clinical question had to address, we followed the PICO (Participants, Interventions, Control group & Outcome) framework.31,32 Discussion amongst the experts was essential to refine the clinical questions.

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Step 3: Identification of evidence

To identify the evidence, in May 2016 we conducted systematic literature searches in PubMed in collaboration with the Cochrane Childhood Cancer Group. We used Medical Subject Headings (MeSH) and keywords to identify all potentially relevant titles and abstracts. Search terms and dates varied according to the topic. For the clinical questions of the first group relating to risk assessment for fertility preservation in CAYA patients with cancer, we updated the searches performed by the surveillance male (1994-2014) and female (1993-2014) fertility IGHG CPGs.23,24

For working group 3 (discussion of fertility preservation) and working group 4 (ethical and legal aspects), we performed the same systematic search in PubMed for the female and male groups.

The systematic search for working group 4 was performed as a general systematic literature search in PubMed, Web of Science and ethical databases (Livivo and Belit) to identify all currently discussed ethical issues related to fertility preservation and cancer.

The systematic search in PubMed for the female group yielded 1641 records and 2108 records for the working groups 1 (risk assessment) and 2 (fertility preservation methods) respectively, and for the male group it yielded 2465 records and 366 records for the working group 1 (risk assessment) and 2 (fertility preservation methods) respectively. We performed the same systematic search in Pubmed for the female and male groups for working group 3 (discussion of fertility preservation) which resulted in 115 records. The systematic search for working group 4 (ethical and legal aspects) in Pubmed, Web of Science and ethical databases resulted in 519 records.

Two independent reviewers selected the articles on the basis of the title and abstract using the inclusion criteria defined for each clinical question. If the abstract was unavailable or it provided insufficient information, we retrieved the full text article for more detailed examination. Discordances between reviewers on inclusion/exclusion were resolved by consensus or if this was not possible, by consulting a third reviewer. Finally, all selected records were assessed in full text by the two independent reviewers to ensure eligibility. Furthermore, we used manual cross-referencing to identify additional references and working group members were invited to suggest additional relevant papers that were missed in the search.

The workload of the first reviewer was shared by dividing the records between the working group leads and members to perform abstract screening. For this, we devised a personalized electronic form with the allocated number of abstracts per individual.

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Step 4: Summary and grading of the evidence

To summarize the evidence we will create evidence summaries for each clinical question. We will draw general conclusions of each clinical question by combining the individual conclusions of the studies. If we lack evidence specifically aimed at the CAYA population, we will carefully extrapolate evidence from relevant studies that do not meet the eligibility criteria of the search. The level of evidence for the overall conclusion will be graded based on published evidence-based medicine methods.26,33-35 The quality of the evidence will be graded according to three categories: Level A (consistent with high level of evidence); level B (consistent with moderate to low level of evidence) and level C (consistent with very low level of evidence) (Table 2).

Step 5: Formulation and grading of recommendations

The panels of experts will discuss the evidence and formulate recommendations taking into account the scientific knowledge gained from the literature searches as well as clinical judgements, decisions about harms and benefits of the interventions, costs and the potential application to healthcare systems in different countries. To facilitate implementation, the recommendations will be categorized as strong, moderate or weak (Table 3). The final recommendations will be critically appraised by external reviewers in the field and four patient representatives from Europe and the United States. We will also set up regular updates of the recommendations every 5 years with updates of the literature search.

Dissemination and implementation of clinical practice guidelines within PanCareLIFE

Dissemination of CPGs is key to the success of their implementation.36 To facilitate dissemination of the recommendations formulated, the recommendations of the CPGs for fertility preservation in CAYAs will be summarized in a manuscript appropriate for publication in a peer-reviewed journal.

PanCareLIFE will also disseminate the recommendations of the CPGs for fertility preservation in CAYAs with cancer by closely collaborating with PanCareSurFup,37 the European Network for Cancer Research in Children and Adolescents, the Multinational Association of Supportive Care in Cancer, SIOP (International Organisation for Paediatric Oncology), and the International Confederation of Childhood Cancer Parent Organizations. To avoid unnecessary duplication, we will have close contact with organizations who have previously conducted CPGs for CAYAs with cancer.

While resources will be taken into account by the experts when formulating

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the final recommendations, we will liaise with the Pediatric Oncology in Developing Countries (PODC) working group at SIOP that aims to develop pediatric oncology in countries with low levels of access to care and/or low standards of care. Together with PODC, our recommendations can be tailored to countries with limited resources and also adapted to different priorities due to cultural or financial reasons.

So far, we have already established a link with the iPOG Network (International Pediatric Oncology Guideline in Supportive Care Network) (www.sickkids.ca/Research/iPOG). This organization which aims to facilitate the creation of high quality CPGs relevant to the supportive care of children with cancer can thus be a platform for future dissemination and implementation of the PanCareLIFE CPGs for fertility preservation.

Conclusion

With the increase in survival amongst CAYAs in recent decades, fertility preservation has become of major importance amongst CAYAs diagnosed with cancer. Current recommendations for fertility preservation in CAYAs are not uniform and of consistently high quality, potentially leading to suboptimal quality of care in this patient group.

Well-developed, transparent and harmonized CPGs are essential to improve the quality of care and can, as a result, potentially enhance the quality of life of CAYA patients with cancer. In this paper we have described the CPGs development for fertility preservation in CAYAs with cancer as part of the EU-funded PanCareLIFE project. The current CPG project uses evidence-based methods previously developed by the IGHG to produce international evidence-based CPGs for fertility preservation.

An important aspect of the current CPG development initiative in PanCareLIFE is international collaboration among different disciplines caring for CAYAs with cancer to comprehensively address issues related to fertility preservation, including ethical and legal aspects, at an early stage of our guideline development process. With our transparent guideline methodology, we aim to increase the reliability and trustworthiness of the CPGs for fertility preservation that we develop. Finally, the rigorous scientific methods we describe in this paper are intended to produce CPGs that will provide a framework for healthcare professionals caring for CAYAs at risk of fertility impairment.

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2. Kenney LB, Cohen LE, Shnorhavorian M, et al. Male Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: A Report From the Children’s Oncology Group. J Clin Oncol. 2012;30:3408-3416.

3. van Dorp W, van Beek RD, Laven JSE, et al. Long-term endocrine side effects of childhood Hodgkin’s lymphoma treatment: a review. Hum Reprod Update. 2012;18:12-28.

4. van Casteren NJ, van der Linden GHM, Hakvoort-Cammel FGAJ, et al. Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood Cancer. 2009;52:108-112.

5. Stein DM, Victorson DE, Choy JT, et al. Fertility Preservation Preferences and Perspectives Among Adult Male Survivors of Pediatric Cancer and Their Parents. J Adolesc Young Adul Oncol. 2014;3:75-82.

6. Zebrack BJ, Casillas J, Nohr L, et al. Fertility issues for young adult survivors of childhood cancer. Psycho-Oncology. 2004;13:689-699.

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8. Köhler TS, Kondapalli LA, Shah A, et al. Results from the survey for preservation of adolescent reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer. J Assist Reprod Genet. 2011;28:269-277.

9. Font-Gonzalez A, Mulder RL, Loeffen EAH, et al. Fertility preservation in children, adolescents, and young adults with cancer: Quality of clinical practice guidelines and variations in recommendations. Cancer. 2016;122(14):2216-2223.

10. Bero LA, Grilli R, Grimshaw JM, et al. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. BMJ. 1998;317:465-468.

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12. Atkins D, Eccles M, Flottorp S, et al. Systems for grading the quality of evidence and the strength of recommendations I: Critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv Res. 2004;4:38-38.

13. PanCareLIFE. http://www.pancarelife.eu/. Accessed 26 July 2016.

14. Winther JF, Kenborg L, Byrne J, et al. Childhood cancer survivor cohorts in Europe. Acta Oncologica. 2015;54(5):655-668.

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15. Cohen CB. Ethical issues regarding fertility preservation in adolescents and children. Pediatric Blood & Cancer. 2009;53(2):249-253.

16. Patrizio P, Caplan AL. Ethical Issues Surrounding Fertility Preservation in Cancer Patients. Clin Obstet Gynecol. 2010;53(4):717-726.

17. Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG). Richtlijn Cryopreservatie van Ovariumweefsel. Utrecht: NVOG;2007.

18. Scottish Intercollegiate Guidelines Network (SIGN). Long term follow up of survivors of childhood cancer (SIGN publication no. 132). Edinburgh: SIGN;2013.

19. Fernbach A, Lockart B, Armus CL, et al. Evidence-Based Recommendations for Fertility Preservation Options for Inclusion in Treatment Protocols for Pediatric and Adolescent Patients Diagnosed With Cancer. J Pediatr Oncol Nurs. 2014;31:211-222.

20. Loren AW, Mangu PB, Beck LN, et al. Fertility Preservation for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2013;31:2500-2510.

21. AYA cancer fertility preservation guidance working group, Clinical Oncology Society of Australia (COSA). Fertility preservation for AYAs diagnosed with cancer: Guidance for health professionals. Sydney: Cancer Council Australia;2011.

22. International Guideline Harmonization Group (IGHG). http://www.ighg.org/. Accessed 05 July 2016.

23. Skinner R, Mulder L, Kremer L, et al. Recommendations for Gonadotoxicity Surveillance in Male Childhood, Adolescent and Young Adult Cancer Survivors: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration with the PanCareSurFup Consortium. Lancet Oncol. 2016;In press.

24. Van Dorp W, Mulder RL, Kremer LCM, et al. Recommendations for premature ovarian insufficiency surveillance for female childhood, adolescent and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. J Clin Oncol. 2016;Epub ahead of print. DOI: 10.1200/JCO.2015.64.3288.

25. Mulder RL, Brown MC, Skinner R, et al on behalf of the IGHG core group and the PCSF-WP6 group. Handbook for guideline development; collaboration between International Guideline Harmonization. PanCareSurFup and Cochrane Childhood Cancer Group; 2016.

26. Kremer LCM, Mulder RL, Oeffinger KC, et al. A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: A report from the international late effects of Childhood Cancer Guideline Harmonization Group. Pediatric Blood & Cancer. 2013;60(4):543-549.

27. Mulder RL, Kremer LCM, Hudson MM, et al. Recommendations for Breast Cancer Surveillance for Female Childhood, Adolescent and Young Adult Cancer Survivors Treated with Chest Radiation: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2013;14:e621-e629.

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28. Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16:e123-e136.

29. Brouwers M KM, Browman GP, Burgers JS, et al for the AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. CMAJ. 2010;182:E839-842.

30. Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press; 2011.

31. Counsell C. Formulating Questions and Locating Primary Studies for Inclusion in Systematic Reviews. Ann Intern Med. 1997;127(5):380-387.

32. Richardson WS, Wilson MC, Nishikawa J, et al. The well-built clinical question: a key to evidence-based decisions. ACP J Club. 1995;123(3):A12-13.

33. Cochrane Childhood Cancer Group. http://ccg.cochrane.org/. Accessed 22 June 2016.

34. Grade Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490-1490.

35. Gibbons RJ, Smith S, Antman E. American College of Cardiology/American Heart Association Clinical Practice Guidelines: Part I: Where Do They Come From? Circulation. 2003;107(23):2979-2986.

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Table 1. Key issues addressed per working group.

Working groups Key issues

Working group 1: Risk assessment

a) ‘Who should be informed about fertility risk in general?’

b) ‘Who should be referred to a fertility expert to receive fertility preservation (based on individual risk)?’

c) ‘When should patients be informed about treatment-related fertility risks and options for fertility preservation?’

Working group 2: Fertility preservation methods

a) ‘What fertility preservation method could be used?’

b) ‘When should fertility preservation be initiated?’

c) ‘What are the logistical aspects in fertility preservation?’

Working group 3Discussion of fertility preservation

a) ‘Who should be involved in the discussion about treatment-related fertility risks and fertility preservation?’

b) ‘Which topics should be included in the discussion on treatment-related fertility risks and fertility preservation?

c) ‘What strategies can be used to help overcome barriers (social, legal, ethical, fi nancial, religious, access) to discussing fertility and to support clinicians in having these discussions?’

Working group 4:Ethical and legal aspects

Ethical and legal issues in fertility preservation in children, adolescents and young adults with cancer

Table 2. Criteria for grading the levels of evidence and formulation of conclusions.

Conclusions of evidence Study quality Study fi ndings for risk factors Wording in

conclusions

A High level of evidence

Evidence from well performed and high quality studies or systematic reviews (low risk of bias, direct,* consistent, precise)

If a risk factor is signifi cantly associated with the outcome in ≥95% of the studies

‘There is evidence…’

B Moderate/ Low level of evidence

Evidence from studies or systematic reviews with few important limitations

If a risk factor is signifi cantly associated with the outcome in ≥50% of the studies reporting on this risk factor, and in the remaining studies this association is not signifi cant

‘Evidence suggests…’

C Very low level of evidence

Evidence from studies with serious fl aws (high risk of bias, indirect, inconsistent, imprecise)

If a risk factor is signifi cantly associated with the outcome in 1 study

‘Some evidence suggests…’

If a risk factor is signifi cantly associated with the outcome in <50% of the studies, while in the remaining studies this association is not signifi cant

If a risk factor is signifi cantly (either positively or negatively) associated with the outcome in >50% of the studies, while the remaining studies show the opposite association of the risk factor and outcome

Confl icting evidence

NA If a risk factor is signifi cantly (both positively and negatively) associated with the outcome in the same number of studies of comparable quality

‘There is confl icting evidence…’

Other evidence NA If a study did not meet the eligibility criteria but was considered by clinical experts to provide important information on a risk factor, and inclusion of this evidence was supported by the working group. No Level A, B or C evidence, nor any contrary evidence, was identifi ed **

‘Other evidence suggests…’

No studies NA If no studies reported on a risk factor ‘No studies reported on…’

Abbreviation: NA, not applicable.* Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important

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GUIDELINE DEVELOPMENT FOR FERTILITY PRESERVATION

Table 1. Key issues addressed per working group.

Working groups Key issues

Working group 1: Risk assessment

a) ‘Who should be informed about fertility risk in general?’

b) ‘Who should be referred to a fertility expert to receive fertility preservation (based on individual risk)?’

c) ‘When should patients be informed about treatment-related fertility risks and options for fertility preservation?’

Working group 2: Fertility preservation methods

a) ‘What fertility preservation method could be used?’

b) ‘When should fertility preservation be initiated?’

c) ‘What are the logistical aspects in fertility preservation?’

Working group 3Discussion of fertility preservation

a) ‘Who should be involved in the discussion about treatment-related fertility risks and fertility preservation?’

b) ‘Which topics should be included in the discussion on treatment-related fertility risks and fertility preservation?

c) ‘What strategies can be used to help overcome barriers (social, legal, ethical, fi nancial, religious, access) to discussing fertility and to support clinicians in having these discussions?’

Working group 4:Ethical and legal aspects

Ethical and legal issues in fertility preservation in children, adolescents and young adults with cancer

Table 2. Criteria for grading the levels of evidence and formulation of conclusions.

Conclusions of evidence Study quality Study fi ndings for risk factors Wording in

conclusions

A High level of evidence

Evidence from well performed and high quality studies or systematic reviews (low risk of bias, direct,* consistent, precise)

If a risk factor is signifi cantly associated with the outcome in ≥95% of the studies

‘There is evidence…’

B Moderate/ Low level of evidence

Evidence from studies or systematic reviews with few important limitations

If a risk factor is signifi cantly associated with the outcome in ≥50% of the studies reporting on this risk factor, and in the remaining studies this association is not signifi cant

‘Evidence suggests…’

C Very low level of evidence

Evidence from studies with serious fl aws (high risk of bias, indirect, inconsistent, imprecise)

If a risk factor is signifi cantly associated with the outcome in 1 study

‘Some evidence suggests…’

If a risk factor is signifi cantly associated with the outcome in <50% of the studies, while in the remaining studies this association is not signifi cant

If a risk factor is signifi cantly (either positively or negatively) associated with the outcome in >50% of the studies, while the remaining studies show the opposite association of the risk factor and outcome

Confl icting evidence

NA If a risk factor is signifi cantly (both positively and negatively) associated with the outcome in the same number of studies of comparable quality

‘There is confl icting evidence…’

Other evidence NA If a study did not meet the eligibility criteria but was considered by clinical experts to provide important information on a risk factor, and inclusion of this evidence was supported by the working group. No Level A, B or C evidence, nor any contrary evidence, was identifi ed **

‘Other evidence suggests…’

No studies NA If no studies reported on a risk factor ‘No studies reported on…’

Abbreviation: NA, not applicable.* Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important

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to patients. Studies are indirect if there are differences in study population (our population of interest is childhood cancer survivors), interventions, or outcome measures, or if there are indirect comparisons of interventions.

** Other evidence: 1) Studies not meeting inclusion criteria regarding quality of evidence: Sample size: <20 patients; Univariable analyses; 2) Studies not meeting inclusion criteria regarding population of interest: Patients >25 years at cancer diagnosis; Outcome measured <2 years after cancer diagnosis; 3) Studies not meeting our inclusion criteria regarding outcome defi nition: Surrogate outcomes.

Table 3. Strength of the Recommendation (based on modifi ed AHA/ACC criteria).

Strong recommendation to doBenefi ts >>> risks & burdensUsing anchor terms such as ‘is recommended’, and with low degree of uncertainty

Moderate recommendation to doBenefi ts >> risks & burdensUsing anchor terms such as ‘is reasonable’, with higher degree of uncertainty

Weak recommendation to doBenefi ts >= risks & benefi tsUsing anchor terms such as ‘may be reasonable’, with high degree of uncertainty; other factors such as patient preferences, clinical scenario and costs need to be considered in the decision making process

Recommendation not to doNo benefi t / Potentially harm

Abbreviations: AHA/ACC, American Heart Association/American College of Cardiology.