Fertility in Pediatric Oncology: Comprehensive Overview and the Way Forward

Despite the successes in improving survival rates in pediatric oncology, this outcome always opens new challenges, especially in fertility. Long-term infertility remains a serious risk in children and adolescents receiving cancer treatments. This overview from the 2024 Oncofertility Consensus document by CCLG Update 2024 elucidates how clinicians can meet these challenges and provide detailed insights into fertility preservation methods and post-treatment fertility care for young patients with cancer.

• Understanding Gonadotoxicity within Pediatric Oncology

Gonadotoxicity means the injury to reproductive organs caused by cancer treatments like chemotherapy, radiotherapy, and certain surgeries. Although these treatments of cancer are required and necessary, they do cause some long-term implications regarding fertility. The magnitude of gonadotoxicity depends upon a number of factors including:

1. Age at treatment: While younger children may have a more favorable initial ovarian or testicular reserve, early exposure prematurely ages these organs.
2. Type and dose of treatment: High-dose alkylating agents, for example, cyclophosphamide; radiation to the pelvic or cranial region; and other intensive protocols can significantly increase the risk of infertility.
3. Sex and stage of development: The disease occurs in males and females, but the specific mechanisms may differ. For example, spermatogonial stem cells are destroyed in males and females have a premature loss of ovarian follicles, potentially resulting in early menopause.

Conservation of Fertility: Tailored Interventions for Children

New 2024 guidelines underscore the importance of individualized fertility preservation before cancer treatment. Depending on gender, age, or kind of cancer therapy, specific methods apply.

Some of the important fertility preservation options for male patients follow:

• Semen Cryopreservation: This is the most established and widely used method for post-pubertal boys. It involves the collection and storage of semen before the commencement of chemotherapy or radiotherapy. The document strongly recommends this for boys mature enough to provide a sample.
• In case a boy is not able to ejaculate a sample, alternative collections like electro-ejaculation or testicular sperm extraction (TESE) are used.

This involves the freezing of testicular tissue that contains spermatogonial stem cells, an experimental technique for prepubertal boys who cannot provide a semen sample. This is still a research area, but future advances might use this tissue for restoring fertility.

For Female Patients:

• Ovarian Tissue Cryopreservation: This is an option available for both prepubertal and postpubertal girls. In this process, ovarian tissue with immature follicles is removed, frozen, and stored for eventual reimplantation or maturation. While promising, this technology remains largely experimental.

• Egg and Embryo Freezing: Egg and embryo freezing represent established methods of fertility preservation in post-pubertal girls. Both these techniques involve hormonal stimulation, followed by the collection of mature eggs, which are then frozen or fertilized to create embryos. Both of these, however, require the patient to delay cancer treatment for several weeks, hence is less feasible in the context of aggressive cancers.

• Ovarian Shielding and Transposition: If pelvic radiotherapy cannot be withheld, physical methods may be utilized, such as ovarian shielding or transposition, in which the ovaries are surgically relocated out of the radiation field.

Novel Preservation Approaches:

Combined Procedures: The combination of various fertility preservation methods, such as the collection of immature oocytes during the cryopreservation of ovarian tissue, is being considered in some centers. Although still in an experimental stage, this technique certainly represents a potential multi-layered approach to fertility preservation.

Strata of Fertility Risk by Type of Cancer and Treatment Protocol

The document is careful in stratifying fertility risk according to the type of cancer and treatment protocol, such that:

• Leukemia: Conventional protocols of treatment, like the ALLTogether1 trial for B-cell ALL, demonstrate that conventional standard and also intermediate-risk protocols pose low to moderate risks for fertility impairment. High-dose protocols involving cyclophosphamide or total body irradiation carry a very high risk for males and females.

• Brain Tumors: Cranial irradiation and chemotherapy pose a very high risk. There is the risk of disruption in hormone regulation due to radiation effects on the hypothalamic-pituitary axis, while chemotherapy drugs contained in protocols for high-risk medulloblastoma, such as cyclophosphamide and cisplatin, hold a very high risk of gonadotoxicity.

• Sarcomas: Survivors of bone and soft tissue sarcomas previously treated with high-dose ifosfamide and high-dose cyclophosphamide are at a very high risk for infertility.

Fertility care does not end when cancer treatment does. Survivors should be followed long-term to assess reproductive health and hormone levels. Some important posttreatment issues to be addressed:

For Males: The integrity of testicular function needs to be monitored by semen analysis and by the hormone levels of FSH, LH, and testosterone. Even with normal testosterone production, sperm production is compromised.

For Women: Ovarian reserve should be assessed by Anti-Müllerian Hormone levels and antral follicle count. Early menopause can occur following treatment with gonadotoxic therapies; thus, long-term HRT may be required to maintain bone density and overall cardiovascular health and well-being.

The paper also focuses on how important contraceptive counseling is since, after treatment, the return of fertility might come along suddenly for some patients. Even for those patients whose risk of fertility is high but do not want to conceive, appropriate contraception will be necessary.

Psychological Sequelae and Early Counselling

Fertility is a very personal crisis and may have implications for a patient's future life and mental health; medical issues of fertility must be addressed as early as possible in the cancer treatment process. This will ensure that patients and their families receive the necessary information to make decisions regarding fertility. Survivors of childhood cancer are often at heightened levels of depression and anxiety related to fertility concerns.

The Future of Oncofertility in Pediatric Oncology

Advances in cancer therapies will come with strategies to maintain fertility. The introduction of newer treatments, for instance immunotherapies and targeted agents, promises less gonadotoxic but also raises new uncertainties. Long-term effects on fertility of these agents are still in the infancy stage of studies, and use of these must be closely monitored and continued under study.

For now, the 2024 Oncofertility Consensus Document offers a framework that is critical to finding fertility risks and preservation in pediatric oncology.

Therein lies an opportunity for collaboration by oncologists, endocrinologists, fertility specialists, and patient families while empowering young survivors of cancer to lead full lives, which one day may include the building of families.

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References:

1. CCLG Oncofertility Consensus Document (2024 Revision). Compiled by the Late Effects Group for the CCLG. Contributors: Dr. Mark Brougham, Prof. Rod Mitchell, Dr. Sheila Lane. [2024 Revision].
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8. Skinner R, Mulder RL, Kremer LC, et al. Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Lancet Oncol (2017); 18: e75–90.