Fertility Preservation in Pediatric and Young Adult Oncology: Navigating Gonadotoxicity and Treatment Strategies

As oncology care continues to evolve, a growing number of pediatric and young adult oncology patients are expected to live into their adult years. One of the key unresolved issues in this patient population is the preservation of fertility.¹ Gonadotoxic effects are present in treatments including chemotherapy, radiation, and surgery at varying intensities. The gonadotoxic effects can result in the disruption of the hypothalamic-pituitary-gonadal (HPG) axis, interference with uterine functionality, and direct DNA damage.

Chemotherapy regimens could have unintended impacts on fertility. | Image credit: © atyrenko | stock.adobe.com

Radiation or surgical procedures in the abdomen, pelvis, or near the hypothalamus can impact fertility, with gonadotoxic risk depending on the radiation dose and area targeted. Chemotherapy, including alkylating agents and platinum-based compounds, disrupt DNA synthesis and result in apoptosis.²

Alkylating agents are widely utilized across various pediatric and young adult chemotherapy protocols. Risks of infertility associated with these agents are not uniform. The cyclophosphamide equivalent dose (CED), expressed in mg/m2, consolidates the exposure from different alkylating agents, adjusting for each agent's equivalence factor.

The equivalence factors are listed in Table 1. It is important to note that the CED serves as a proxy for evaluating infertility risk, as it was established by correlating hematologic toxicity among agents.³ The infertility risk of the alkylating agent being utilized must also be evaluated in the context of the chemotherapy regimen used, in addition to what surgical procedures and radiation are being given.

The Children’s Oncology Group (COG) assessed recently conducted phase 3 clinical trials conducted from 2000 to 2022 to evaluate the gonadotoxic risks of commonly utilized standard chemotherapy regimens.^4,5 Therapies were categorized into low, moderate, and high risk for both biological males and females. Factors contributing to risk included exposure to alkylating agents or heavy metals, conditioning for hematopoietic stem cell transplant (HSCT), and radiation targeting the hypothalamus or gonadal areas. Therapies were stratified into minimal, significantly increased, and high level of increased risk in accordance with the Oncofertility Consortium Pediatric Initiative Network (PIN).⁶ Risk factors for gonadotoxicity include use of alkylating agents or heavy metals, HSCT conditioning regimens, and radiation therapy to either the hypothalamus or gonadal area. CEDs of > 4 g/m2 in males or > 8 g/m2 and > 12 g/m2 in pubertal and prepubertal females respectively were considered high risk.

Based on this assessment, the investigators were able to identify the risk of infertility among standard, commonly utilized regimens in pediatric oncology. For osteosarcoma, standard chemotherapy of cisplatin, doxorubicin, and methotrexate (MAP) is considered low risk for all patients, where as Ewing sarcoma patients receiving vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VCD/IE) were considered high risk.

Treatment for other solid tumors include but are not limited to Wilm’s tumor, hepatoblastoma, rhabdomyosarcoma, and neuroblastoma, which carry variability in gonadal toxicity risk depending on patient sex and pubertal status in addition to the specific regimen being utilized. Patients with Philadelphia chromosome negative B-cell acute lymphoblastic leukemia (B-ALL) treated with current COG regimens are considered minimal risk for infertility, whereas patients with acute myeloid leukemia (AML) are considered unlikely to experience significant gonadotoxicity outside of high-risk protocols requiring allogeneic HSCT.^5,6 

Choice of treatment to prevent or mitigate infertility depends on many variables, including patient specific factors, timing of fertility preservation strategies, as well as cost. For males, the primary method for preserving fertility is cryopreservation before starting chemotherapy. For female adolescents and young adults, the most effective methods include freezing embryos, oocytes, or ovarian tissue.⁷

Gonadotropin-releasing hormone (GnRH) agonists represent one of the few pharmacological options for preserving female fertility. The competitive binding to GnRH causes a subsequent downregulation of GnRH receptors and a decrease in GnRH secretion, which in turn lowers the levels of follicle-stimulating hormone, luteinizing hormone, and sex hormones.⁸ It is crucial to inform patients that while leuprolide can suppress the menstrual cycle, it should not be relied upon as an effective contraceptive method. Ideally, leuprolide should be administered 7 to 10 days before the start of chemotherapy to prevent ovarian flare, but logistical issues often arise, as delaying chemotherapy might not be feasible for aggressive cancers. If patients experience symptoms related to reduced estrogen, such as hot flashes and insomnia, adding hormonal therapies such as norethindrone acetate or an oral contraceptive pill (OCP) containing norethindrone can help alleviate symptoms as well as maintain bone mineral density.

During adolescence, bone development is crucial, with over 50% of peak bone mass being established in the teenage years. This is a key factor in predicting postmenopausal osteoporosis. GnRH agonists can increase bone turnover if used for more than 6 months, with potential long-term effects. Patients should be advised to take vitamin D and calcium supplements to support bone health while undergoing GnRH agonist treatment, especially for prolonged periods.⁹

Fertility preservation remains a challenging area in pediatric and young adult oncology. Oncology pharmacists can play a crucial role in evaluating gonadotoxicity, recommending fertility preservation methods and counseling on GnRH agonists.

REFERENCES

1. Salama M, Anazodo A, Woodruff TK. Preserving fertility in female patients with hematologic malignancies: a multidisciplinary Oncofertility approach. Ann Oncol. 2019;30(11):1760-1775. doi: 10.1093/annonc/mdz284

2. Blumenfeld Z. Chemotherapy and fertility. Best Prac Clin Obstet Gynecol. 2012;26(3):379-390.

3. Green DM, Nolan VG, Goodman PJ, et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2014;61(1):53-67. https://doi.org/10.1002/pbc.24679

4. Close A, Burns K, Bjornard K, et al. Fertility preservation in pediatric leukemia and lymphoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2023;70(8):e30407. doi: 10.1002/pbc.30407

5. Bjornard K, Close A, Burns K, et al. Fertility preservation in pediatric solid tumors: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2024;71(6):e30960. https://doi.org/10.1002/pbc.30960

6. Meacham LR, Burns K, Orwig KE, Levine J. Standardizing risk assessment for treatment-related gonadal insufficiency and infertility in childhood adolescent and young adult cancer: the Pediatric Initiative Network Risk Stratification System. 2020;9(6):662-666. https://doi.org/10.1089/jayao.2020.0012

7. Yang EH, Harmonie BS, Su HI. Fertility preservation before and after cancer treatment in children, adolescents and young adults. Cancer. 2023;130(3):344-355.

8. Garner C. Use of GnRH agonists. J Obset Gynecol Neonatal Nurs. 1994;23(7):563-70.

9. Kaya A, Cayir A, Turan MI, Ozkan B. An examination of the effects of leuprolide acetate used in the treatment of central precocious puberty on bone mineral density and 25-hydroxy vitamin D. West Indian Med J. 2015;64(2):104-107