Wassim Chemaitilly

Childhood cancer survivors are at risk for developing endocrine disorders, including deficits in growth hormone, thyroid hormone and sex hormones. The influence these hormones have on cell growth and metabolism has raised concerns regarding the safety of their use as treatments in survivors of childhood cancer and brain tumors. This manuscript offers a summary of current knowledge, controversies and areas for future research pertaining to this area.

E22021 Background: Survivors of childhood cancer are at risk for BMD deficits. Contributions of treatment, physical and lifestyle factors to overall risk are unknown as are long-term consequences of moderate and severe deficits. Methods: BMD deficits were evaluated in 3919 five-year childhood cancer survivors in the St. Jude Lifetime Cohort (median age 31.7 [range 18.0-69.9] years, 52.6% male, 80.4% non-Hispanic White) using lumbar quantitative computed tomography and classified by age- and sex-specific Z-scores as moderate (<-1SD) or severe deficit (<-2SD). Multivariable logistic regression estimated odds ratios (OR), risk factor attributable fractions (AF), and associations between BMD deficits and long-term outcomes (social/functional outcomes, fracture, mortality). Results: BMD deficits were moderate in 21.7% (95% CI 20.4%-23.0%) and severe in 6.9% (95% CI 6.1%-7.7%) of survivors. Risk factors for moderate deficit included age 5-9 years at diagnosis (OR 1.63, 95% CI 1.31-2.03), >20Gy cranial radiotherapy (OR 1.75, 95% CI 1.41-2.18), >3240 mg/m² glucocorticoids (OR 1.34, 95% CI 1.09-1.66), and smoking (OR 1.55, 95% CI 1.27-1.90). AF were 7.2%, 0.7%, 5.9%, and 6.1% respectively; 80.1% of risk was unexplained. Risk factors for severe deficits included age 5-9 years at diagnosis (OR 1.95, 95% CI 1.36-2.80), BMI20Gy cranial radiotherapy (OR 5.22, 95% CI 3.74-7.30), testicular/pelvic radiation (OR 1.70, 95% CI 1.19-2.44), smoking (OR 1.71, 95% CI 1.21-2.43), and physical inactivity (OR 1.91, 95% CI 1.10-3.33). AFs were 10.9%, 7.0%, 2.9%, 11.5%, 6.7%, and 3.2% respectively; 57.8% of risk was unexplained. Those with deficits were less likely to live independently, to be employed, and more likely to require assistance with personal care needs (Table). Fracture risk was greatest among those with any BMD deficit, and mortality risk was greatest among those with severe deficits. Conclusions: Deficits in BMD among childhood cancer survivors are related not only to treatment, but also to modifiable health behaviors. In this population, children exposed to radiation or glucocorticoids are at greatest risk for poor bone quality and should be counselled to optimize health behaviors.

Background: Data on primary hypothyroidism and its long‐term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes.Methods: This was a retrospective study with a cross‐sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer‐related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored.Results: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%‐16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03‐1.08), was less likely in non‐Whites (OR, 0.96; 95% CI, 0.93‐0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01‐1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05‐2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14‐2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12‐2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07‐2.12).Conclusions: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.

Hypothalamic-pituitary (HP) dysfunctions are commonly reported complications in survivors of childhood cancer. These include growth hormone deficiency, luteinizing hormone/follicle-stimulating hormone deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, central precocious puberty, hyperprolactinemia, and central diabetes insipidus. Local tumor invasion and surgical or radiation-induced injury represent the highest risk factors. New treatment modalities, such as immunotherapy and molecular targeted therapy have the potential to cause autoimmune hypophysitis. Untreated HP dysfunctions are associated with adverse physical and psychosocial consequences and reduced quality of life. Systematic and periodic endocrine assessments optimize early diagnosis and timely treatment and may improve long-term health outcomes.

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome‐wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time‐to‐event analysis) and prioritized sex‐ and treatment‐stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome‐wide significant (p < 5 × 10⁻⁸) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex‐specific effects (p_{sex‐heterogeneity} < 7 × 10⁻⁶). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10⁻⁹; n = 1935 women) at this locus. In treatment‐stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95–1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54–2.28, p = 2.4 × 10⁻¹⁰; >36 Gray only: HR = 3.79, 95% CI 1.95–7.34, p = 8.2 × 10⁻⁵). These head/neck RT‐specific HAGHL single‐nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR).

To read the full J Clin Oncol. 2019;37(32):3018–3031. wassim.chemaitilly@stjude.org This retrospective study, with cross-sectional health outcomes analysis, evaluated Leydig cell function in 1516 childhood cancer survivors at a median duration of 22.0 years after cancer diagnosis. These patients are part of the St Jude Lifetime Cohort. An age- and sex-matched community control group was recruited among friends and relatives of patients. Leydig cell failure (LCF) was defined as serum total testosterone 9.85 IU/l, while Leydig cell dysfunction (LCD) was defined as testosterone ≥250 ng/dl and LH >9.85 IU/l. Follow-up data were available on 683 participants (45.2%). The point prevalence of LCF and LCD at the most recent evaluation was 6.9% and 14.7%, respectively; 42/104 patients with LCF (40.4%) used hormone replacement therapy. Eight controls, (4.8%) were receiving testosterone, but the indications for treatment were not available. No control had LCF, while 4 individuals had LCD. Independent risk factors for LCF included: age ≥26 years at assessment, testicular radiotherapy, and alkylating agents at cyclophosphamide equivalent doses ≥4000 mg/m². LCF was also associated with: abdominal obesity, diabetes mellitus, erectile dysfunction (ED), muscle weakness, and all-cause mortality. Hormone-treated LCF was associated with increased waist circumference, ED, muscle weakness, and depression, but not with all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF. No significant associations of LCF and LCD with adverse physical or psychosocial outcomes were found. The study reveals that despite the availability of hormonal replacement therapy, only a minority (40.4%) of patients with LCD receive such treatment. On the other hand, many of the associations between LCF and long-term adverse physical and psychosexual health outcomes persisted even among individuals who reported to be treated with hormonal replacement therapy. The selection of control subjects may be questioned, as some of them were treated with testosterone for unclear reasons. Finally, the cohort of survivors was not homogeneous, but included patients with different cancer diagnoses and prevalence estimates have to be interpreted with caution, given the substantial number of nonparticipants.

Hematopoietic stem cell transplantation (HSCT) is used in children to treat a variety of malignant and nonmalignant hematologic conditions and certain inborn errors of metabolism. Survivors of HSCT are markedly affected by disease and treatment toxicity. Endocrine complications are among the most commonly reported chronic health conditions in this population. In this review, we summarize the most common endocrine late effects after pediatric HSCT. We also highlight the importance of systematic and longitudinal evaluations to achieve early diagnoses and treatment for these conditions and improve the long-term health outcomes for patients who received HSCT as children.

Context: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. Objective: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). Design: Retrospective with cross-sectional health outcomes analysis. Setting: Established cohort; tertiary care center. Patients: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. Main Outcome Measure: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. Results: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and 30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). Conclusion: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.