Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort.

Context: Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. Objective: To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes. Design: Cross-sectional. Setting: The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center. Patients: Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. Main Outcome Measure: POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). Results: The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. Conclusion: High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.

Frailty in childhood cancer survivors.

Young adult childhood cancer survivors are at an increased risk of frailty, a physiologic phenotype typically found among older adults. This phenotype is associated with new-onset chronic health conditions and mortality among both older adults and childhood cancer survivors. Mounting evidence suggests that poor fitness, muscular weakness, and cognitive decline are common among adults treated for childhood malignancies, and that risk factors for these outcomes are not limited to those treated with cranial radiation. Although the pathobiology of this phenotype is not known, early cellular senescence, sterile inflammation, and mitochondrial dysfunction in response to initial cancer or treatment-related insults are hypothesized to play a role. To the authors' knowledge, interventions to prevent or remediate frailty among childhood cancer survivors have not been tested to date. Pharmaceutical, nutraceutical, and lifestyle interventions have demonstrated some promise.

Bone mineral density deficits and fractures in survivors of childhood cancer.

Although substantial increases in survival rates among children diagnosed with cancer have been observed in recent decades, survivors are at risk of developing therapy-related chronic health conditions. Among children and adolescents treated for cancer, acquisition of peak bone mass may be compromised by cancer therapies, nutritional deficiencies, and reduced physical activity. Accordingly, failure to accrue optimal bone mass during childhood may place survivors at increased risk for deficits in bone density and fracture in later life. Current recommendations for the treatment of bone density decrements among cancer survivors include dietary counseling and supplementation to ensure adequate calcium and vitamin D intake. Few strategies exist to prevent or treat bone loss. Moving forward, studies characterizing the trajectory of changes in bone density over time will facilitate the development of interventions and novel therapies aimed at minimizing bone loss among survivors of childhood cancer.