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Survivors of childhood cancer face a lifelong risk of endocrine disorders, which increase with time and the aggressiveness of cancer therapy, a review of 14,000 patients showed.

Patients exposed to high-risk therapies had risks that were five to 10 times higher for various thyroid disorders and growth hormone deficiency, as compared with survivors' siblings. The risk of obesity and diabetes were twice as high among survivors exposed to high-risk treatment regimens.

Aggressive treatment significantly increased the likelihood of premature ovarian insufficiency in women and the need for testosterone replacement therapy in men, , of Children's Hospital of Philadelphia, and coauthors reported online in the .

"The prevalence and cumulative incidence of endocrine outcomes continue to increase as survivors age, particularly after high-risk treatment exposures," the authors concluded. "These findings underscore the importance of lifelong screening of at-risk childhood cancer survivors for endocrine abnormalities."

Primary care physicians, oncologists, and endocrinologists should find the study informative with respect to recognizing, monitoring, and managing endocrinopathies in survivors of childhood cancer, said , of the Banner University Medical Group in Arizona.

"The critical issue is that these young people with malignancies are going to be referred on as adults, either to oncologists or adult primary care specialists, and it's important to know that there are endocrine deficiencies that can occur as a result of the therapies," said Levy, a clinical expert for the American Academy of Clinical Endocrinology. "It might be helpful to have a condensed guide or outline to show that patients with a specific type of cancer might be prone to certain endocrine disorders."

"The awareness needs to be there in the endocrine population, as well, particularly later, when the patients are out of the pediatric age range," he added.

As patients transition from care provided by pediatricians and pediatric oncologists to specialists in adult medicine, an endocrinology consultation probably would be a good idea, said Levy.

Advances in the diagnosis and treatment of childhood cancers has led to a . The clinical success also has led to a growing population of survivors, currently .

Survivors of childhood cancers have an increased risk for a variety of health disorders, including endocrine abnormalities. Endocrine effects of cancer often arise many years after treatment, and an increase in frequency is expected over time, the authors noted. However, little information exists with respect to endocrinopathies in cancer survivors beyond young adulthood.

Mostoufi-Moab and colleagues performed an analysis to determine more precisely the prevalence and incidence of endocrine disorders in survivors of childhood cancers. They used data from the Childhood Cancer Survivor Study, a longitudinal, multi-institutional cohort study.

Comparing the cancer survivors and siblings (as well as patients exposed to high-risk therapies versus those who were not), the authors sought to quantify the incidence, prevalence, and risk estimates (hazard ratios) for primary hypothyroidism, hyperthyroidism, thyroid neoplasms, hypopituitarism, obesity, diabetes mellitus, and gonadal dysfunction. Treatment exposures were classified as high risk for endocrine disorders in accordance with the Children's Oncology Group .

The analysis included 14,290 patients with cancer diagnoses before age 21, treated from 1970 through 1986, and who were alive 5 years after diagnosis. Investigators included patients with Hodgkin or non-Hodgkin lymphoma, leukemia, central nervous system (CNS) malignancy, Wilms tumor, neuroblastoma, sarcoma, or bone malignancy.

The study population had a median age at cancer diagnosis of 6 years and a median age at last follow-up of 32. Overall, 44% of the survivors had at least one endocrine disorder, 16.7% had two or more, and 6.6% had three or more. Endocrinopathies occurred most often in survivors of Hodgkin lymphoma (60.1%), followed by CNS tumors (54%), leukemia (45.6%), sarcoma (41.3%), non-Hodgkin lymphoma (39.7%), neuroblastoma (31.9%), Wilms tumor (28.5%), and bone cancer (27.8%).

The cumulative rate of all thyroid disorders increased with survivor age versus siblings. Significant differences persisted even for cancer survivors not exposed to high-risk therapies.

Comparison of patients exposed or not exposed to high-risk therapies revealed significant differences in the risk of:

• Primary hypothyroidism -- HR 6.6, 95% CI 5.6-7.8;
• Hyperthyroidism -- HR 1.8, 95% CI 1.2-2.8;
• Thyroid nodules -- HR 6.3, 95% CI 5.2-.75;
• Thyroid cancer -- HR 9.2, 95% CI 6.2-13.7;
• Growth hormone deficiency -- HR 5.3, 95% CI 4.3-6.4;
• Obesity -- RR 1.8, 95% CI 1.7-2.0; and
• Diabetes mellitus -- RR 1.9, 95% CI 1.6-2.4.

Women exposed to high-risk therapies had a six-fold greater risk of premature ovarian insufficiency, and men had a significantly increased likelihood of requiring testosterone replacement after a cyclophosphamide equivalent dose of 20 g/m² or testicular irradiation.

Survivors had an increased risk of all thyroid disorders and diabetes mellitus, regardless of treatment exposures, compared with siblings, the authors reported.

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