Diabetes in Cancer Survivors a Late Effect of Abdominal Radiation?

Roxanne Nelson, BSN, RN

January 19, 2016

SAN FRANCISCO — Children and young adults treated with total body or abdominal radiotherapy have an increased risk for insulin resistance and diabetes mellitus, but the exact underlying mechanisms remain unclear. However, findings from a small pilot study suggest that even in individuals who are not overweight, this subset of childhood cancer survivors might be at high risk for subclinical derangements of glucose and insulin.

"Our preliminary data suggest abnormal glucose and insulin dynamics are indeed prevalent in childhood cancer survivors who are exposed to abdominal radiation," said lead author Danielle Friedman, MD, from the Pediatric Long-term Follow-up Program at the Memorial Sloan Kettering Cancer Center in New York City.

"These derangements are apparent at a very young age, even in the absence of clinical obesity," explained Dr Friedman, who presented the study results here at the Cancer Survivorship Symposium Advancing Care and Research. "Loss of insulin sensitivity and defects in secretion may play a pivotal role in mediating this process," she added.

Importantly, she noted, these results "are not consistent with an autoimmune disorder" as the underlying mechanism.

What Mechanism Is Involved?

There have been previous reports from a number of studies that childhood cancer survivors exposed to abdominal radiation are at increased risk for both insulin- and noninsulin-dependent diabetes, as reported by Medscape Medial News.

Several factors have been identified that are associated with a higher risk for subsequent diabetes. These include radiation dose to the pancreas, younger age at treatment, and longer time since completion of treatment, with a minimum latency of about 20 years, Dr Friedman reported, but the specific underlying mechanism has yet to be determined.

Dr Friedman and her colleagues set out to learn more about the pathophysiology leading to these derangements. "We wanted to also explore whether there is an autoimmune component involved in the development of diabetes," she said.

The cross-sectional pilot study involved cancer survivors who were treated at Memorial Sloan Kettering and who were off treatment for at least 2 years. All 26 study participants enrolled to date were quite young at the time of radiation exposure; mean age was 3.3 years and median age at the time of the study was 14.4 years.

Twenty participants had a primary diagnosis of neuroblastoma. Twenty-four participants received a maximal radiation dose to the pancreas of 20 to 29 Gy, one received 10.8 Gy, and one received 36 Gy.

At study entry, only three survivors were overweight and none were obese. Waist-to-height ratio was normal in 20 participants and was mildly elevated (0.5% - 0.6%) in six.

All participants underwent formal 2-hour glucose tolerance testing and were assessed for autoantibodies (insulin autoantibodies, islet cell autoantibody, glutamic acid decarboxylase), which are typically present in patients with type 1 diabetes. Hemoglobin A1c levels were also evaluated.

Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda Index.

Nine of the 26 participants (34.6%) had evidence of abnormal glucose or insulin homeostasis. "But importantly, none had overt diabetes, none had autoantibodies, and none had an abnormal A1c level," Dr Friedman reported. "Looking at a breakdown, we can see that there is no discreet pattern of abnormal levels."

For example, of the six participants with abnormal glucose homeostasis, the two with impaired fasting glucose also had reduced insulin sensitivity. Of the four participants with impaired glucose tolerance, two had normal insulin homeostasis and two had defects in insulin secretion.

"When we looked at the Matsuda Index in relation to time since radiotherapy, we saw an interesting trend of increasing insulin resistance with increasing time since radiotherapy," said Dr Friedman. "This will be an area that will be interesting to investigate in the future with larger numbers of patients."

She added that the team hopes to enroll more patients, especially adults whose radiation therapy was completed some time ago.

There might be a positive side to these findings, said Kathryn H. Schmitz, PhD, MPH, professor of epidemiology in biostatistics and epidemiology at the University of Pennsylvania in Philadelphia.

"This pilot study provided evidence that diabetes that follows pediatric cancers is not consistent with an autoimmune disorder," she explained. "In my book, that is really good news, as there is broad availability of nonpharmacologic health behavior lifestyle interventions that have been demonstrated to be effective in prediabetes."

An example is the Diabetes Prevention Program (Diabetes Care. 2002;25:2165-2171), which showed that lifestyle intervention resulted in a 58% reduction in the incidence rate of diabetes. "Taken together with other data presented at this meeting, which underscore the value of diet and lifestyle interventions in cancer survivors, we should do a better job in promoting physical activity and dietary and weight-loss programs in the context of survivorship care models," she added.

Dr Friedman and Dr Schmitz have disclosed no relevant financial relationships. Several coauthors report relationships with industry, as noted in the abstract.

Cancer Survivorship Symposium (CSS) Advancing Care and Research: Abstract 108. Presented January 16, 2016.

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