Adolescent Oncofertility Discussions and Decision Making in Pediatric Oncology
A doctoral dissertation by
Dorit Barlevy
Original document stored on the publication server of the University of Basel
Adolescent Oncofertility Discussions and Decision Making in Pediatric Oncology
Inaugural dissertation to
be awarded the degree of Dr. sc. med.
presented at the Faculty of Medicine of the University of Basel
by
Dorit Barlevy
from California, USA
(Basel, 2021)
Approved by the Faculty of Medicine On application of
Dr. Vardit Ravitsky, Dr. Tenzin Wangmo, Prof. Dr. Bernice S. Elger, and Dr. Veerle Provoost (Members of PhD committee)
Basel, June 24, 2019
(Date of the acceptance of the Faculty)
Prof. Dr. Primo Leo Schär Dean
TABLE OF CONTENTS
Acknowledgements ___________________________________________________ vii
Chapter 1: Introduction ________________________________________________ 1 1.1: Adolescent cancer and fertility preservation ______________________________ 3 1.2: Why specifically study adolescent cancer? ________________________________ 6 1.3: Why specifically study adolescent oncofertility decision making in Israel and Switzerland? ____________________________________________________________ 7 1.4: Study objectives ______________________________________________________ 8 1.5: References __________________________________________________________ 9 Figure 1.1: Spectrum of attitudes and policies regarding fertility and ARTs __________ 13
Chapter 2: Methodology ______________________________________________ 15 2.1: Literature review ____________________________________________________ 17 2.2: Qualitative study of adolescent and parent oncofertility decision making ______ 18 2.2.a: Israeli participant recruitment _______________________________________ 20 2.2.b: Swiss participant recruitment ________________________________________ 20 2.3: Quantitative study of physicians’ perspectives and practices with respect to
adolescent oncofertility _______________________________________________ 21 2.4: References _________________________________________________________ 22 Appendix 2.1: Questionnaire for pediatric oncologists on adolescent oncofertility _____ 23
Chapter 3: Attitudes, beliefs, and trends regarding adolescent oncofertility
discussions: A systematic literature review ______________________ 31 3.1: Abstract ___________________________________________________________ 33 3.2: Introduction ________________________________________________________ 34
3.3: Methods ___________________________________________________________ 35 3.4: Results _____________________________________________________________ 36 3.4.a: Adolescent patients ________________________________________________ 36 3.4.a.i: Information and counseling needs _____________________________________ 36 3.4.a.ii: Causes of distress __________________________________________________ 37 3.4.a.iii: Gender differences _________________________________________________ 38 3.4.a.iv: Age differences____________________________________________________ 39 3.4.b: Parents _________________________________________________________ 40 3.4.b.i: Information and counseling needs _____________________________________ 40 3.4.b.ii: Parents’ understanding of adolescents’ needs and concerns ______________ 41 3.4.c: Healthcare professionals ___________________________________________ 41 3.4.c.i: Varying beliefs regarding oncofertility _________________________________ 41 3.4.c.ii: Variation in practice ________________________________________________ 43 3.4.c.iii: Input on how to have successful oncofertility discussions _______________ 44 3.4.c.iv: Barriers to oncofertility discussions __________________________________ 44 3.5: Discussion __________________________________________________________ 46 3.5.a: Research gaps ____________________________________________________ 48 3.5.b: Limitations ______________________________________________________ 49 3.6: Conclusion _________________________________________________________ 50 3.7: References _________________________________________________________ 51 Table 3.1: Literature search results _______________________________________ 62 Figure 3.1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) flow diagram ______________________________________ 63 Table 3.2: Included literature ___________________________________________ 64 Table 3.3: Other adolescent perspectives ___________________________________ 70
Table 3.4: Other parent perspectives ______________________________________ 71 Table 3.5: Other barriers to oncofertility discussions as reported by healthcare
professionals _______________________________________________________ 72
Chapter 4: Adolescent oncofertility discussions: Recommendations from a
systematic literature review ___________________________________ 73 4.1: Abstract ___________________________________________________________ 75 4.2: Introduction ________________________________________________________ 76 4.3: Methods ___________________________________________________________ 78 4.4: Results _____________________________________________________________ 79 4.4.a: The nature of oncofertility discussions _________________________________ 79 4.4.a.i: Initiating discussions ________________________________________________ 79 4.4.a.ii: Discussions with which patients ______________________________________ 80 4.4.a.iii: When to discuss ___________________________________________________ 80 4.4.a.iv: What to discuss ____________________________________________________ 81 4.4.a.v: How to discuss _____________________________________________________ 83 4.4.a.vi: Parental role in these discussions _____________________________________ 85 4.4.b: Systemic improvements _____________________________________________ 86 4.4.b.i: Education/training of professionals ____________________________________ 86 4.4.b.ii: Educational tools ___________________________________________________ 87 4.4.b.iii: Interdisciplinary collaboration _______________________________________ 87 4.4.b.iv: Guidelines/policies ________________________________________________ 87 4.4.b.v: Expanding insurance coverage _______________________________________ 88 4.4.b.vi: Specific improvements for sperm collection ___________________________ 88 4.4.b.vii: Advancements in female FP technology ______________________________ 89 4.5: Discussion __________________________________________________________ 89
4.5.a: Limitations ______________________________________________________ 94 4.6: References _________________________________________________________ 94 Table 4.1: Article tally for each theme ____________________________________ 108
Chapter 5: Oncofertility decision making: Findings from Israeli adolescents and parents __________________________________________________ 109 5.1: Abstract __________________________________________________________ 111 5.2: Introduction _______________________________________________________ 112 5.3: Methods __________________________________________________________ 113 5.4: Results ____________________________________________________________ 114 5.4.a: How the topic of FP arises _________________________________________ 114 5.4.b: Who decides on FP _______________________________________________ 115 5.4.c: Factors involved in FP decision _____________________________________ 116 5.4.c.i: Adolescent desire for parenthood later in life __________________________ 116 5.4.c.ii: Physician influence ________________________________________________ 117 5.4.c.iii: Various considerations ____________________________________________ 118 5.4.c.iv: Time pressure ____________________________________________________ 118 5.4.d: Justifications for FP decisions ______________________________________ 119 5.4.e: Uncertainty regarding future use of preserved biological materials _________ 120 5.4.f: Coping with fertility status post-treatment _____________________________ 121 5.5: Discussion _________________________________________________________ 122 5.5.a: Limitations _____________________________________________________ 125 5.6: Conclusion ________________________________________________________ 126 5.7: References ________________________________________________________ 127 Appendix 5.1: Adolescent interview guide _________________________________ 134 Appendix 5.2: Parent interview guide ____________________________________ 137
Table 5.1: Adolescent demographics, N = 16 _______________________________ 140 Table 5.2: Parent demographics, N = 24 ___________________________________ 141 Figure 5.1: Adolescent FP decisions, N = 20 _______________________________ 142 Table 5.3: Diagnoses, N = 20 __________________________________________ 143
Chapter 6: The meaning and importance of genetic relatedness: Fertility
preservation decision making among Israeli adolescent cancer survivors and their parents __________________________________________ 145 6.1: Abstract __________________________________________________________ 147 6.2: Introduction _______________________________________________________ 148 6.3: Methods __________________________________________________________ 149 6.4: Results ____________________________________________________________ 151 6.4.a: Genetic relatedness _______________________________________________ 151 6.4.b: Alternative parenting options _______________________________________ 155 6.4.b.i: Advantages _______________________________________________________ 156 6.4.b.ii: Disadvantages ____________________________________________________ 157 6.5: Discussion _________________________________________________________ 159 6.5.a: The importance of genetic relatedness for study participants ______________ 160 6.5.b: Views of non-genetic parenthood ____________________________________ 162 6.5.c: Contextualizing the findings – cultural background ______________________ 163 6.5.d: Contextualizing the findings – societal background ______________________ 164 6.5.e: Limitations _____________________________________________________ 164 6.6: Conclusion ________________________________________________________ 165 6.7: References ________________________________________________________ 166 Table 6.1: Adolescent responses regarding importance of genetic relatedness between
her/himself and possible future child(ren) _________________________ 171
Table 6.2: Parent responses regarding importance of genetic relatedness between their child and possible future grandchild(ren) ______________________________ 174
Chapter 7: Conclusion _______________________________________________ 177 7.1: Addressing survivors’ preoccupation with normalcy _____________________ 179 7.2: Challenging the notion of genetic parenthood as “normal” ________________ 181 7.3: (In)fertility as human variation _______________________________________ 182 7.4: Fertility as a means to parenthood _____________________________________ 183 7.5: The value of pregnancy ______________________________________________ 185 7.6: Summary _________________________________________________________ 185 7.7: References ________________________________________________________ 186
Acknowledgements
First and foremost I would like to thank the participants of the qualitative part of this study. I am so touched and honored that they shared some of their most intimate experiences and thoughts with me. While it might have been therapeutic for them to discuss these difficult experiences, all agreed to be interviewed with the generous spirit of contributing to research for the purpose of helping others that would find themselves in similar difficult situations. Not only do I appreciate their open and honest approach with me, but also the fact that they took time to share their stories with me for the ultimate goal of helping future patients and families.
I am grateful to the Botnar Foundation of the University of Basel and the Swiss Cancer League for their generous financial support of the project. The Botnar Foundation awarded me a grant to pursue many aspects of the study – namely the systematic literature review, the Israeli qualitative component, and the international quantitative component. The Swiss Cancer League’s award enabled pursuit of the Swiss qualitative component of the project.
Many thanks also go to the members of my advisory committee, whose help, insight, and patience were invaluable. I owe so much to Dr. Vardit Ravitsky, who allotted time in her busy schedule to work with me remotely and serve as my primary advisor. I am thankful for her belief in me and the project, even during its many setbacks. Dr. Tenzin Wangmo’s feedback was integral to qualitative and quantitative tool development, qualitative analysis, and manuscript development. I appreciate her continued support of me and my work. Prof. Bernice Elger, who opened the doors of her Institute to me, was magnanimous with her feedback on manuscript development and financial support at the end of the study. And thank you to Dr.
Veerle Provoost, serving as my external advisor, for providing me with recommendations on literature regarding qualitative methodology.
Completion of the project would not have been possible without the assistance and collaboration of specific Swiss and Israeli physicians as well as professional bodies. I wish to
express my gratitude to Dr. Tamara Diesch, Prof. Thomas Kühne, and Prof. Nicolas von der Weid of the Universitaets-Kinderspital beider Basel, Dr. Fabienne Gumy-Pause of Hôpitaux Universitaires de Genève, and Dr. Maja Beck-Popovic of Centre Hospitalier Universitaire Vaudois for their assistance in identifying and inviting potential participants for interviews in Switzerland. Additionally, thanks go to the Swiss Pediatric Oncology Group (SPOG) for endorsing the project and disseminating a link to the online questionnaire. I sincerely appreciate the assistance of and collaboration with Dr. Shifra Ash of Schneider Children’s Medical Center of Israel, who believed in the importance of the study and recruited her department to identify and invite potential participants for interviews in Israel. As the head of the Israeli Society for Pediatric Hematologists and Oncologists, she also assisted in disseminating a link to the online questionnaire to physician members.
I am indebted to Olivier Christe, for his work in interviewing Swiss participants, as well as transcribing and translating those interviews into English. Thank you to Alon Steinhorn for his careful work in checking the English translation of all Hebrew recorded interviews.
My appreciation extends also to my dear friend, Sarah Werren, and former colleagues, David T. Wasserman and Eloise Gennet, for their thoughtful and constructive feedback on select parts of this dissertation.
Last, but certainly not least, I would like to thank a few members of my family. First, I thank my lovely cousin, Ido Kalir, for his generosity in hosting me during my stays in Israel to conduct qualitative research and share my findings at conferences. I thank my father, Rami Barlevy, for his ongoing encouragement of me throughout this project and my entire life. And finally, I am immensely grateful to my partner, Christian Winger, for his patience, support, and love for me, especially during the latter and more trying stages of the project.
Chapter 1
Introduction
1.1 ADOLESCENT CANCER AND FERTILITY PRESERVATION
In 2014, in the United States there was an estimated 10,450 new cases of cancer among children (those from birth to 14 years of age) and an additional 5,330 new cases of cancer among adolescents (those aged 15 to 19 years) (Ward, DeSantis et al. 2014). Since 1975, the incidence rate of pediatric cancer in the United States has increased at an annual rate of 0.6%, possibly due to environmental factors and/or improved diagnosis and access to medical care (Ward, DeSantis et al. 2014). Despite this slight increase in incidence, pediatric cancer has become a success story of modern medicine whereby advances in therapeutics have led to dramatic increases in overall survival rates: from 58% during the mid-1970s to 83% during 2006-2012 for children and from 68% to 84% for adolescents (Siegel, Miller et al. 2017).1 Approximately one of every 750 individuals in the United States is a survivor of childhood or adolescent cancer (Robison and Hudson 2014).
Although long term survival is a guiding goal in the care for cancer patients, increasing survival means that physicians must also care for quality of life concerns during survivorship (Institute of Medicine and National Research Council 2003). A salient quality of life concern for cancer survivors of reproductive age is family building, especially considering that cancer and/or its treatment may negatively impact fertility, depending on various factors such as type of cancer, type and amount of chemotherapy or radiotherapy, as well as the age and gender of the patient (Goodwin, Elizabeth Oosterhuis et al. 2007, Vadaparampil, Quinn et al. 2008).
Cancer survivors may suffer long-term distress over their diminished fertility or infertility if they were treated for their cancer prior to having had a chance to start or complete their own families (Schover 2009). Studies also indicate that young survivors fear being rejected by romantic partners on account of their diminished fertility or infertility (Nieman, Kinahan et al.
2007, Schover 2009).
1 Survival rates vary substantially by cancer type and age at diagnosis.
In response, strides have been made to preserve patients’ fertility prior to cancer treatment. For males at risk of infertility, an established fertility preservation (FP) option is sperm cryopreservation, while for females, established options include oocyte cryopreservation2 and oophoropexy3 (Ethics Committee of the American Society for Reproductive Medicine 2018). Gonadal shielding and embryo cryopreservation are also established methods of FP for both genders, however adolescents rarely have a specific partner or donor for employment of the latter method (Ethics Committee of the American Society for Reproductive Medicine 2018). Undergoing sperm cryopreservation usually results in a 24 to 72 hour-delay of cancer treatment, as compared to probable treatment delay of 2 to 6 weeks when pursuing oocyte cryopreservation. An experimental option for prepubescent males is testicular tissue cryopreservation (Ethics Committee of the American Society for Reproductive Medicine 2018). Delay in cancer treatment as a result of pursuing this FP option is equivalent to that of sperm cryopreservation. Ovarian tissue cryopreservation is an experimental option for prepubescent females (Ethics Committee of the American Society for Reproductive Medicine 2018). Pursuit of this FP option results in a delay in cancer treatment that is roughly equivalent to that due to pursuing male cryopreservation options – notably significantly less time than that caused by undergoing oocyte cryopreservation.
In their 2018 committee opinion, the American Society for Reproductive Medicine (ASRM) recommends that all individuals of reproductive age be offered established FP options prior to cancer treatment. Recommendations extend to include offering experimental procedures only in research settings with proper ethical oversight. In cases of minors, ASRM suggest parents decide and act to preserve their child’s fertility with the individual child’s
2 The American Society of Reproductive Medicine’s 2013 guidelines on mature oocyte cryopreservation changed the procedure’s designation from experimental to an established method of female FP.
3 Oophoropexy is the surgical movement of the ovaries from the field of radiation.
assent. These guidelines reflect the two bioethical principles of respect for autonomy and non- maleficence (Quinn, Murphy et al. 2011).
In light of advances in reproductive assisted technologies (ARTs) (i.e. in-vitro fertilization, intracytoplasmic sperm injection, gamete or embryo donation, and surrogacy services) and other long-established family building options (i.e. fostering and adoption), efforts continue to be made to save individuals’ capabilities of having genetically-related children. To be clear, FP not only enables an individual possibly to become a parent,4 but specifically a genetically-related parent. Genetic parenthood is generally considered a good worthy of value and protection (Boivin and Pennings 2005). There is consensus within the bioethical community that children have the right not to be sterilized (Weintraub, Gross et al. 2007). Thus, children and adolescents’ fertility ought to be protected and due care must be taken to avoid impairment until they are of age to exercise their autonomy with regard to procreation (Weintraub, Gross et al. 2007, Quinn, Stearsman et al. 2012). However, it is debatable whether there is a positive right to genetic parenthood (Boivin and Pennings 2005). Faced with the need to undergo life-saving treatment, which is potentially gonadotoxic, and the multitude of options that enable individuals to become parents, it is worthwhile examining the role that interest in genetic parenthood plays in FP decision making. To date, there are no publications investigating this possible factor of FP decision making.
Thus, this study sets out to explore oncofertility5 discussions and decision making within the context of diagnosis and treatment for adolescent cancer patients in Israel and
4 Rates of live-birth/ongoing pregnancy with frozen oocytes are comparable to that with fresh oocytes: 57%. [Grifo, J. A. and N. Noyes (2010). "Delivery rate using cryopreserved oocytes is comparable to conventional in vitro fertilization using fresh oocytes: potential fertility preservation for female cancer patients." Fertil Steril 93(2): 391- 396.] Pregnancy rates after intracytoplasmic sperm injection with fresh sperm (38.2% per transferred embryo) are not significantly different than with frozen sperm (26.5% per transferred embryo). [De Croo, I., J. Van der Elst, K. Everaert, P. De Sutter and M. Dhont (1998). "Fertilization, pregnancy and embryo implantation rates after ICSI with fresh or frozen-thawed testicular spermatozoa." Hum Reprod 13(7): 1893-1897.]
5 Oncofertility is understood as FP and/or the potentially gonadotoxic effects of cancer and/or its treatment.
Switzerland – two countries where such research has not been conducted before. In order for healthcare professionals to better discuss and counsel adolescent patients about oncofertility, it is important to understand their thought processes involved in making a decision about FP.
After all, adolescents who may never have had to make a serious decision about their lives must decide whether to undergo procedures that may preserve their fertility while delaying life- saving treatment (Clayman, Galvin et al. 2007). Furthermore, conducting such research in two previously unstudied contexts may lead to a greater diversity of responses, possibly reflecting contextual influences on decision making that might not be accounted for in previous studies largely situated in English-speaking countries and Western Europe.
1.2 WHY SPECIFICALLY STUDY ADOLESCENT CANCER?
Although adolescents are most often treated in pediatric wards, it is vital to note that cancers in adolescents (those between the ages of 15 and 19 years) differ somewhat from those in children (those between the ages of 1 and 14 years) in terms of type and distribution (Siegel, Miller et al. 2017). The most common cancer type in adolescents is lymphoma (21%), almost two-thirds of which is of the Hodgkin’s variety (Siegel, Miller et al. 2017). Cancers of the brain and nervous system account for 17% of cases of cancers diagnosed in this age group, followed by leukemia (14%), germ cell and gonadal tumors (12%), thyroid carcinoma (11%), and melanoma (5%) (Siegel, Miller et al. 2017).
Additionally, decision making with respect to adolescent cancer entail multiple stakeholders: the patient, parent(s), and healthcare provider(s). Previously, medical decision making was characteristically paternalistic whereby physicians would direct parents of young patients as to what course of action to take. However, medicine has shifted from a paternalistic paradigm to a consumerist one in which medical decisions are joint or shared as a result of triadic participation, thereby respecting the autonomy or developing autonomy of all participants (Knapp, Quinn et al. 2010). Adolescence is an important stage of psychosocial
development during which an individual transitions from childhood to adulthood. Although more and more jurisdictions recognize the importance of obtaining minors’ assent to medical procedures, in addition to those of their parents (Kuther 2003), adolescents’ developing capacities allow them to reflect upon and articulate their decision making processes better than younger children.
Furthermore, since FP techniques for pubertal and postpubertal adolescents are established procedures as compared to those for prepubertal children that are still considered experimental, focusing on the oncofertility decisions of adolescents is more medically relevant to the current state of medicine.
Finally, adolescents are an underrepresented and under-researched population in cancer studies (Howarth 2017). Though many times adolescent oncofertility decisions are made in consultation with their parents (Ginsberg, Ogle et al. 2008), it is imperative to understand adolescents’ unique perspectives so that they not feel alienated or lose their voice in the decision making process.
1.3 WHY SPECIFICALLY STUDY ADOLESCENT ONCOFERTILITY DECISION MAKING IN ISRAEL AND SWITZERLAND?
As noted above, the majority of studies investigating adolescent oncofertility discussions and decisions have been conducted in English-speaking countries and Western Europe. Exploring the topic in other jurisdictions has the potential to highlight patients’ culture- specific sensitivities and/or needs. To adequately assess whether such cultural differences exist, it is best for additional jurisdictions of study to have comparable rates of cancer incidence and survival with those in which the topic has been examined. Both Israel and Switzerland have comparable rates of cancer incidence and survival with the United States (Steliarova-Foucher, Stiller et al. 2004, Rabinowicz, Barchana et al. 2012).
And though Switzerland covers approximately twice as much area as Israel, both countries’ populations are roughly equivalent (OECD 2019). This fact is crucial in terms of also designing the study to be comparative between the two countries.
Moreover, studying oncofertility decision making specifically in Israel and Switzerland provides contextual variation with respect to reproductive policies. If one were to imagine a spectrum of attitudes and policies regarding fertility and ARTs, where the left end represents conservative attitudes and restrictive policies and the right indicates liberal views and permissive policies, then with the United States situated right of center, Israel would be further right of the United States, and Switzerland near the opposite end (see Figure 1.1). Although both Israel and the USA are permissive in terms of ARTs, Israel’s pronatalism6 and enthusiastic attitudes toward reproductive technologies make it an outlier (Kahn 2000, Waldman 2006). In contrast, Switzerland’s conservatism and cautious approach to new technologies classifies it as having restrictive policies (Rothmayr, Varone et al. 2003).
1.4 STUDY OBJECTIVES
The objectives of this study are three-fold: 1) assessment of all literature on adolescent oncofertility discussions, 2) qualitative investigation of adolescent and parents’ oncofertility decision making in Israel and Switzerland, and 3) quantitative investigation of Israeli and Swiss pediatric oncologists’ knowledge, attitudes, and practices with respect to adolescent oncofertility.
Considering the fact that FP is a relatively recent technological development and concern that warrants attention within the course of care for cancer patients, it is important to
6 Israel’s pronatalism is largely due to three factors: 1) religion – the Biblical imperative to be fruitful and multiple, 2) history – the desire to replenish the populations decimated in the Holocaust, and 3) demographics – the existential need for Israel to remain a Jewish democratic-state by maintaining a Jewish majority. [Kahn, S. M.
(2000). Reproducing Jews: A Cultural Account of Assisted Conception in Israel. Durham, N.C., Duke University Press.]
review and assess the current state of research. By systematically reviewing the literature focused on discussions of adolescent oncofertility, the hope is to capture the perspectives of all stakeholders in the triadic relationship and identify current research gaps. Such review will assist in the development of the study’s qualitative and quantitative tools (i.e. interview guides and questionnaires) necessary for achieving goals #2 and #3.
Few studies have previously qualitatively investigated adolescent oncofertility decision making, particularly with respect to adolescent and parent perspectives. Thus, more qualitative research should be conducted to produce a body of data which can generate hypotheses that can then be quantitatively tested. Qualitative research is especially important when conducting research in cultural contexts that have not been previously studied (e.g. Israel and Switzerland).
This type of research is ideal for in-depth exploration of individual experiences situated within a sociocultural context.
In contrast, previous research has qualitatively and quantitatively investigated healthcare professionals’ perspectives and practices with respect to adolescent oncofertility, albeit in limited cultural contexts. Therefore, quantitative survey methods are warranted in order to test whether practicing in Israel or Switzerland influences healthcare professionals’
perspectives and practices with respect to adolescent oncofertility.
1.5 REFERENCES
Boivin, J. and G. Pennings (2005). "Parenthood should be regarded as a right." Arch Dis Child 90(8): 784-785.
Clayman, M. L., K. M. Galvin and P. Arntson (2007). Shared decision making: Fertility and pediatric cancers. Oncofertility: Fertility Preservation for Cancer Survivors. T. K.
Woodruff and K. A. Snyder. New York, Springer: 149-160.
De Croo, I., J. Van der Elst, K. Everaert, P. De Sutter and M. Dhont (1998). "Fertilization, pregnancy and embryo implantation rates after ICSI with fresh or frozen-thawed testicular spermatozoa." Hum Reprod 13(7): 1893-1897.
Ethics Committee of the American Society for Reproductive Medicine (2018). "Fertility preservation and reproduction in patients facing gonadotoxic therapies: an Ethics Committee opinion." Fertil Steril 110(3): 380-386.
Ginsberg, J. P., S. K. Ogle, L. K. Tuchman, C. A. Carlson, M. M. Reilly, W. L. Hobbie, M.
Rourke, H. Zhao and A. T. Meadows (2008). "Sperm banking for adolescent and young adult cancer patients: sperm quality, patient, and parent perspectives." Pediatr Blood Cancer 50(3): 594-598.
Goodwin, T., B. Elizabeth Oosterhuis, M. Kiernan, M. M. Hudson and G. V. Dahl (2007).
"Attitudes and practices of pediatric oncology providers regarding fertility issues."
Pediatr Blood Cancer 48(1): 80-85.
Grifo, J. A. and N. Noyes (2010). "Delivery rate using cryopreserved oocytes is comparable to conventional in vitro fertilization using fresh oocytes: potential fertility preservation for female cancer patients." Fertil Steril 93(2): 391-396.
Howarth, S. (2017). Recruitment Challenges in Adolescent and Young Adult Cancer Survivors, Texas Christian University.
Institute of Medicine and National Research Council (2003). Childhood Cancer Survivorship:
Improving Care and Quality of Life. Washington, DC, The National Academies Press.
Kahn, S. M. (2000). Reproducing Jews: A Cultural Account of Assisted Conception in Israel.
Durham, N.C., Duke University Press.
Knapp, C., G. P. Quinn, D. Murphy, R. Brown and V. Madden (2010). "Adolescents with life- threatening illnesses." Am J Hosp Palliat Care 27(2): 139-144.
Kuther, T. L. (2003). "Medical decision-making and minors: issues of consent and assent."
Adolescence 38(150): 343-358.
Nieman, C. L., K. E. Kinahan, S. E. Yount, S. K. Rosenbloom, K. J. Yost, E. A. Hahn, T. Volpe, K. J. Dilley, L. Zoloth and T. K. Woodruff (2007). "Fertility preservation and adolescent cancer patients: Lessons from adult survivors of childhood cancer and their parents."
Cancer Treat Res 138: 201-217.
OECD. (2019). "Population (indicator)." Retrieved February 26, 2019, from https://data.oecd.org/pop/population.htm.
Quinn, G. P., D. Murphy, C. Knapp, D. K. Stearsman, K. L. Bradley-Klug, K. Sawczyn and M.
L. Clayman (2011). "Who decides? Decision making and fertility preservation in teens with cancer: a review of the literature." J Adolesc Health 49(4): 337-346.
Quinn, G. P., D. K. Stearsman, L. Campo-Engelstein and D. Murphy (2012). "Preserving the right to future children: an ethical case analysis." Am J Bioeth 12(6): 38-43.
Rabinowicz, R., M. Barchana, I. Liphshiz, B. Futerman, S. Linn and M. Weyl-Ben-Arush (2012). "Cancer incidence and survival among children and adolescents in Israel during the years 1998 to 2007." J Pediatr Hematol Oncol 34(6): 421-429.
Robison, L. L. and M. M. Hudson (2014). "Survivors of childhood and adolescent cancer: life- long risks and responsibilities." Nat Rev Cancer 14(1): 61-70.
Rothmayr, C., F. Varone and É. Montpetit (2003). "Does federalism matter for biopolicies?
Switzerland in comparative perspective." Swiss Political Science Review 9(1): 109-136.
Schover, L. R. (2009). "Patient attitudes toward fertility preservation." Pediatr Blood Cancer 53(2): 281-284.
Siegel, R. L., K. D. Miller and A. Jemal (2017). "Cancer Statistics, 2017." CA Cancer J Clin 67(1): 7-30.
Steliarova-Foucher, E., C. Stiller, P. Kaatsch, F. Berrino, J.-W. Coebergh, B. Lacour and M.
Perkin (2004). "Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study." The Lancet 364(9451): 2097-2105.
Vadaparampil, S., G. Quinn, L. King, C. Wilson and M. Nieder (2008). "Barriers to fertility preservation among pediatric oncologists." Patient Educ Couns 72(3): 402-410.
Waldman, E. (2006). "Cultural priorities revealed: the development and regulation of assisted reproduction in the United States and Israel." Health Matrix Clevel 16(1): 65-106.
Ward, E., C. DeSantis, A. Robbins, B. Kohler and A. Jemal (2014). "Childhood and adolescent cancer statistics, 2014." CA Cancer J Clin 64(2): 83-103.
Weintraub, M., E. Gross, A. Kadari, V. Ravitsky, A. Safran, N. Laufer and A. Revel (2007).
"Should ovarian cryopreservation be offered to girls with cancer." Pediatr Blood Cancer 48(1): 4-9.
Figure 1.1: Spectrum of attitudes and policies regarding fertility and ARTs
___________________________________________________________________________
Israel Switzerland USA
<<< CONSERVATIVE/RESTRICTIVE LIBERAL/PERMISSIVE >>>
Chapter 2
Methodology
2.1 LITERATURE REVIEW
A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher, Liberati et al.
2009). Articles published until December 31, 2014 were identified via four databases: Web of Science, PubMed, CINAHL, and PsycInfo. Since fertility preservation (FP) in oncology is a relatively recent phenomenon, the search was not limited by a start date. To generate a list of articles concerning discussions about adolescent oncofertility, multiple searches were conducted using the following combination of terms: [“pediatric oncology” OR “paediatric oncology”] AND “fertility preservation”; [“pediatric oncology” OR “paediatric oncology”]
AND “fertility preservation” AND “adolescent decision making”; [“pediatric oncofertility” OR
“paediatric oncofertility”] AND [“decision making” OR “discussion”]; “adolescent” AND [“oncofertility” OR “fertility preservation”] AND [“decision making” OR “discussion”]. Two advisors and I reviewed all resulting article abstracts in English, French, and German – the languages in which at least one of us is fluent. Literature – including book chapters, dissertations, and peer-reviewed quantitative and qualitative studies – was excluded if it did not specifically address adolescent cancer patients or if it solely addressed prepubertal populations and/or FP techniques. Conference abstracts were also excluded due to their scant information.
After systematic removal of duplicates and articles that met the above exclusion criteria, relevant cited references in the retrieved papers and relevant articles with which I or my advisors were familiar were added. All articles were then read and summarized. Thematic analysis was then applied to these summaries to arrive at repeating themes that were then grouped into larger thematic categories. An essentialist/realist method of thematic analysis was utilized, based upon the included literature’s reported experiences, meanings, and reality (Braun and Clarke 2006).
An inductive approach to thematic analysis was also applied, whereby identified themes are strongly linked to the data and not driven by a pre-existing coding frame or the researcher’s analytic preconceptions (Braun and Clarke 2006).
2.2 QUALITATIVE STUDY OF ADOLESCENT AND PARENT ONCOFERTILITY DECISION MAKING
Results from the systematic literature review on adolescent oncofertility discussions informed the development of semi-structured interview guides, with probes for investigation of specific themes. Two semi-structured interview guides were devised – one for adolescents1 and another for parents. Assent and consent forms were also devised: one assent form for patients below the age of 18 to participate, one consent form for patients 18 or older to participate, one consent form for parents to participate, and one consent form for parents to agree for their adolescent below the age of 18 to participate. All interview guides and assent/consent forms were translated into German, French, and Hebrew. Ethics approval for the study was sought and obtained by the Swiss ethics committee (EKNZ 2014-307 / PB_2016-01252) and relevant cantonal ethics committees of Vaud and Geneva (GE 15-054) in Switzerland, as well as Schneider Children’s Medical Center’s research ethics committee in Israel (0309-15).
Participant inclusion criteria were as follows: patients currently between the ages of 12 and 19 years who were in remission for at least 2 months and had been offered FP options of sperm, oocyte, or ovary cryopreservation,2 as well as their parents. The particular age range was formulated to include adolescents who would have been either pubertal or postpubertal at the time of cancer treatment and therefore eligible for established methods of FP. The inclusion criterion of at least 2 months’ remission was devised specifically so that adolescents and their parents would be past the intensity of cancer diagnosis and treatment, thereby having enough time to process and reflect upon their oncofertility decision making experiences. Interviews
1 Developmentally-appropriate terminology was specifically used in the interview guide for adolescents.
2 Although ovary cryopreservation remains an experimental FP technique, medical professionals often offer it alongside oocyte cryopreservation to young female patients, especially when there is urgency to treat.
with adolescents were purposefully conducted separate from those with parents to reduce parental influence and thus give credence to adolescents’ voices.
All interviews were digitally recorded and then translated and transcribed into English – the language understood by all study team members. Translated transcripts from Israel were checked against the Hebrew recordings for accuracy by an independent person, fluent in both Hebrew and English. Swiss interviews were transcribed in French and translated into English.3 All English transcripts were then thematically analyzed with the assistance of MAXQDA 12 software. An essentialist/realist approach to thematic analysis was largely employed such that prevalent patterned responses, or themes, were based upon participants’ reported experiences, meanings, and reality (Braun and Clarke 2006). However, some themes were further analyzed using a contextualist approach that acknowledges the ways individuals make meaning of their experience, but situates those experiences within the broader social context to understand how the latter influences the former (Braun and Clarke 2006). Semi-structuring the interview guides allowed for the use of both theoretical and inductive approaches of thematic analysis. With the theoretical approach, some themes for investigation are integrated into the interview guide with specific probing questions. Thus, these themes are predetermined (i.e. top-down). The inductive approach allows for other, unanticipated themes to arise, generated by the qualitative data that results from more open-ended questions. Repeating language or ideas expressed by multiple participants can form the basis of these themes (i.e. bottom-up) (Braun and Clarke 2006).
In addition to my analysis of all transcripts from Israel, a quarter of them were read by an advisor, who also reviewed and examined all thematic codes based on her readings of the full transcripts. Discussion was held between us to resolve any initial discrepancies.
3 Independent validation of the French to English translations is still necessary at this point.
2.2.a Israeli participant recruitment
Schneider Children’s Medical Center assisted with participant recruitment in Israel.
Centrally located, Schneider is the only tertiary children’s hospital in Israel, treating patients from all over the country and even abroad. To conduct interviews with Israeli participants, 3 visits were made to Israel between January and June 2016, with each visit lasting approximately 2 to 3 weeks. Pediatric oncologists at Schneider assisted in recruiting patients who met the study’s inclusion criteria and were scheduled for follow-up appointments during the interviewer’s visits. Patients and their parents were invited to participate in the study by their treating physician, either by phone prior to the scheduled follow-up visit or in person during the appointment. The interviewer contacted those patients and/or parents who agreed to be interviewed to schedule a time and place to conduct the interview at the participant’s discretion – an empty office at Schneider, the participant’s home, or a café. All participants signed Hebrew assent/consent forms and interviews were conducted in Hebrew on an individual basis with adolescents and separately with either one or both parents.
2.2.b Swiss participant recruitment
Three medical centers in Switzerland assisted with participant recruitment: the Universitaets-Kinderspital beider Basel (UKBB) in Basel, the Hopitaux Universitaires Geneve (HUG) in Geneva, and the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne.
These hospitals treat both German and French-speaking Swiss populations.4 Between September 2015 and August 2016, patients and their parents who met the study’s inclusion criteria were invited to participate in the study by their treating physician during scheduled follow-up appointments. Those who expressed an interest in participating were then contacted by the interviewer to schedule a time and place to conduct the interview at the participant’s discretion – an empty office at the treating hospital, the participant’s home, or a café. All
4 Requests to collaborate with other hospitals in German-speaking cantons were declined. The study’s limited funding exempted collaboration with Italian-speaking cantons.
potential participants were offered the option of being interviewed in either French or (Swiss) German. Thus far, all participants signed French assent/consent forms and interviews were conducted in French on an individual basis with adolescents and separately with either one or both parents.5
2.3 QUANTITATIVE STUDY OF PHYSICIANS’ PERSPECTIVES AND PRACTICES WITH RESPECT TO ADOLESCENT ONCOFERTILITY
The systematic literature review included literature reporting on studies of healthcare professionals’ perspectives and practices with respect to adolescent oncofertility. Some of these prior studies directly informed the development of this study’s questionnaire.6 Survey questions were designed to specifically examine participants’ knowledge, attitude, and practices with respect to adolescent oncofertility. Some questions had binary responses and others had responses along a 3 or 5-point Likert scale (see Appendix 2.1). Participant demographics were collected in order to determine whether any correlate to responses, specifically those variables not previously tested, such as respondent’s jurisdiction of practice, parental status, religion, and patient population profile.
5 Unfortunately, due to initial poor response rate in the Swiss component of the qualitative study (of 18 invited pairs of adolescents and parents, 1 adolescent and 6 parents – 4 individuals and 1 couple – agreed to be interviewed), Swiss results are not reported in this dissertation. Therefore, ongoing participant recruitment continues in Switzerland. Preliminary findings will be analyzed in combination with the new data. These results will be published at a later date.
6 For example, the finding that professional referral patterns vary according to patient gender [Anderson, R. A., A.
Weddell, H. A. Spoudeas, C. Douglas, S. M. Shalet, G. Levitt and W. H. Wallace (2008). "Do doctors discuss fertility issues before they treat young patients with cancer?" Hum Reprod 23(10): 2246-2251, Vadaparampil, S.
T., G. P. Quinn, H. B. Clayton, L. M. King and C. A. Miree (2008). "Institutional availability of fertility preservation." Clin Pediatr (Phila) 47(3): 302-305.] was incorporated into the design of this study’s questionnaire, whereby questions pertaining to practice and beliefs were asked twice: once with respect to male pubertal patients and once with respect to female pubertal patients.
With the assistance of professional bodies in Israel and Switzerland (i.e. the Israeli Society for Pediatric Hematologists and Oncologists7 and the Swiss Pediatric Oncology Group8) healthcare professionals were invited to answer the online English questionnaire from September 1, 2016 until November 30, 2016. During the 3-month time period that the online survey was open, two reminder emails were sent to potential participants.9
2.4 REFERENCES
Anderson, R. A., A. Weddell, H. A. Spoudeas, C. Douglas, S. M. Shalet, G. Levitt and W. H.
Wallace (2008). "Do doctors discuss fertility issues before they treat young patients with cancer?" Hum Reprod 23(10): 2246-2251.
Braun, V. and V. Clarke (2006). "Using thematic analysis in psychology." Qual Res Psychol 3(2): 77-101.
Moher, D., A. Liberati, J. Tetzlaff, D. G. Altman and P. Group (2009). "Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement." PLoS Med 6(7): e1000097.
Vadaparampil, S. T., G. P. Quinn, H. B. Clayton, L. M. King and C. A. Miree (2008).
"Institutional availability of fertility preservation." Clin Pediatr (Phila) 47(3): 302-305.
7 The Israeli Society for Pediatric Hematologist and Oncologists maintains an email distribution list of all Israeli pediatric oncologists and hematologists.
8 The Swiss Pediatric Oncology Group (SPOG) does not maintain an email distribution list of all pediatric oncologists and hematologists in Switzerland. It is up to the heads of member institutions to decide whether SPOG has a complete list of their team doctors. However, all heads of SPOG member institutions were sent the email and thereby had the possibility to spread it further within their teams.
9 Unfortunately due to poor response rate, especially among Israelis (10/129), quantitative results are not reported in this dissertation. Hopefully Swiss quantitative results (with a response rate of 19/48) will be published alongside the qualitative findings. Analysis will include descriptive and inferential statistics.
Appendix 2.1: Questionnaire for pediatric oncologists on adolescent oncofertility r the purposes of this questionnaire, pubertal males refers to those aged 12-18 years old who have reached spermarche, and pubertal females are those aged 12-18 years old ho have reached menarche. )Questions concerning fertility preservation techniques 1)Sperm cryopreservation is an established technique of fertility preservation in pubertal male cancer patients. agree disagree unsure ☐☐ ☐ 2)Ovarian transposition is an established technique of fertility preservation in pubertal female cancer patients. agree disagree unsure ☐☐ ☐ 3)Oocyte cryopreservation is an established technique of fertility preservation in pubertal female cancer patients. agree disagree unsure ☐☐ ☐ Questions regarding your communication and general practices with PUBERTAL MALE PATIENTS 1)I tell all my pubertal male patients about potential drug or radiation damage to the testicles prior to treatment. always never ☐☐ 2)I referall my pubertal male patients to a fertility specialist prior to the start of cancer therapy if there is the possibility that the cancer or treatment can negatively impact fertility. always never ☐☐ 3)I discuss fertility preservation techniques with my pubertal male patients prior to the start of cancer therapy if there is the possibility that the cancer or treatment can negatively impact fertility. always sometimes never ☐☐ ☐
4)I refer my pubertal male patients to a psychosocial provider (e.g. social worker or psychologist) before beginning cancer therapy to discuss distress over cancer treatment-related infertility, and/or fertility preservation. always sometimes never ☐☐ ☐ 5)I regularly talk about fertility preservation techniques with my pubertal male patients during cancer therapy if there is the possibility that the cancer or treatment can negatively impact fertility. always sometimes never ☐☐ ☐ 6)I discuss alternative methods of becoming a parent with my pubertal male patients, such as use of donor gametes or adoption. always sometimes never ☐☐ ☐ 7)I use decision trees or other decision tools in discussions with my pubertal male patients on fertility preservation options. always sometimes never ☐☐ ☐ 8)I discuss with my pubertal male patients what should be done with cryopreserved gametes in the case of their death. always sometimes never ☐☐ ☐ 9)I discuss fertility-related side effects of cancer therapy with my pubertal male patients after the completion of treatment. always sometimes never ☐☐ ☐
