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/m2 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.
In the largest study to date to our knowledge, we examined the evolution of endocrine outcomes in aging survivors of childhood cancer in the context of prior treatment exposures. Our findings indicate that the cumulative risk of developing endocrine disorders steadily increases over time for most outcomes. These risks are particularly great for survivors previously treated with specific high-risk exposures, such as high-dose irradiation of the head, neck, or pelvis, and after exposure to high doses of alkylating agents. For many outcomes, even survivors exposed to non–high-risk therapies were significantly more likely to develop an endocrine disorder compared with siblings.
The magnitude and burden of endocrine abnormalities in childhood cancer survivors, particularly after high-risk cancer therapies, are striking.7,8,16,17 In a study of 310 adult survivors, Brignardello et al7 reported at least one endocrine disorder in more than half of survivors, 16 years after the diagnosis of childhood cancer. Patterson et al16 described a wide range of endocrine health conditions in 519 pediatric-age survivors observed in a survivor program, with many of the identified endocrinopathies associated with radiotherapy or stem-cell transplantation; however, their study did not include survivors of brain tumors, a group typically affected by endocrinopathies. In our study, nearly half of childhood cancer survivors experienced at least one endocrine abnormality, 16.7% at least two, and 6.6% three or more.
Among aging survivors, particularly after cranial irradiation, endocrine conditions with vague or minimal clinical symptoms, such as HP deficits, frequently remain undiagnosed or undertreated because of a lack of formal assessment. In this study, cumulative incidence of GH deficiency in CCSS participants after HP irradiation with 18 Gy or greater reached 17.3% within 15 years of primary cancer diagnosis and subsequently plateaued (Fig 5). These findings reflect an underascertainment of GH-deficient adult CCSS participants without a prior diagnosis of GH deficiency during childhood, resulting from a lack of systematic clinical follow-up. In contrast, Chemaitilly et al8 demonstrated an increasing prevalence of unrecognized adult GH deficiency in a cohort of childhood cancer survivors exposed to cranial irradiation when risk-based screening was applied. Furthermore, they reported a frailty phenotype of 13.1% in their survivors with untreated pituitary deficits at a median age of 33.6 years, a rate observed in the general population among individuals age 65 years or older. These findings underscore the long-term morbidity associated with unrecognized and untreated endocrinopathies in adult childhood cancer survivors.
Similarly, male survivors born in the 1950s were less likely to receive testosterone replacement, despite treatment exposures associated with the development of primary gonadal dysfunction, compared with survivors born after the 1980s. This likely reflects both underdiagnosis and undertreatment of this outcome. Because untreated gonadal insufficiency in men is associated with abdominal obesity, hypertension, dyslipidemia, low bone mineral density, sarcopenia, and frailty,8 timely diagnosis and treatment of gonadal dysfunction in aging male survivors is critical.
The COG-LTFU Guidelines provide consensus-based, exposure-specific recommendations for screening and management of late effects of pediatric cancer therapy and are intended for survivors 2 or more years after completion of therapy.13Both our data and those from the recent St Jude Life studies8,18 validate the utility of the COG-LTFU Guidelines for identifying survivors with exposures that place them at high risk for late adverse endocrine outcomes.19 Nevertheless, as noted in our study, even childhood cancer survivors treated with non–high-risk therapies demonstrated an increased risk for certain endocrine outcomes compared with siblings, highlighting the need for long-term surveillance and individualized screening practices in childhood cancer survivors even in the absence of high-risk treatment exposures.
The CCSS has many unique strengths, including longitudinal characterization of overall health conditions in a large, geographically diverse population of aging childhood cancer survivors, with detailed treatment information through middle adulthood, along with a sibling comparison population. Despite these strengths, a number of limitations must be considered when interpreting our findings. First, the outcomes are self-reported, with external validation only for thyroid malignancies, which could lead to both over- and under-reporting of certain outcomes; however, we used strict criteria, such as reported use of hormone replacement for endocrine outcomes of interest, to overcome some of these limitations. Second, given the lack of hormone data to differentiate between primary versus central endocrine dysfunction in some instances, our findings may have resulted in some misclassification of these outcomes. Third, the role of selection and surveillance bias should be considered when interpreting these results. The latter may explain, at least in part, the elevated risk of thyroid cancer in survivors in the non–high-risk exposure group. Finally, treatments for childhood malignancies have evolved over time, and for some cancers, such as HL and acute lymphoblastic leukemia, in which irradiation has been either eliminated or the dose fields reduced, the risks for several endocrine disorders will likely be lower than those reported in this study. However, the chemotherapy and radiotherapy treatments used in this cohort remain the backbone of therapeutic protocols for many childhood malignancies.20,21 Lastly, our findings are based on the most recent COG-LTFU Guidelines (ie, version 4.0), which provide consensus-based definitions for high-risk exposures for endocrine outcomes of interest. As new information emerges, these definitions may change, which could affect the reported risk estimates.
In summary, the prevalence and cumulative incidence of endocrine outcomes continue to increase as survivors age, particularly after high-risk treatment exposures. These findings underscore the importance of lifelong screening of at-risk childhood cancer survivors for endocrine abnormalities. The National Cancer Policy Board of the Institute of Medicine recommends that survivors receive risk-based care22; thus, our findings provide a compelling rationale for continued risk-based endocrine screening throughout adulthood.