Bench to Bedside | September 2016

Study Confirms Increasing Endocrine Disorders in Aging Childhood Cancer Survivors

A notable glowing success in the world of pediatric oncology is that there are more candles lighting up birthday cakes of young cancer survivors. As the years add up, these milestones are also significant reminders that cancer survivors must remain vigilant throughout their lifetimes to protect their hard-won health.

An estimated 420,000 childhood cancer survivors are in the U.S., and their remarkable recoveries are mainly due to significant advances in cancer therapies. Yet these same life-saving treatments often lead to several late effects in survivors as they reach adolescent and adult years, said Sogol Mostoufi-Moab, MD, MSCE, an oncologist and endocrinologist at The Children’s Hospital of Philadelphia.

Dr. Mostoufi-Moab recently led a study that showed childhood cancer survivors are at increased risk for endocrine system disorders over time. The endocrine system, a group of glands that help control growth, metabolism, puberty, and stress responses, is especially sensitive to chemotherapy and radiation.

“Endocrine abnormalities constitute a significant burden of late effects in childhood cancer survivors,” Dr. Mostoufi-Moab said. “Childhood cancer survivors demonstrate common endocrine abnormalities, such as thyroid disorders or type 2 diabetes mellitus commonly seen in older adult life, but at a much younger age.”

The investigators analyzed 14,290 survivors who participated in the Childhood Cancer Survivor Study (CCSS). Survivors were diagnosed with various cancers before age 21 and treated between 1970 and 1986. Their median age of cancer diagnosis was 6 years, and median age at last follow-up was 32. The study participants completed multi-item surveys that included their age at the onset of endocrine conditions such as underactive or overactive thyroid, thyroid nodule, thyroid cancer, hypopituitarism, osteoporosis, obesity, diabetes mellitus, male gonadal dysfunction, and premature ovarian insufficiency.

The researchers also collected information about the study participants’ prior exposures to cancer therapy, including head and neck, pelvic, abdominal or total body radiation, and alkylating chemotherapy. They adapted the Children’s Oncology Group Long-Term Follow-Up Guidelines to classify endocrine outcomes according to these treatment exposures. The study team analyzed this data to determine the likelihood of developing a specific endocrine disorder depending on disease diagnosis and type of therapy.

“The magnitude and burden of endocrine abnormalities in childhood cancer survivors, particularly after high-risk cancer therapies, are striking,” the study authors wrote.

The results, which were published in the Journal of Clinical Oncology, showed that 44 percent of survivors demonstrated at least one endocrinopathy, 16.7 percent at least two, and 6.6 percent three or more. Survivors of Hodgkin lymphoma had the highest frequency of an endocrine abnormality (60 percent), followed by survivors of central nervous system tumors (54 percent), leukemia (45.6 percent), sarcoma (41.3 percent), non-Hodgkin lymphoma (39.7 percent), neuroblastoma (31.9 percent), Wilms tumor (28.5 percent), and bone cancer (27.8 percent).

For common endocrine disorders such as thyroid abnormalities, obesity, and diabetes mellitus, survivors were compared to 4,031 siblings with no history of cancer. The findings showed that overall, childhood cancer survivors had much higher prevalence of common types of endocrine problems as they aged compared to their siblings. Those survivors who had very high-risk treatments, such as neck radiation or radiation to the head area, demonstrated significantly higher frequency of these disorders.

An important take-home message from the study, Dr. Mostoufi-Moab pointed out, is that even survivors without exposure to “high-risk” therapies still demonstrated significant late effects in common endocrine abnormalities such as thyroid disorders, obesity, and diabetes mellitus compared to siblings.

“These results highlight that there is no such thing as a ‘low-risk’ cancer survivor,” Dr. Mostoufi-Moab said. “Any adult who is a survivor of a childhood cancer should be considered at risk for endocrine late effects. Our findings emphasize the need for lifelong risk-based endocrine screening in the growing population of childhood cancer survivors.”

Childhood cancer survivors should also take an active role participating in their healthcare, particularly as they enter adulthood, she added. Primary care physicians without expertise in pediatric cancer may not recognize the need to provide appropriate surveillance-guided care, such as yearly screening evaluation for thyroid studies and diabetes mellitus, and to emphasize appropriate lifestyle modifications to address or prevent obesity. However, the Children’s Oncology Group Long-Term Follow Up Guidelines serves as a useful tool with helpful information for providers caring for childhood cancer survivors.

The current study raises awareness among adult primary care physicians about the importance of continued risk-based endocrine screening. For example, a 25-year-old survivor with previous history of total body or abdominal radiation during childhood should increase awareness regarding risk of early onset insulin resistance and type 2 diabetes mellitus. Therefore, once the screening values suggest pre-diabetes or early diabetes, initiating treatment at earlier stages is important as it can markedly reduce future life threatening cardiovascular outcomes, particularly at a younger age.

While currently there are new approaches to pediatric cancer diagnosis and treatments that have evolved over the past decade, raising the possibility that the risks for endocrine disorders in recent generations of cancer survivors may be lower than what was reported in this study, the authors point out that “the chemotherapy and radiotherapy treatments used in the CCSS study cohort remain the backbone of many therapeutic protocols for common childhood malignancies.”

Future research should focus on clinical trials aimed at finding ways to intervene at earlier stages to help prevent negative outcomes that are the direct consequences of cancer therapy, Dr. Mostoufi-Moab said. If successful, these results may contribute to many additional years to blow out more birthday candles.


www.research.chop.edu

Produced by The Children’s Hospital of Philadelphia Research Institute.

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