An ongoing pilot study, designed to assess dynamic indices of insulin and glucose homeostasis in childhood cancer survivors exposed to abdominal radiation, has found a variety of derangements in glucose and insulin homeostasis in this cohort.¹ According to an analysis presented at the 2016 Cancer Survivorship Symposium, these data were not consistent with an underlying autoimmune disorder.

“These preliminary data suggest that abnormal glucose and insulin dynamics are indeed prevalent in childhood cancer survivors exposed to abdominal radiation,” said Danielle Novetsky Friedman, MD, of Memorial Sloan Kettering Cancer Center, New York. “These derangements are apparent at a very young age, even in the absence of clinical obesity. Loss of insulin sensitivity and defects in insulin secretion may play a pivotal role in mediating this process,” she added.

Increased Risk for Diabetes

As Dr. Friedman reported, it is well known that childhood cancer survivors treated with abdominal radiation are at increased risk for diabetes, with reports suggesting an increased risk of both insulin-dependent and noninsulin-dependent diabetes.

Although risk factors have been identified, including radiation dose to the tail of the pancreas, younger age at treatment, and longer time since completion of therapy, the exact mechanisms leading to diabetes in this population remain unknown.

Pilot Study Details

Dr. Friedman and colleagues performed a cross-sectional analysis of 26 survivors diagnosed up to 21 years of age and 2 or more years from completion of therapy. Participants were required to have received prior treatment with abdominal radiation at Memorial Sloan Kettering to allow for radiation dose reconstruction to the pancreas. Patients with a known diagnosis of diabetes as well as those previously exposed to radiation impacting the brain were excluded from the study.

Following an overnight fast, glucose and insulin levels were assessed at baseline and then 0, 30, 60, 90, and 120 minutes after a glucose load (1.75 g/ kg). Additional testing included hemoglobin A1C levels and autoantibodies typically present in patients with type 1 diabetes. Researchers also checked height, weight, and waist circumference of participants.

The average age of participants at the time of abdominal radiation therapy was 3.3 years, and the median age at the time of study was 14.1 years. Among the 26 participants (12 female), 20 had a primary diagnosis of neuroblastoma.

In addition, 23 participants were normal or underweight, 3 were overweight, and none met the clinical conditions for obesity. In terms of abdominal adiposity, 20 of 26 participants had a normal waist-to-height ratio, and 6 had an elevated waist-to-height ratio.

Derangements in Glucose and Insulin Homeostasis

Among the 26 participants, 9 (24.6% of the cohort) showed evidence of abnormal glucose and insulin homeostasis. However, none of the participants had overt diabetes, positive autoantibodies, or abnormal hemoglobin A1C level, Dr. Friedman reported.

“When we look at the specific breakdown of these derangements, we can see that there’s no discrete pattern in these subjects with abnormal levels,” said Dr. Friedman. “However, of the six participants with abnormal glucose homeostasis, we can see that two patients with impaired fasting glucose also have reduced insulin sensitivity.”

“In addition,” Dr. Friedman noted, “among the four participants with impaired glucose tolerance, two had normal insulin homeostasis, and two had defects in insulin secretion.” Of the three participants with abnormal insulin levels, two had reduced insulin sensitivity, and one had a defect of insulin secretion.

For participants with abnormal glucose or insulin homeostasis, the age at radiation therapy was also quite young, with maximum pancreatic radiation doses ranging from 21 Gy to 24 Gy. The median time since radiotherapy was 8.4 years and 8.5 years for participants with abnormal glucose and insulin, respectively.

“When we looked at the Matsuda index in relation to time since radiation,” said Dr. Friedman, “we saw a nonsignificant but interesting trend toward an increase in insulin resistance with increased time since radiotherapy. This will be an exciting area to investigate in the future in larger numbers of patients.”

Dr. Friedman cited the small cohort and short follow-up as possible limitations of this study.

“In the future, we hope to enroll additional patients in this study, especially adults with longer elapsed time since completion of radiotherapy,” she concluded. “We also plan to analyze the impact of abdominal radiation dose and volume on diabetes risk in survivors in the Childhood Cancer Survivor Study.” ■

Disclosure: Dr. Friedman reported no potential conflicts of interest.

Reference

1. Friedman DN, Wolden SL, Antal Z, et al: Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study. 2016 Cancer Survivorship Symposium. Abstract 108. Presented January 16, 2016.