Childhood Cancer Survivors Face Increased Risk of Endocrine Disorders as Adults

Comments by Lead Author Sogol Mostoufi-Moab, MD, MSCE and Melissa M. Hudson, MD

Cancer word on wooden blocksChildhood cancer survivors are at increased risk for endocrine disorders into adulthood, with the cumulative incidence and prevalence increasing over time, according to a long-term follow-up study published online ahead of print in the Journal of Clinical Oncology.

“Childhood cancer survivors who were not diagnosed with an endocrine abnormality in childhood are still at significant risk for developing treatment-associated endocrine abnormalities in adulthood,” said lead author Sogol Mostoufi-Moab, MD, MSCE, an Assistant Professor of Pediatrics in the Divisions of Oncology and Endocrinology at The Children's Hospital of Philadelphia. “With increasing age, the cumulative incidence and the prevalence of endocrinopathies increase in childhood cancer survivors.”

Data Was Derived From the Long-Term Childhood Cancer Survivor Study
The investigators analyzed endocrinopathies in 14,290 participants enrolled in the Childhood Cancer Survivor Study, a multi-institutional cohort of long-term childhood cancer survivors. The participants had survived for at least 5 years after a primary diagnosis of childhood cancers (ie, leukemia, central nervous system [CNS] malignancy, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, sarcoma, or bone malignancy). The median age at cancer diagnosis was 6 years and at last follow-up was 32 years.

Nearly half of the cancer survivors (44%) had at least one endocrinopathy; in addition, 16.7% had two and 6.6% had three endocrine abnormalities. These disorders were most common among survivors of Hodgkin lymphoma (60.1%), CNS tumor (54%), and leukemia (45.6%).  

The cumulative incidence and prevalence of all endocrinopathies increased with age among survivors (P<0.01). The risk was significantly higher in subjects exposed to treatments that are known to place them at high risk for endocrine disorders, such as high-dose irradiation of the head, neck, or pelvis or high-dose treatment with alkylating agents (Table).
Table. Hazard Ratio for Endocrine Abnormalities Among Survivors of Childhood Cancers Based on Risk ExposureAs noted in the Table, Dr. Mostoufi-Moab pointed out that even survivors exposed to non-high risk therapies were significantly more likely to develop thyroid disorders and diabetes mellitus (DM) compared with their siblings, suggesting the inappropriate categorization of a childhood cancer survivor as “low risk” with respect to developing endocrine abnormalities following cancer therapy.

Screening for Endocrine Disorders Is Essential to Care in Childhood Cancer Survivors
“Surveillance screening is very important in the care of cancer survivors,” Dr. Mostoufi-Moab said. She recommends that every survivor see a physician—typically a survivorship physician or endocrinologist—at least once a year for comprehensive evaluation and appropriate screen for common endocrine disorders, as well as other endocrine abnormalities (such as deficits in hypothalamic pituitary hormones) based on past cancer treatment exposure. “Recognizing endocrinopathies timely in childhood cancer survivors provides an opportunity for early initiation of treatment, particularly as cancer survivors demonstrate an increased risk for other morbidities (eg, cardiovascular) as a result of their cancer treatment.”

“Most adult providers may not initiate medical treatment for type 2 DM in adult patients with early laboratory evaluation suggesting pre-DM or early-onset DM, such as mild elevations in the Hemoglobin A1C. However, childhood cancer survivors with prior history of radiation and chemotherapy may have treatment-associated toxic effects on other organ systems, resulting in long-term morbidities that may become life threatening (eg, stroke or heart failure). Therefore, the additional diagnosis of DM, even at early stages, can notably increase the risk for these other long-term morbidities that can manifest at an earlier age.”

“The National Cancer Policy Board of the Institute of Medicine recommends that cancer survivors receive risk-based medical care, and the findings in our study provide a compelling rational for continued risk-based endocrine screening throughout adulthood” Dr. Mostoufi-Moab concludes.  “Given the growing number of childhood cancer survivors, adult medical providers should be aware of their needs to deliver the appropriate care necessary for these patients.”

Commentary

Melissa M. Hudson, MD
American Society of Clinical Oncology Expert, Pediatric Cancer
Director, Cancer Survivorship Division, St. Jude Children’s Research Hospital
Memphis, Tennessee

Endocrine disorders are among the most common late effects experienced by childhood cancer survivors and frequently develop many years following cancer treatment. Mostoufi-Moab and colleagues clearly demonstrate that the prevalence and risk of many endocrine disorders steadily increase over time in adults who were treated for childhood cancers. These data underscore the importance of maintaining vigilance for endocrine dysfunction in this population because of its potential adverse impact on a variety of metabolic functions, body composition, skeletal, cardiovascular and reproductive health, functional status, and quality of life.

This study confirms that individuals treated with radiation to body regions, including or near endocrine organs (brain, head/neck, pelvis) are at risk for hypothalamic-pituitary, thyroid, and gonadal hormone deficiencies. Dose thresholds for specific endocrinopathies have been reported, which generally show that risk increases in association with higher doses. Alkylating agents also can impact gonadal hormone production, most often following very high doses of these agents. These data help identify the very high-risk groups to target for screening, but clinicians should be aware that some survivors may be vulnerable even after lower dose exposure. The Children’s Oncology Group has used the evidence from outcomes research in childhood cancer survivors to guide recommendations for endocrinopathy screening of at risk survivors (see www.survivorshipguidelines.org).

It should be noted that the health outcomes data used in this study was based on medical conditions reported by the survivors, which means that the survivor had to present with clinical symptoms of endocrine dysfunction to establish the diagnosis or had to be under the care of an informed clinician who proactively screened for the condition. Data from studies performing standardized medical assessments in aging survivors have disclosed a substantial proportion of undiagnosed and untreated endocrine dysfunction, suggesting that the findings reported in the Mostoufi-Moab study represent an underestimate of the true prevalence of endocrinopathy.

Another interesting finding is the demonstration of increased risk for specific endocrine disorders (thyroid disease, diabetes) in survivors (compared to siblings) who did not receive high-risk treatments. Further research is required to identify treatment and other factors that contribute to this risk to guide surveillance recommendations.

September 6, 2016

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