Childhood Cancer Survivors Face Increased Risk of Endocrine Disorders as Adults

Comments by lead author Sogol Mostoufi-Moab, MD, MSCE and expert commentary provided by Melissa M. Hudson, MD.

Childhood 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 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.”

Cancer word on wooden blocks

Insights Gained 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 children had lived for at least five years after a primary diagnosis of childhood cancer (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 old and at the final follow-up visits, the average age of these individuals was about 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, which is evident in the Table  that follows:

Table. Hazard Ratio for Endocrine Abnormalities Among Survivors of Childhood Cancers Based on Risk Exposure

Dr. Mostoufi-Moab said 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 annually to receive a comprehensive evaluation and appropriate screening for common endocrine disorders, as well as other endocrine abnormalities (such as deficits in hypothalamic-pituitary hormones, and growth hormone deficiency) 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 diabetes in adult patients with early laboratory evaluation suggesting pre-diabetes or early-onset diabetes, such as mild elevations in hemoglobin A1c, she told EndocrineWeb.

"However, childhood cancer survivors with a 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).," Dr. 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 rationale for continued risk-based endocrine screening throughout adulthood,” Dr. Mostoufi-Moab said. “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.”

Caring for Pediatric Patients in the Post-Cancer Phase

Endocrine disorders are among the most common late effects experienced by childhood cancer survivors and frequently develop many years following cancer treatment, according to 

In an interview with Melissa M. Hudson, MD, director of the Cancer Survivorship Division at St. Jude Children’s Research Hospital in Memphis, Tennessee, and an American Society of Clinical Oncology expert in pediatric cancers, she told EndocrineWeb that Dr. Mostoufi-Moab and colleagues had demonstrated 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," said Dr. Hudson.

Furthermore, 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, according to Dr. Hudson.

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 findings will 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," she said, and 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 patient had to present with clinical symptoms of endocrine dysfunction for a diagnosis to be established or the patient had to be under the care of a clinician who had 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," said Dr. Hudson.

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, she said. Further research is required to identify treatment and other factors that contribute to this risk to guide surveillance recommendations.

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