The risk of developing diabetes later in life is greatly increased in childhood cancer survivors treated with radiotherapy (RT), specifically those who had the tail of their pancreas exposed to radiation, according to a study published online Aug. 23 in The Lancet.

In their study, Florent de Vathaire, PhD, of the Gustave Roussy Institute in Villejuif, France, and colleagues said the results mark the first estimation of a dose-response between radiation dose and the risk of subsequent diabetes mellitus.

The findings were based on responses to a questionnaire sent by the researchers to nearly 3,500 survivors of childhood cancer treated in France and the U.K. between 1946 and 1985. A total of 2,520 surveys were returned and self-declarations of diabetes were confirmed by respondents’ physicians. Radiation doses to various anatomical sites were then estimate.

By sending questionnaires to people treated in 1985 or earlier, the researchers ensured that all respondents would have a follow-up period of at least 20 years to allow adequate time for diabetes to present itself.

Sixty-five cases of diabetes were validated, according to de Vathaire and colleagues. By 45 years of age, 2.3 percent of patients who had not received RT had been diagnosed with diabetes, compared with 6.6 percent of those who were treated with RT.

Through a reconstruction of how RT treatments would have been applied, the authors determined patients were significantly more likely to be diagnosed with diabetes later in life when the tail of the pancreas is exposed to radiation, but the same is not true for other parts of the pancreas. They speculated this is because the islets of Langerhans—cells involved in insulin production—are primarily located in the tail.

Higher doses of radiation resulted in a greater chance of acquiring diabetes, according to the authors. Patients receiving an average dose of 24.2 Gy to the tail of the pancreas were found to be 12.6 times more likely to be diagnosed with diabetes within 20 years of RT compared with patients who did not undergo RT.

Cancer type also affected diabetes risk, as 14.7 percent of patients treated for nephroblastoma (kidney cancer) had been diagnosed with diabetes by age 45 compared with an average of 3.1 percent for other cancer types included in the study, according to the authors. RT for nephroblastoma focuses on the abdominal area, increasing the chance that the tail of the pancreas will be exposed.

“Radiation therapy techniques have changed since 1986, and therefore our findings of radiotherapy as a diabetes risk factor may not be applied to children treated more recently,” wrote the authors. “However, doses and dose rates have not substantially changed since this time, and there is no clear reason why the relation between pancreas radiation dose and diabetes risk that we estimated should not apply to patients treated more recently.”

In the accompanying commentary, Kevin C. Oeffinger, MD, of the Memorial Sloan-Kettering Cancer Center in New York City, underscored the implications of the study as RT remains a part of treatment for many children with neuroblastoma and kidney cancer. “Diabetes is a major risk factor for all-cause and cardiovascular mortality. Further study is therefore needed to clarify the mechanisms underlying diabetes after abdominal radiation. Understanding these mechanisms will, hopefully, result in the development of targeted interventions that will lead to a reduction in risk in this population,” he wrote.

de Vathaire and colleagues called for the pancreas to be regarded as a critical organ with planning RT, and said follow-up of patients should include diabetes screening. “Our investigation emphasizes the importance of long term follow-up of childhood cancer survivors; almost no diabetes mellitus was seen in our cohort, or those of others, before 20 years of follow up. It emphasizes the need for contouring the pancreas when planning radiation therapy to achieve as low as possible radiation dose to this organ, and certainly not exceeding a few Gy.”