Abstract
Fertility preservation (FP) in pediatric and adolescent oncology patients presents a complex interplay between cancer treatment imperatives and reproductive aspirations, demanding a multi-disciplinary approach. Essential guidelines emphasize the importance of early referrals to FP specialists, ensuring timely counseling on oocyte and ovarian tissue cryopreservation options. Proper patient selection and risk assessment, considering intrinsic and extrinsic factors, is crucial for judicious resource utilization and optimal outcomes. Gonadotoxic effects of cancer treatments pose significant threats to reproductive capabilities. Oocyte cryopreservation (OC) is preferred in post-pubertal adolescents without partners. Cultural and religious concerns, especially regarding hymenal integrity, influence FP decisions, necessitating culturally sensitive consent processes. Ovarian tissue cryopreservation (OTC) offers an alternative for those unfit for OC. Despite its experimental label in some societies, emerging data support the efficacy of OTC, with ovarian tissue transplantation (OTT) showing promise in restoring ovarian function. However, the reintroduction of potentially malignant cells during transplantation remains a concern. Overall, while FP offers hope for future parenthood, the intricacies of decision-making and the potential medical, ethical, and cultural challenges underscore the importance of a personalized, multi-disciplinary approach. In this review, guidelines from various societies have been comprehensively reviewed and analyzed to provide insight into the clinical practice of oncofertility.
- Fertility preservation
- adolescent oncology
- oocyte cryopreservation
- ovarian tissue cryopreservation
- multi-disciplinary approach
- review
Recent epidemiological data highlight a noteworthy increase in survival rates for pediatric and adolescent cancer patients, now exceeding a 70% five-year survival rate (1). Although this signifies a monumental advance in oncological therapies, it also necessitates an enhanced focus on long-term quality of life, specifically on fertility preservation (2). In addition, patients under the age of 15 and between the ages of 15 and 20 years have different cancer incidence and diagnosis characteristics and require different attention compared to the young adult population (3, 4). Fertility impairment by cancer treatment, including alkylating agents and radiotherapy, may affect the ovarian function of young female cancer survivors (5), resulting in premature ovarian insufficiency with estrogen deficiency and infertility (6). Guidelines for fertility preservation are being published for children and adolescents by various societies, and oocyte/embryo cryopreservation, ovarian tissue cryopreservation (OTC), and ovarian transposition (OT) are proposed as options for children and adolescents (7-11). In particular, the American Society for Reproductive Medicine (ASRM) 2019 guideline announced that OTC in prepubertal girls is no longer experimental, and several studies published on OTC have shown subsequent hormonal function recovery and pregnancy (12).
This review furnishes a comprehensive and multi-disciplinary examination of fertility preservation strategies tailored for pediatric and adolescent female oncology patients. The manuscript is segmented into four pivotal sections: an overview of extant guidelines, as established by authoritative societies; a commentary on optimal timing for referrals and assessments; the current status of oocyte cryopreservation (OC); and a thorough analysis of the emerging and increasingly validated method of OTC. The clinical relevance of this review lies in its provision of evidence-based recommendations designed to inform and augment fertility preservation decisions, especially when conventional methods are either impractical or suboptimal. By examining the recent scientific advancements and the existing challenges in oncofertility, this review aims to refine and optimize clinical practices related to fertility preservation among pediatric and adolescent female cancer patients.
Current Guidelines and Recommendations
The burgeoning emphasis on the quality of life among cancer survivors has amplified the importance of fertility preservation (FP), particularly for the Adolescent and Young Adult (AYA) group. This shift has catalyzed the incorporation of FP recommendations into oncological guidelines, engendering a multi-disciplinary approach that amalgamates insights from various specialties. Within this evolving landscape, this article dissects the FP guidelines from six influential societies: the National Comprehensive Cancer Network (NCCN) (7) and the European Society for Medical Oncology (ESMO) (9), representing oncology, along with the ASRM (12), the European Society of Human Reproduction and Embryology (ESHRE) (13), and the German consortium FertiPROTEKT (10, 11) in the realm of reproductive medicine. Children’s Oncology Group (COG) recently endorsed the American Society of Clinical Oncology (ASCO) guideline for the fertility preservation of pediatric and adolescent patients; COG recommendation is not included in this review (14). It is pivotal to note that ESMO diverges from other guidelines by circumscribing its recommendations to post-pubertal individuals, thus introducing a notable limitation in scope (9). Significant findings from six guidelines are summarized in Table I.
Comparative analysis of recent guidelines: focus on key options for fertility preservation by oncology and endocrinology societies.
A salient point of divergence between these guidelines resides in the treatment of OTC in the prepubertal population. Oncology-centric guidelines, primarily from NCCN, ASCO, and ESMO, position OTC within an experimental purview, advocating its use under constrained circumstances such as expedited treatment as in prepuberty girls under institutional review board approval (7-9). These societies also caution against the potential risks of re-implanting cancer cells during ovarian tissue transplantation, particularly in patients with systemic malignancies, such as leukemia, or those at high risk for ovarian metastasis. Significantly, the ESMO guidelines noted pelvic cancers and advanced-stage diseases, including lymphoma, sarcoma, and breast cancer (9). The NCCN guidelines focus on BRCA mutation carriers as a contraindication for OTC because of ovarian cancer risk (7).
Conversely, societies anchored in reproductive medicine, notably FertiPROTEKT, ASRM, and ESHRE, categorize OTC as an established procedure contingent upon specific clinical conditions (10-13). In 2019, the ASRM became the first organization to officially categorize OTC as a non-experimental method for FP, highlighting OTC as the sole option for prepubertal girls and a viable alternative for women who cannot undergo ovarian stimulation due to time constraints (12). The ESHRE guidelines provide nuanced recommendations concerning OTC and ovarian tissue transplantation (OTT) for specific cancer types (13). For instance, it is contraindicated for ovarian tumors and requires extreme caution in cases involving leukemia and CNS tumors (13). However, these guidelines consider these procedures safe for patients with non-Hodgkin and Hodgkin lymphoma, cervical cancer, and other solid tumors, provided metastatic risk is assessed during OTC (13). The FertiPROTEKT guidelines focus on specific disease groups when recommending OTC for breast cancer and Hodkin lymphoma, cautious discussion for early-stage cervical endometrial cancer, contraindicating for ovarian cancer (11).
All guidelines analyzed converged on a universally supported consensus for OC and for post-pubertal patients; however, embryo cryopreservation is not an option for unmarried or partnerless pediatric and adolescent patients, and the ESHRE and FertiPROTEKT guidelines specifically noted differences in FP options based on cultural and religious differences (11, 13).
Regarding the use of gonadotropin-releasing hormone (GnRH) analogs for hormonal suppression, the guidelines from oncological and reproductive medicine societies advocate for a cautious approach. These guidelines recommend using GnRH analogs, primarily in post-pubertal populations (7-9, 11-13). Although evidence exists to support the beneficial effects of goserelin in reducing ovarian failure in patients with early-stage hormone receptor-negative breast cancer, these guidelines tend to recommend GnRH analogs for patients with early breast cancer (15). Nevertheless, the empirical foundation for such use is most compelling in the context of early-stage breast cancer. Furthermore, the NCCN guidelines emphasize the utility of GnRH analogs in reducing the risk of menorrhagia among patients who present with thrombocytopenia or anemia during cancer treatment rather than focusing solely on their gonadal protective effects (7). Therefore, these guidelines advise exercising prudential discretion in using GnRH analogs for other clinical scenarios, citing insufficient evidence to support broader application, and should not be used as an alternative for other FP options.
In summary, while general agreement exists on the endorsement of OC and the limited approval of GnRH analogs, the guidelines differ significantly in their views on OTC. This difference highlights the complex nature of decision-making in fertility preservation, emphasizing the need for a coordinated, evidence-based approach. The evidence-based approach is summarized in Figure 1.
Fertility preservation approach for adolescent women diagnosed with cancer.
Risk Assessment and Decision-making for FP
Early referral. Indeed, the risk assessment and decision-making process for fertility preservation (FP) involves a complex interplay between oncological imperatives and reproductive aspirations, necessitating a multi-disciplinary approach for optimal patient outcomes (16). Effective communication between various oncology specialists—including medical, surgical, and radiation oncologists—and reproductive endocrinology experts specializing in assisted reproductive technologies (ART) is fundamental for this endeavor, especially in pediatric and adolescent patient populations (8, 13). The ESHRE guidelines suggest setting key coordination personnel and incorporating pediatric specialists for constructing a multi-disciplinary team; timely referral and communication may be more effective (13). Furthermore, the NCCN guidelines suggest referring to the FP clinic within 24 hours for all AYA patients interested in FP (7). Referral of cancer patients requiring FP as early as possible offers distinct advantages. Firstly, early referral to an FP specialist allows the patient to consult about various options before starting treatment. Early referral is crucial for options like ovarian stimulation, which are time-sensitive and require careful planning. The quick referral ensures that these time-intensive options remain viable for the patient, thereby not limiting their range of FP strategies before initiation of cancer treatment (7-9). Second, this consultation time can serve as a buffer, allowing the patient adequate time to contemplate the most suitable FP option. Such an approach aids the patient’s decision-making process and helps strike a complicated balance between cancer treatment and fertility preservation (13, 17).
Patient selection and risk assessment. While some studies advocate for educating and counseling all patients of reproductive age about fertility preservation, the necessity for a more targeted approach cannot be overstated (18). In contrast, not every patient opts for or benefits from fertility preservation (19). Therefore, the key lies in carefully selecting patients who are likely to benefit from these procedures based on a thorough assessment. Such a nuanced evaluation allows for a more reasonable use of resources and ensures that fertility preservation methods are applied in a way most likely to be effective and meaningful for the patient. Then, the physician should perform a structured assessment according to the patient’s status as follows (19). First, intrinsic factors include general health status regarding the disease status, patient and parents’ consent for FP counseling, developmental status of puberty, and ovarian reserve by AMH assessment. Additionally, when considering FP options, anesthetic complications, thromboembolic risk, thrombocytopenia or anemia status regarding hemorrhagic events, infection risk of neutropenic patients, and hormonal sensitivity of the tumor should be considered (13). Second, for assessing extrinsic factors, predicted treatment type, allowed time before cancer treatment, and availability of ART professionals and equipment, including laboratory, should be considered (19). Also, these factors should be documented with available and suitable FP options after consultation with patients and parents (20).
The extent of ovarian function impairment risk due to cancer treatments like cytotoxic chemotherapy and radiation is well discussed in prior publications (9, 21-23). Although effective in eradicating cancer cells, these treatments often cause collateral damage to rapidly dividing non-malignant cells, including those in ovarian follicles. The resulting gonadotoxic effects are of significant concern, affecting both immediate reproductive capabilities and broader physiological health, including the potential for premature menopause (7). Chemotherapy has both immediate and long-term effects on ovarian function. In the short term, chemotherapeutic agents damage growing follicles and cause amenorrhea through DNA alterations and impaired hormone production (24). In the long term, it depletes the ovarian reserve, raising the risk of premature ovarian insufficiency and infertility, particularly in older women. Different classes of drugs exert these effects via various mechanisms, ranging from DNA damage to vascular injury (24). In terms of gonadotoxic risk, high-risk treatments—those with a greater than 80% likelihood of causing ovarian damage—are predominantly alkylating agents, including cyclophosphamide, carmustine, ifosfamide, busulfan, chlorambucil, melphalan, procarbazine, lomustine, thio-THEPA, and nitrogen mustard as well as pelvic radiotherapy, total body irradiation, and cisplatin dose more than 600 mg/m2 (9, 22, 24). These agents exhibit cumulative, dose-dependent effects (21, 23). To better predict the risk of premature ovarian insufficiency, Green et al. proposed calculating the cyclophosphamide equivalent dose (CED) (22, 23). CED>8,000 mg/m2 and ovarian radiation at any dose were associated with an increased risk of premature ovarian insufficiency (23). Intermediate-risk gonadotoxic treatment includes cytarabine, vinblastine, taxes, doxorubicin, etoposide, and cisplatin less than 600 mg/m2. At the same time, methotrexate, mercaptopurine, fluorouracil, gemcitabine, vincristine, bleomycin, dactinomycin, daunorubicin, epirubicin, and mitomycin were of low risk for gonadotoxicity (24). Still, targeted agents and immunotherapy are emerging in pediatric oncology, and some evidence implies possible risk of gonadotoxicity, but clinical outcome is not well elucidated (9, 24-26).
Oocyte Cryopreservation in Adolescents
Oocyte retrieval and OC is the preferred option for post-pubertal adolescents, compared to embryo cryopreservation (EC), because most adolescents have no designated spouse. The ovarian follicles in women at near puberty exhibit physiological differences compared to those in adult women. Specifically, follicle growth demonstrates distinct patterns in post-pubertal girls who have experienced regular menstruation for less than five years (27). Furthermore, a case series study focusing on fertility preservation in patients with sickle cell anemia suggests that an increased dosage of recombinant follicle-stimulating hormone for ovarian stimulation may be necessary for these younger patients to achieve adequate follicular maturation (28). However, there is some variance; certain studies have indicated a need for higher doses for adequate follicle development in adolescents compared to adults, while other research suggests that the dosage requirements are not significantly different (29-35).
Methodology and current protocols. Specifically in the realm of oncofertility, the urgency of treatment often necessitates the use of ‘random start’ ovarian hyperstimulation protocols, with initial dosages mirroring those administered to adult populations. Starting controlled ovarian stimulation regardless of follicular or luteal phase, the number of retrieved oocytes was not different in the adult population (36, 37), but there was still a lack of evidence in terms of fertility and pregnancy outcome, and no reported pregnancy utilizing cryopreserved oocytes before 18 years old in female cancer survivors (38).
Ethical issues and informed consent. In many Middle Eastern societies, as well as in various religious communities around the world, the concept of virginity holds significant value. It is often associated with the physical state of the hymen; an intact hymen is frequently considered evidence of virginity and, by extension, a woman’s moral virtue. This belief holds substantial implications for medical procedures that require transvaginal access, including oocyte retrieval for OC. Notably, a study in Lebanon reported hymen disruption as a factor in parents’ refusal of FP after an adolescent child’s cancer diagnosis in 28.6% of cases (39). Furthermore, in a study of patients undergoing medical and social freezes, procedure-related hymenal disruption remains a barrier to the procedure in women over the age of 18, at 13-19% (40). If hymenal disruption is a reason for FP refusal, it may be possible to attempt oocyte retrieval through the abdomen, and a related case report utilized laparoscopy (41). In addition to hymen disruption, religion can also be a barrier to OC. However, there has been a recent trend toward acceptance of OC for FP before chemotherapy in many religious cultures (42-44). Recent studies have also reported that race or religion is not a significant factor in FP selection (45).
In pediatric medical practice, parental consent is typically required for minors undergoing medical procedures (46). However, when it comes to OC, a procedure with far-reaching implications for an adolescent’s bodily autonomy and future reproductive life, many argue that the adolescent’s assent should also be obtained. Assent, in this context, is not merely the absence of objection but an affirmative agreement from the minor. This notion aligns with medical ethics and pediatric guidelines, which advocate for the adolescent’s developing autonomy to be respected, especially in decisions affecting their long-term well-being (46, 47). In light of this, a shared decision-making model involving parents and adolescents is often recommended for FP procedures (45, 48-50). Comprehensive informed consent forms should incorporate medical facts and potential cultural and religious considerations, such as hymen integrity (50). Employing a multi-disciplinary approach, which may include healthcare providers, ethicists, and even religious or community leaders, can help create informed consent documents that are both medically sound and culturally sensitive.
Ovarian Tissue Cryopreservation in Adolescent Patients
OTC offers an alternative option to OC for adolescents facing medical, physiological, or time constraints for ovarian stimulation. OTC is still considered experimental in several societies, but the practice committee of ASRM published OTC as an established option for prepubertal girls, who are not candidates for ovarian stimulation (12), based on a large prospective cohort study in which 44 of 800 patients undergoing OTC underwent OTT and reported a live birth rate of 18.2% (51). However, OTC is still practiced in many parts of the world based on studies that have gone through institutional review boards.
Technical aspects of ovarian tissue cryopreservation. Unilateral oophorectomy or ovarian cortex biopsy are both tolerable, and in terms of surgical approach, laparoendoscopic single-site and multi-port laparoscopic access with or without robotic assistance are both reported to be feasible, and mini-laparotomy is also being utilized (52-55). The surgical approach did not influence the hospitalization period or chemotherapy delay (56). Although the impact of gonadotoxic treatment with and without unilateral oophorectomy has not yet been fully reported, the FetriPROTKET network group recommended that only 50% of one ovary to be removed and cryopreserved in adult women and that unilateral oophorectomy to be performed in prepubertal girls with small ovarian volumes (10). In addition, OTC can be combined with other procedures, including ovarian stimulation or transposition (13). OTC has been reported not to affect oocyte retrieval outcomes when performed before oocyte retrieval, but no transplant-related long-term outcomes have been reported when performed afterward (57-59).
Ovarian tissue transplantation techniques. Ovarian tissue can be reintroduced to the patients after completion of treatment for malignant disease, and transplantation can be performed on orthotopic (ovarian sites or peritoneal pocket) or heterotopic sites (arm, rectus muscle, abdominal wall) (60). However, orthotopic transplantation has been reported to result in better angiogenesis and tissue engraftment; therefore, orthotopic transplantation is preferred (61). OTT can be performed via laparoscopic or robotic surgery after the end of treatment, and a meta-analysis of several studies reported restoration of transplanted ovarian function at 3 months to 3.88 months (62).
Fertility outcomes after ovarian tissue cryopreservation. The first live birth case was reported in 2012 in a survivor of Hodgkin’s lymphoma who underwent OTT after five years of complete remission (63). Recent studies have shown endocrine function recovery in 94-95% of patients with premature ovarian insufficiency (64, 65) and a live birth rate of 26-41% in female cancer survivors after ovarian tissue transplantation (64-68). However, outcomes related to pregnancy after OTC in prepubertal girls have not yet been reported in this specific population, but it is possible to expect good clinical outcomes (69).
Special caution should be exercised during ovarian transplantation; one must know the risks of reintroducing malignant cells. Although it can be relatively safely performed for solid tumors, including cervical cancer, gastro-intestinal cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma with regional stage and exclusion of ovarian metastasis, OTC and transplantation have been considered a relative contraindication for tumors of the central nervous system, ovarian or adnexal tumor, and systemic malignant disorders such as leukemia (8, 9, 13). However, recently, a case series of six women with a mean age of 20 years reported that ovarian transplantation for leukemia was performed with detailed histologic evaluation, immunohistochemical assay, and molecular maker evaluation using FISH, and transplantation was performed to confirm oncologic safety and the transplanted ovary was removed during cesarean section in a single patient (70). In a study of 2,475 patients with 22-year follow-up, 75.7% of those who banked ovarian tissue after OTC stopped banking, with 49.1% citing pregnancy and 25.9% citing not wanting to have a baby as the main reasons (71).
Conclusion
Summary of findings. This review highlights the importance and complexity of fertility preservation in pediatric and adolescent cancer patients. The need for a multi-disciplinary approach encompassing oncology, reproductive medicine, psychology, ethics, and legal considerations is apparent. Emerging technologies and methodologies continue to expand the pool of patients who can benefit from these fertility-saving interventions, although patient selection remains a nuanced process requiring careful risk-benefit analysis. Significant advancements in clinical outcomes have been noted, particularly with methods such as OTC, which has shown promise in restoring endocrine function and facilitating live births in a significant proportion of adult female cancer survivors. However, there are cautionary notes, particularly in relation to the reintroduction of malignant cells, which remains a concern for certain types of cancers. Underutilization of banked ovarian tissues after OTC remains a significant issue, raising questions about long-term patient intentions and how well these align with medical procedures performed during the acute phase of cancer treatment.
Future directions and recommendations for research. The field of fertility preservation is evolving, and several gaps need to be filled. First, the long-term outcomes of these preservation techniques, particularly in pediatric and adolescent populations, require further exploration. Research should aim to gather more robust data on the efficacy and safety of these procedures over an extended period. Second, there is a lack of information on the psychological and emotional impact of fertility preservation procedures on minors and their families. Studies focusing on patient experiences and post-procedure quality of life are crucial for tailoring a more patient-centric approach. Third, ethical considerations, especially when dealing with minors, need to be scrutinized. Studies exploring the ethical landscape can offer guidelines and help inform legal parameters around fertility preservation in this sensitive population. Finally, additional studies should focus on the cost, accessibility, and health disparities in the availability of fertility preservation methods. Research in this direction could help formulate policy, making these vital services more universally accessible. In conclusion, future research in fertility preservation needs to be multifaceted and integrative, addressing not just the medical but also the psychological, ethical, and societal implications of these complex procedures.
Footnotes
Authors’ Contributions
Soo Jin Park: conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing original draft, visualization, funding acquisition. Ji Yeon Han: Validation, investigation, writing-review and editing, supervision. Sung Woo Kim: Validation, investigation, writing-review and editing, supervision. Hoon Kim: Methodology, validation, investigation, writing-review and editing, supervision. Seung-Yup Ku: Conceptualization, methodology, investigation, resources, writing-review and editing, supervision, project administration.
Funding
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C1424).
Conflicts of Interest
All Authors have no conflicts of interest to declare in relation to this study.
- Received September 24, 2023.
- Revision received October 12, 2023.
- Accepted October 13, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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