Fertility preservation in the male pediatric population: factors influencing the decision of parents and children.

How can the decision process for fertility preservation (FP) in adolescents and prepubertal boys be improved based on patient and parent feelings about FP counseling? The content of information given to patients and parents and hope for future parenthood appeared to positively impact on the decision to preserve fertility in the pediatric population and, therefore, deserves special attention to improve FP care. A vast body of literature on adult cancer patients shows that reproductive capacity is a major quality-of-life issue. Patients also have a strong desire to be informed of available FP options with a view to future parenthood of their own genetic child, considering that <10% chose to adopt or used donated gametes. Furthermore, the quality of fertility counseling provided at the time of cancer diagnosis has been identified as a crucial factor in the decision-making process. By contrast, in the pediatric population, while it was shown that parents were able to make an informed and voluntary decision for their prepubertal sons despite the heavy emotional burden at the time of diagnosis, there is so far very limited information on patient expectations regarding FP. A lack of awareness often equates to suboptimal care by oncologists and FP specialists, and poor access to FP, therefore improving knowledge and identifying the expectations of pediatric patients and their parents are crucial for optimizing multidisciplinary collaborative care pathways (MCCPs), including counseling and access to FP methods, in the youngest population. A questionnaire survey was posted to an eligible population between May 2005 and May 2013. A total of 348 prepubertal boys and adolescents aged 0-18 years, diagnosed with cancer in a university hospital setting, were eligible. Three different questionnaires for two age groups of children (<12 and 12-18 years) and parents were established based on information from focus groups. Questions were subsequently reviewed by the institutional ethics board before being sent. Of the 348 eligible patients, 44 died and 14 were lost to follow-up. Thus, 290 patients (77 aged 12-18 years and 213 aged <12 years) were sent a questionnaire. In total, 120 questionnaires were recovered, 45.5% (n = 35/77) from adolescents and 39.9% (n = 85/213) from children. FP acceptance rates were, respectively, 74 and 78.6% for boys aged <12 and 12-18 years. The content of information provided to patients and parents appeared to positively impact on the decision to preserve fertility (P = 0.04). While the majority of boys aged >12 years considered the information to be clear (72%), complete (80%) and understandable (90.9%), only 33.3% of boys aged <12 years were able to comprehend the information. Pressure from doctors to reduce the delay between diagnosis and cancer treatment increased the number of refusals (P<0.01), while hope for future parenthood favored acceptance (P < 0.01). Family support was considered important for 75% of adolescents and 58% of children, and medical support for 50% of adolescents and 42% of children. This single-center survey does not allow extrapolation of the information to other settings. Recall bias and lack of full external validation of the questionnaires are further limitations. Modification of the current MCCP should be further evaluated according to our results. Acknowledging the issues faced and familiarizing oneself with the care of patients undergoing fertility-threatening therapies supply primary care providers with the appropriate quality management tools in the field of FP in centers for reproductive medicine. Expectations reported in the survey allow appropriate support to be included within the MCCP design. Funding by hospital/clinic(s); Cliniques Universitaires Saint Luc, Brussels, Belgium. The authors have no conflict of interest to declare. NCT02411214.

Wyns C ，Collienne C ，Shenfield F ，Robert A ，Laurent P ，Roegiers L ，Brichard B ... -  《-》

Decision-making in female fertility preservation is balancing the expected burden of fertility preservation treatment and the wish to conceive.

What are the decisive factors in fertility preservation (FP) decision-making in young women scheduled for gonadotoxic therapy? FP decision-making in young women scheduled for gonadotoxic therapy is mainly based on weighing two issues: the intensity of the wish to conceive a child in the future and the expected burden of undergoing FP treatment. Future fertility is of importance for young cancer patients whose reproductive function is being threatened by oncological therapy. To prevent or reduce severe psychological effects of infertility as well as feelings of regret about their FP decision after cancer treatment, the quality of fertility preservation counselling (FPC) should be improved. To improve care, those issues forming a decisive factor in FP decision-making for patients should be clarified, as these issues deserve extensive discussion during FPC. Until now, decisive factors have not been isolated from the complex interplay of all aspects of FP that women contemplate during FP decision-making. By using a mixed methods methodology, a questionnaire developed after qualitative research involving a selected group of five women who previously received FPC was retrospectively sent to eligible patients (n = 143) who had received FPC (1999 - July 2013) and to whom at least one FP option was offered. Patients had received FPC at a university hospital in the Netherlands, in a setting where financial factors do not play a role in FP. They were aged ≥16 years and were scheduled for gonadotoxic treatment. The relationship between patients' baseline characteristics, their attributed importance to 28 relevant importance items and their FP choices was investigated. After five interviews, 28 importance items for FP decision-making were identified and included in our questionnaire. Of these 28 importance items, 24 items could be clustered into seven importance themes. A total of 87 patients (61%) responded to our questionnaire. After performing a multivariable logistic regression analysis, proceeding with FP was related to higher attributed importance during FP decision-making to the theme 'Wish to conceive (in the future)' (odds ratio (OR) 10.8, 95% confidence interval (CI) 3.5-34.4) and the item 'Having a stable partner relationship' (OR 2.0, 95% CI 1.0-4.1), while higher attributed importance to the theme 'Expected burden of FP' during FP decision-making (OR 0.08, 95% CI 0.02-0.3) more often resulted in refraining from treatment. Besides possible recall and selection bias, the fact that this study was performed in Dutch patients aged ≥16 years counselled in a single centre, where finance was not an additional consideration, possibly limits the generalizability of our results to a broader European population of cancer patients. Furthermore, we are not able to draw conclusions about the causality of the associations observed in our study. The wish to conceive and the expected burden of FP treatment should be discussed carefully with patients during FP decision-making, either by the referring healthcare provider or by reproductive medicine specialist. Prospective research is needed to explore the causality of the associations found in this study. Furthermore, in order to deliver high quality patient-centred care, the development of tools to explore patients' wish to conceive (for example in different age categories) and tools to provide clear information about the burden of FP treatments (using the preferred information channels suggested by patients) is needed. This work was supported by the Radboud Institute for Health Sciences (research school affiliated to the Radboud university medical center). The authors have declared no conflicts of interest with respect to this work.

Baysal Ö ，Bastings L ，Beerendonk CC ，Postma SA ，IntHout J ，Verhaak CM ，Braat DD ，Nelen WL ... -  《-》

Deciding about fertility preservation after specialist counselling.

How do female patients experience fertility preservation (FP) consultation (FPC) with a specialist in reproductive medicine and subsequent decision-making on FP? Most patients had positive experiences with FPC, but negative experiences were found to be associated with decisional conflict and decision regret. When confronted with a need for gonadotoxic treatment, girls and young women will have to make an irreversible decision with regard to FP. Patients may experience decisional conflict and develop regret about their decision during follow-up. Patients' opportunities to ask questions during FPC and their knowledge about FP have been inversely related to decisional conflict. A questionnaire on experiences with FPC, designed after qualitative research, was retrospectively distributed to 108 patients to whom FP was offered after FPC between July 2008 and July 2013. Aiming to minimize recall bias, we defined a subgroup of patients counselled since 2011 who had not yet tried to conceive after FPC. Patients were aged ≥16 years and had either cancer or a benign disease that required gonadotoxic therapy. They received FPC in a single university hospital in the Netherlands. Apart from patients' experiences, patients' characteristics, decisional conflict and decision regret were assessed. A total of 64 patients (59.3%) responded to the questionnaire. Patients generally had positive experiences with FPC, but indicated room for improvement. Negative experiences were associated with decisional conflict regarding the FP decision (not enough time for counselling: P < 0.0001; not having the opportunity to ask all questions during FPC: P < 0.0001; not feeling supported by the counsellor during decision-making: P = 0.0003; not all applicable options were discussed: P = 0.0001; benefits and disadvantages of FP options were not clearly explained: P = 0.0005). Decisional conflict was correlated to decision regret (P < 0.0001). In the subgroup of patients counselled after 2011 who had not tried to conceive (n = 33), similar results as for the total study population were found for the association of patient experiences with decisional conflict. Given our retrospective design, we were not informed about the causality of the associations observed. We studied Dutch patients who were counselled in a single centre and were at least 16 years old when filling in the questionnaire. This may limit the generalizability of our data to other settings and populations. More attention should be paid to improving FPC care. Interventions aiming at improving patients' comprehension of the topic of FP and their feelings of being supported in decision-making are advisable. This work was supported by the Radboud Institute for Health and an unconditional grant from Merck Serono. The authors have declared no conflicts of interest with respect to this work.

Bastings L ，Baysal Ö ，Beerendonk CC ，IntHout J ，Traas MA ，Verhaak CM ，Braat DD ，Nelen WL ... -  《-》

Long-term follow-up of boys who have undergone a testicular biopsy for fertility preservation.

What is the long-term reproductive health outcome of patients who have undergone testicular sampling for fertility preservation (FP) before and during the pubertal transition period? In long-term follow-up after testicular sampling for FP, hormonal data showed that 33% of patients had primary seminiferous tubule insufficiency (high FSH) while semen analyses showed 52% of patients having a severe reduction in total sperm counts or complete absence of ejaculated sperm. During childhood and adolescence, both treatments for cancer and benign haematological diseases that require a bone marrow transplantation, can be detrimental to spermatogenesis by depleting the spermatogonial stem cell population. A testicular biopsy prior to chemotherapy or radiotherapy, even though still an experimental procedure, is now recommended for FP by European and USA oncofertility societies if performed within an institutional research setting. While short-term follow-up studies showed little to no post-operative complications and a normal testicular development after 1 year, data regarding the long-term follow-up of boys who have undergone this procedure are still lacking. This is a longitudinal retrospective cohort study that reports on the long-term follow-up of pre- and peri-pubertal boys who have undergone a testicular biopsy for FP between May 2005 and May 2020. All the patients included in this study were referred to our programme by haematologists-oncologists who are part of a regional multi-centric collaborative care pathway. Of the 151 boys referred to our FP programme, 139 parents/legal guardians accepted that their child undergo a testicular biopsy. Patient characteristics (i.e. age at biopsy, urogenital history, pubertal status at diagnosis), indications (disease type and dosage of gonadotoxic treatments), operative and post-operative data (biopsy volume, surgical complications), anatomopathological analyses (presence/absence of spermatogonia, Johnsen score) and reproductive data (semen analyses, FSH, LH, testosterone levels) were collected from the institutions' FP database and medical records or from the 'Brussels Health Network'. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Patients who were 14 years or older at the time of the follow-up and in whom the testicular tissue was shown to contain spermatogonia were included in the reproductive outcome analysis. Comparison of the sperm count findings (absence/presence of spermatozoa) and FSH levels (high (≥10 IU/l)/normal) between patients who were either pre- (Tanner 1) or peri-pubertal (Tanner >1) at the time of the biopsy was done using the Mann-Whitney U or Fisher's tests. A multiple logistic regression was used to study the relationship between the hormone reproductive outcome (high versus normal FSH), as a proxy marker for fertility, and both the pubertal status (Tanner 1 versus Tanner >1) and Johnsen score at the time of the biopsy, while adjusting for CED. A testicular biopsy was performed in 139 patients either before (129/139) or after (10/139) the start of a gonadotoxic treatment. Post-operative complications occurred in 2.1% (3/139). At the time of the procedure, 88% (122/139) of patients were pre-pubertal and 12% (17/139) were peri-pubertal. The presence of spermatogonia was documented in 92% (128/139) of cases. Follow-up data were available for 114 patients after excluding 23 deceased and two patients lost to follow-up. A paediatric endocrinologist's follow-up including clinical examination and data on reproductive hormones was available for 57 patients (age ≥14) and 19 (33%) of these were found to have high FSH levels (20 ± 8.8 IU/l). There were 37 patients who had returned to the reproductive specialist's consultation for post-treatment fertility counselling and results on semen analysis were available in 27 of these cases; 14/27 (52%) had severely impaired semen parameters including 8 who were azoospermic. Among patients who received an alkylating agent-based treatment (n = 42), a peri-pubertal status (Tanner >1) at the time of diagnosis/biopsy was found to be associated with a higher risk of having primary testicular failure (defined by an FSH ≥ 10 IU/l) after treatment completion with an OR of 6.4 (95% CI 1.22-33.9; P = 0.03). Of all the patients, 2.6% had already fulfilled their wish to build a family or were actively seeking parenthood. Although this is the largest cohort with follow-up data providing proxy markers of the reproductive potential of boys in whom a testicular biopsy for FP was performed before puberty or during the pubertal transition period, the amount of data provided is limited, and originating from a single programme. Further data collection to confirm the observations in other settings is therefore awaited. Testicular sampling for FP should be offered to boys at risk of losing their fertility (and is recommended for those at high risk) as part of ethically approved research programmes. Long-term follow-up data on increasing numbers of boys who have undergone an FP procedure will help improve patient care in the future as patient-specific factors (e.g. urogenital history, age at gonadotoxic therapy) appear to influence their reproductive potential after gonadotoxic therapies. FNRS-Télévie, the Salus Sanguinis Foundation and the Belgian Foundation against Cancer supported the studies required to launch the FP programme. The authors declare that they have no conflict of interest. N/A.

Kanbar M ，de Michele F ，Giudice MG ，Desmet L ，Poels J ，Wyns C ... -  《-》

Randomized controlled trial on the effect of an online decision aid for young female cancer patients regarding fertility preservation.

Does the use of an online decision aid (DA) about fertility preservation (FP), in addition to standard counselling by a specialist in reproductive medicine, reduce decisional conflict compared to standard counselling alone? Female cancer patients who could make use of the online DA had a significantly lower short-term decisional conflict score. Nowadays, female cancer patients have several options for preserving fertility, but having to decide whether to opt for FP within a short time frame after cancer diagnosis and before the start of treatment is challenging. According to previous studies focussing mainly on breast cancer patients, decisional conflict among these women is high, and they have expressed the need for additional support. The study was a randomized controlled trial including female cancer patients who were referred by their treating oncologist to a specialist in reproductive medicine for fertility counselling. Participants were randomly assigned to the control group (counselling only) or to the intervention group (counselling and additional use of the online DA immediately after counselling). Recruitment was ongoing from July 2016 to December 2017 at eight fertility centres in Switzerland and Germany. The online DA was developed by an interdisciplinary team of specialists in reproductive medicine, gynaecologists, oncologists and psychologists. Of 79 recruited participants, 59 completed the first assessment and could therefore be enrolled in the study. They were asked to complete an online questionnaire at three time points: at T1, after counselling (control group, n = 27) or after counselling and the additional use of the DA (intervention group, n = 24); at T2, 1 month later (N = 41: control group, n = 23; intervention group, n = 18); and at T3, 12 months later (N = 37: control group, n = 20; intervention group, n = 17). The survey comprised questions about fertility-related knowledge, attitude towards FP, willingness to undergo FP and socio-demographic data, as well as the decisional conflict and decisional regret scales. All participants showed low decisional conflict scores. Women who used the online DA in addition to counselling (intervention group) showed a significantly lower total score on the Decisional Conflict Scale (DCS) compared to the control group at T1 (P = 0.008; M = 12.15, SD = 4.38; 95% CI, 3.35-20.95) and at T2 (P = 0.043; M = 9.35, SD = 4.48; 95% CI, 0.31-18.38). At T3, the mean total score of the DCS was still lower in the intervention group compared to the control group; however, this group difference was no longer significant (P = 0.199, M = 6.86, SD = 5.24; 95% CI, -3.78 to 17.51). The majority of participants had already made a decision regarding FP (yes or no) at T1 (72.5%): 91.7% in the intervention group compared to 55.6% in the control group (P = 0.014). Those who had decided already at T1 showed significantly lower decisional conflict (P = 0.007; M = 13.69, SD = 4.89; 95% CI, 3.86-23.52). The average number of DA sessions per user was 2.23, and 80.8% of the participants completed the DA's value clarification exercises. Participants in the intervention group were satisfied with the DA and would recommend it to other patients. The recruitment of participants was challenging because of the emotionally difficult situation patients were in. This led to the limited sample size for final analysis. Education levels were high in two-thirds of the participants. It is difficult to say whether the DA would be equally effective in women with a lower educational background. There is evidence that the DA served as a helpful complement to the decision-making process for young female cancer patients qualifying for FP. This is, to our knowledge, the first randomized controlled trial evaluating a DA targeted at patients with several cancer types and in a language other than English (i.e. German). This study contributes to extending the range of the still limited number of DAs in the context of FP. The study was supported by a research grant of the Swiss Cancer Research. The authors declare that no competing interests exist. Clinicaltrials.gov, trial no. NCT02404883. 19 March 2015. 4 July 2016.

Ehrbar V ，Urech C ，Rochlitz C ，Zanetti Dällenbach R ，Moffat R ，Stiller R ，Germeyer A ，Nawroth F ，Dangel A ，Findeklee S ，Tschudin S ... -  《-》