Endocrine Abnormalities in Aging Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Abstract

Purpose: The development of endocrinopathies in survivors of childhood cancer as they age remains understudied. We characterized endocrine outcomes in aging survivors from the Childhood Cancer Survivor Study on the basis of therapeutic exposures.

Patients and methods: We analyzed self-reported conditions in 14,290 5-year survivors from the Childhood Cancer Survivor Study, with a median age 6 years (range, < 1 to 20 years) at diagnosis and 32 years (range, 5 to 58 years) at last follow-up. Identification of high-risk therapeutic exposures was adopted from the Children's Oncology Group Long-Term Follow-Up Guidelines. Cumulative incidence curves and prevalence estimates quantified and regression models compared risks of primary hypothyroidism, hyperthyroidism, thyroid neoplasms, hypopituitarism, obesity, diabetes mellitus, or gonadal dysfunction between survivors and siblings.

Results: The cumulative incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors (P < .01 for all). Risk was significantly higher in survivors exposed to high-risk therapies compared with survivors not so exposed for primary hypothyroidism (hazard ratio [HR], 6.6; 95% CI, 5.6 to 7.8), hyperthyroidism (HR, 1.8; 95% CI, 1.2 to 2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2 to 7.5), thyroid cancer (HR, 9.2; 95% CI, 6.2 to 13.7), growth hormone deficiency (HR, 5.3; 95% CI, 4.3 to 6.4), obesity (relative risk, 1.8; 95% CI, 1.7 to 2.0), and diabetes mellitus (relative risk, 1.9; 95% CI, 1.6 to 2.4). Women exposed to high-risk therapies had six-fold increased risk for premature ovarian insufficiency (P < .001), and men demonstrated higher prevalence of testosterone replacement (P < .001) after cyclophosphamide equivalent dose of 20 g/m(2) or greater or testicular irradiation with 20 Gy or greater. Survivors demonstrated an increased risk for all thyroid disorders and diabetes mellitus regardless of treatment exposures compared with siblings (P < .001 for all).

Conclusion: Endocrinopathies in survivors increased substantially over time, underscoring the need for lifelong subspecialty follow-up of those at risk.

Fig 1.

Cumulative incidence of thyroid disorders: (A, B) underactive thyroid, (C, D) overactive thyroid, (E, F) thyroid nodules, and (G, H) thyroid cancer in (A, C, E, G) survivors overall and (B, D, F, H) survivors stratified by treatment exposure. Thin lines represent 95% CIs. HP, hypothalamic pituitary. (*) P < .01 for comparison versus the non–high-risk exposure group.

Fig 2.

Risk for (A, B) underactive thyroid and (C, D) other thyroid disorders, obesity, and diabetes mellitus in (A, C) survivors compared with siblings and (B, D) survivors according to treatment exposure. Bars represent 95% CIs. For obesity outcome, the 95% CIs are narrower than the width of the square plotting symbol. High-risk exposure for thyroid cancer includes thyroid irradiation with > 5 to 30 Gy, and non–high-risk exposure includes thyroid irradiation with 0 to ≤ 5 Gy or > 30 Gy. HP, hypothalamic pituitary.

Fig 3.

Prevalence of (A, B) obesity and (C, D) diabetes mellitus in (A, C) survivors overall compared with siblings and (B, D) survivors according to treatment exposure. Bars represent 95% CIs. TBI, total-body irradiation. (*) P < .05.

Fig 4.

Prevalence of (A) premature ovarian insufficiency in female survivors and (B) testosterone medication use in male survivors by age according to treatment exposure. Bars represent 95% CIs. CED, cyclophosphamide equivalent dose. (*) P < .001. (†) P < .01.

Fig 5.

Cumulative incidence of self-reported growth hormone deficiency in survivors by treatment exposure. Thin lines represent 95% CIs. HP, hypothalamic pituitary. (*) P < .001.

Fig A1.

Prevalence of adrenocorticotropic hormone deficiency by age among survivors by treatment exposure. Bars denote 95% CIs. HP, hypothalamic pituitary. (*) P < .05.