Fertility preservation in pediatric leukemia and lymphoma: A report from the Children's Oncology Group

Abstract

Certain chemotherapy agents, radiation, and surgery can all negatively impact future fertility. Consults regarding treatment-related risk for infertility and gonadal late effects of these agents should occur at the time of diagnosis as well as during survivorship. Counseling on fertility risk has traditionally varied significantly across providers and institutions. We aim to provide a guide to standardize the assignment of gonadotoxic risk, which can be used in counseling patients both at the time of diagnosis and in survivorship. Gonadotoxic therapies were abstracted from 26 frontline Children's Oncology Group (COG) phase III protocols for leukemia/lymphoma, in use from 2000-2022. A stratification system based on gonadotoxic therapies, sex, and pubertal status was used to assign treatments into minimal, significant, and high level of increased risk for gonadal dysfunction/infertility. Risk levels were assigned to protocols and different treatment arms to aid oncologists and survivor care providers in counseling patients regarding treatment-related gonadotoxicity. Males were most commonly at high risk, with at least one high-risk arm in 14/26 protocols (54%), followed by pubertal females (23% of protocols) and prepubertal females (15% of protocols). All patients who received direct gonadal radiation or hematopoietic stem cell transplant (HSCT) were considered at high risk. Partnering with patients and their oncology/survivorship team is imperative for effective fertility counseling both prior to and post treatment, and this comprehensive guide can be used as a tool to standardize and improve reproductive health counseling in patients undergoing COG-based leukemia/lymphoma care.

Fertility preservation in pediatric solid tumors: A report from the Children's Oncology Group

“…While we found based on the PIN risk stratification system from the Oncofertility Consortium that there was a range of risk levels across COG protocols, a significant proportion of studies contained at least one arm conferring a high level of risk to female patients (17/32 or 53.1% prepubertal and 19/32 or 59.4% of pubertal) and male patients (21/32 or 65.6%). Compared to our prior report on leukemia/lymphoma protocols, 17 solid tumor protocols were more likely to deliver therapy in the high gonadotoxic risk category to all sex/pubertal groups, and the total dose of alkylating agents was substantially higher across solid tumor protocols. If considering the highest possible CED among protocol arms containing alkylating agents, the average CED dose among solid tumor protocols is 20.9 g/m 2 , with a maximum of 70.6 g/m 2 , compared to 4 g/m 2 , with a maximum of 13.2 g/m 2 among leukemia/lymphoma protocols.…”

“…Similar to prior published reports, 17 risk levels ( minimal, significant , or high ) were assigned by two separate authors based on the previously published PIN Risk Stratification System (Figure 1) for prepubertal females, pubertal females, and males 18 . Any discrepancies in risk assignment were resolved through team consensus.…”

“…Although certainly not guaranteed, survivors may have opportunities for fertility preservation post therapy, which underscores the importance of on‐going conversations post therapy and into survivorship. COG phase III leukemia and lymphoma protocols have been published, 17 and we are currently working on similarly stratifying the COG phase III neuro‐oncology protocols. It is our hope that in the future, these risk stratifications will be imbedded into research protocols, further reducing the barriers to fertility preservation and that a similar model can be employed throughout other international cooperative groups to allow for more uniform risk stratification and risk counseling globally.…”

“…Dosing in mg/m 2 was utilized for risk stratification, and any dosing in mg/kg was converted to mg/m 2 using the 30‐rule 23 . Relapsed trials, pilot studies, ancillary studies not containing chemotherapy, and phase I–II studies were excluded 17 . Two phase III therapeutic trials for melanoma were also excluded, as they were coordinated by study groups other than the COG.…”

“…Due to the gonadotoxic risks of therapy, multiple national and international cancer organizations, including the American Society of Clinical Oncology (ASCO), American Society of Reproductive Medicine (ASRM), European Society for Medical Oncology (ESMO), European Society for Paediatric Oncology (SIOPE), American Academy of Pediatrics (AAP), and the National Comprehensive Cancer Network (NCCN), suggest that fertility risk counseling should occur for all patients at the time of diagnosis and continue through survivorship, and that those interested should be referred for fertility preservation, 9–14 including ovarian stimulation and oocyte retrieval, ovarian tissue cryopreservation (OTC), testicular tissue cryopreservation (TTC), currently an experimental technology, 15,16 and sperm cryopreservation. We have previously summarized gonadotoxic risk for leukemia and lymphoma protocols from the Children's Oncology Group (COG) 17 . Due to the complexity of treatment for many solid tumors, such as exposure to more than one gonadotoxic chemotherapy agent or multiple treatment modalities, risk assessments for gonadotoxicity can be challenging, and we present a summary of those protocols in this manuscript.…”