Optimizing the process of fertility preservation in pediatric female cancer patients – a multidisciplinary program

Approximately 12,000 adolescents and children under the age of 18 are diagnosed with cancer each year in the United States. Fortunately, therapeutic advances have resulted in increased survival while five-year survival rate for pediatric cancer currently approaches 80 % [1, 2]. Cancer during childhood and adolescence introduces major challenges regarding treatment-related late effects, and as survival rate improves, there is much attention on interventions to improve the quality of life during survivorship [2].

Up until 2013, the standard methods to preserve fertility were ovarian transposition for female patients undergoing pelvic radiation and embryo cryopreservation for pubertal female patients before initiation of gonadotoxic chemotherapy, whereas oocyte preservation and ovarian cryopreservation have been considered experimental. Recently, the American Society for Reproductive Medicine (ASRM) revised its guidelines for fertility preservation (FP) in cancer patients and acknowledged oocyte harvesting and cryopreservation as an ancillary standard procedure of FP prior to gonadotoxic treatment. Following the establishment of ASRM that pregnancy rates resemble in both oocyte cryopreservation and embryo cryopreservation; the American Society of Clinical Oncology (ASCO) has concurred its recent guidelines with those of the ASRM, stating oocyte cryopreservation is recommended as a standard option for FP for pubertal females [3]. This revision carries highest impact for young pubertal female patients that until recently were asked to preserve embryos using donor sperm, with complicated future implications who now may undergo a much useful methodology that may better serve their future needs whether facing late-term infertility. For prepubertal girls, ovarian tissue cryopreservation is the only option to restore gametes. Since the benefit to the patient is not yet established, ASCO and ASRM guidelines state that ovarian tissue cryopreservation should be considered experimental and offered only in a research setting with Institutional Review Board (IRB) approval [3]. Ovarian cryopreservation has been widely studied and methods have improved in many cancer centers worldwide [4–6].

Fertility preservation in pediatric and adolescent patients has gained better appreciation throughout the past years with improving rates of ovarian cryopreservation and continuous crosstalk and collaborative frameworks between oncologists and reproductive endocrinologists and with the advent of skilled laboratories that handle ovarian tissue [3, 4, 6].

This unique population presents psychosocial challenges derived from the decisions about FP, which may have a substantial impact on the adolescent as an adult survivor. For the pediatric patient, these bothersome decisions are taken by her caregiver, what may aggravate the primary stressful situation [7].

Former studies indicate that adolescents with cancer appreciate information prior to initiation of treatment on gonadal toxicity and potential impact to future fertility, valid options for FP and wish to take active part in the decision making process regarding FP [7]. Several studies confirm that adult survivors of pediatric cancer regret they had not been given more detailed information of options about FP, even though experimental [8–10]. For parents feeling uncertain in making the decision about FP on behalf of their young girl, the ASRM [8] offers guidance for counseling parents of children with cancer of either sperm banking or ovarian cryopreservation. Several studies have implied that establishing the right setting for fertility counseling for young patients and parents regarding fertility and cancer treatments carries high implications to alleviate the psychological stressors associated with both the acknowledgement of cancer diagnosis and the risk of future infertility [9–11].

Fertility represents a key issue in cancer survivorship of pediatric or young adult patients. Follow-up surveys developed by ASCO aiming at cancer survivors indicate that those who are infertile following anti-cancer treatments are at increased risk for emotional distress [12–14]. Yet, despite the paramount significance, the current evidence points at a sub-optimal approach to discussion of FP by the health care providers reflected by still lower referral numbers of eligible patients to FP or even routine discussion on this matter. The literature implies that although most oncologists recognize the importance of raising the issue of treatment-related infertility, the actual lack of discussion may derive from desire to commence immediate treatment and sub optimal connection between oncologists and reproductive endocrinologists [11–13].

On this ground we have developed a unique program that aimed at facilitating the daily practice and collaboration between the various contributors to the process of fertility preservation, emphasizing practical issues of enhancing the end-products of the process, focusing on the psychosocial aspects and utilizing this platform to prospectively assess gonadotoxicity throughout time following anti-cancer treatments under IRB approval. The program serves male patients (for sperm banking and recently a newly approved protocol of testicular biopsy cryopreservation) and female patients (oocyte and ovarian cryopreservation). The availability of providing banking of gonadal tissue requires a unified multidisciplinary team with appropriate laboratory resources. We herein present our paradigm, the shift in referral of pediatric and adolescent patients in the last 36 months following launching the program and our experience of fertility preservation in prepubertal and post-pubertal young female cancer patients.

In an era of improving treatment protocols and subsequent increased survival of pediatric cancer patients, where 5-year survival reaches 80 % [1, 2], fertility preservation has become a pivotal survivorship issue. For younger prepubertal female patients, ovarian tissue cryopreservation carries promise for future use in experimental protocols, such as ovarian transplantation after which live births had occurred, though only while the tissue had been retrieved from adult patients [3]. In vitro follicle maturation has been intensively studied and carries high implication to practice since it is devoid of any risk of disease recrudescence [22–24], especially for survivors of hematologic malignancies.

Former studies have evaluated the adherence of care providers to ASCO recommendation of thorough discussion of fertility and referral to fertility preservation [3]. Studies which assessed the patients’ notion on the issue revealed that most of the adolescent patients as well as parents of pediatric patients felt unsatisfied with the degree of discussion and the very limited information received, and the majority stated that they wished to have a deeper discussion to resolve many unclear questions and thoughts [25–27]. It has been formerly established that other than actual preservation of fertility for the future, the discussion and referral to FP helps the patients to cope better with their condition and treatment. Studies performed in adolescent males who were referred to sperm banking demonstrated that sperm banking was considered by the patients as a strong positive factor in coping emotionally with cancer [27, 28]. A study of testicular preservation in prepubertal boys, revealed that families are willing to undergo an experimental protocol even when there were no guarantees that the science will exist in the future to allow their sons to use this banked tissue to achieve pregnancy [29]. For many parents and adolescents, the discussion of future fertility is acknowledged as a discussion on the “day after” and carries hope [29, 30]. From the medical facet, provider perceptions were appraised in several studies and revealed that although most oncologists recognized the significance of discussing fertility with the patients, in routine practice, less than half of the pediatric oncologists referred the patients to FP [31–33]. In an analysis of the factors that contributed most to the lack of referral to FP, availability of fertility specialist and time constraints, were identified as the most common [31].

Former reports have implied that following development of a designated and standardized process of offering FP to adolescents and young adults, there has been a substantial increase in the proportion of patients that were referred for FP [29, 34–36].

Our comprehensive multidisciplinary program was developed to pursue the complex issues associated with fertility and cancer. We aimed to encompass both fertility preservation form the clinical aspect but also to employ this setting as a platform for translational research on gonadotoxicity. The program was designed to provide care for both male patients (for sperm banking and recently a newly approved protocol of testicular biopsy cryopreservation) and female patients (oocyte and ovarian cryopreservation). From the clinical perspective, our concept lied on the perceptions and needs observed in our patient population on upon the literature. We intended to raise the awareness of the caregivers to the issue of fertility, facilitate the process of referral, and serve as an approachable service for the patient. Once notified by the treating oncologist, an appointment would be scheduled within a short time and the algorithm of referral would be operated. We refined the algorithm of treatment based upon perceptions and feedback from the patients, parents and the pediatric oncologists. We had found that an initial discussion performed in the clinic by a trained oncologist contributed to “priming” of the parents, who were then referred for a broader discussion with the reproductive specialist and a specialized psychologist of the reproductive endocrinology service. Following the algorithm, the parents and adolescents felt less stressful and less concerned of how the FP procedure may affect their cancer (that was mostly evident with adolescent pubertal patients that were undergoing ovulation induction for oocyte cryopreservation). The multidisciplinary paradigm entails a better collaboration between all disciplines – availability of personnel to carry the appointments, flexibility of operation schedule by skilled surgeons, and most importantly appropriate laboratory resources. By meticulous handling of the ovarian tissue, we managed to aspirate immature germinal vesicle oocytes that had already commenced maturation process and to complete the maturation in vitro. By that, the pediatric patient gained additional source of FP and had not only stored ovarian tissue but rather mature oocytes. The multidisciplinary infrastructure enables us to expand our program also to testicular preservation in prepubertal boys, a process which has been implemented very recently. Our multidisciplinary program has led to a significant increase in referrals of pediatric patients. With the advent of oocyte cryopreservation as a standard option of FP, the program facilitated this clinical application reflected by higher referral rates of pubertal patients (that up until recently were referred for embryo cryopreservation with sperm donation, an option that is considered highly problematic for young adolescents). From the research perspective, every patient that is referred to the clinic is enrolled into an IRB-approved prospective longitudinal study of gonadotoxicity related outcomes in young patients who are treated with various anti-cancer therapies. Gonadotoxic outcomes are serially measured even if eventually the patient does not undergo actual fertility preservation. Since there are very few prospective studies assessing gonadal function and fertility in survivors of childhood cancer, a longitudinal evaluation is imperative, particularly with all newer regimens which their gonadal effect remains to be elucidated. We also developed a parallel preclinical setting to study mechanisms of gonadotoxicity of anti-cancer treatments in a mouse model. Clinical dilemmas and questions are being translated into studying the effect in the animal setting, while themes and outcomes from the preclinical setting are being implemented into observational studies in the patient cohort (i.e. biomarkers for gonadal toxicity).

Due to the uncertainty over the risk of gonadotoxicity and infertility associated with different treatment protocols in children and young adults, it is mandatory to create a “risk assessment” model to guide the decision on referral to FP. The indication for FP in adolescents has become broader since FP options have become standard (sperm banking or oocyte cryopreservation) and not experimental. Our strategy is to discuss these options with all patients that are candidates for chemotherapy, not only highly gonadotoxic (i.e. ABVD protocol). For the prepubertal girls, risk assessment is performed by the treating oncologist. High risk patients are referred for FP, while intermediate risk are usually referred for discussion, and the actual decision on FP would be made by the joined professional team and the parents. Our results indicate that in chemotherapy-naïve patients the yield of isolating immature oocytes from the retrieved ovary and the success rate of IVM is significantly higher than in previously treated patients (even with less gonadotoxic regimens as anthracyclines). We therefore suggest a “risk assessment” process before starting any treatment. If the chances of protocol conversion into a high gonadotoxic regimen are high, the case should be discussed in a multidisciplinary setting to weigh whether the patient should be referred in advance for FP to enhance the yield of fertility preservation.

AMH, anti mullerian hormone; ASCO, American Society of Clinical Oncology; ASRM, American Society for Reproductive Medicine; BMT, bone marrow transplantation; FP, fertility preservation; IVM, in vitro maturation; OCP, ovarian cryopreservation