Children with cancer who undergo radiation to the pancreas are at increased risk for developing diabetes decades later, particularly when the exposure involves high doses, European researchers found.
The estimated relative risk for later diabetes was 1.61 (95% CI 1.21 to 2.68) when the radiation dose to the pancreas totaled 1 Gy, according to Florent de Vathaire, MD, of the Institut Gustave Roussy in Villejuif, France, and colleagues.
But among children who were exposed to doses of 10 Gy and higher to the tail of the pancreas, where most of the islets of Langerhans are found, the relative risk rose to 11.5 (95% CI 3.9 to 34), the researchers reported online in Lancet Oncology.
"Our investigation emphasizes the importance of long-term follow-up of childhood cancer survivors," they advised.
Childhood cancer survivors are at risk for various health difficulties later in life, including disorders of the endocrine system, and one earlier study identified a link with diabetes among patients who had undergone radiation therapy.
To confirm this in a large cohort, de Vathaire and colleagues contacted 2,520 individuals in France and the U.K. who had been treated for lymphoma or a solid cancer between 1985 and 1995 and survived for at least 20 years. Their medical records were examined to ascertain the details of their treatment. Diabetes was patient-reported and the diagnosis was confirmed with their medical doctors.
A total of 65% had undergone radiation for malignancies including nephroblastoma, neuroblastoma, non-Hodgkin's lymphoma, and tumors of the central nervous system.
Three-quarters had received a single course of of radiotherapy, while smaller numbers were given multiple courses.
The mean radiation dose to the body of the pancreas was 12 Gy, while the dose to the tail averaged 8.8 Gy.
During 30 years of follow-up, 65 patients developed confirmed diabetes. The condition was rare before adulthood, but these cumulative incidence rates were seen by age 45:
- Overall, 5.5% (95% CI 4.1 to 7.5)
- No radiation treatment, 2.3% (95% CI 0.8 to 6.4)
- Radiation treatment, 6.6% (95% CI 4.8 to 9, P=0.0003)
There also was a clear dose-response effect, with a cumulative incidence at age 45 of 16.3% for individuals with exposure to the tail of the pancreas exceeding 10 Gy.
The dose-response effect was independent of body mass index and was apparent in both insulin-dependent and non-insulin dependent diabetes as well as in both men and women.
The youngest patients were more susceptible to later diabetes, with an excess relative risk of 1.19 per Gy (95% CI 0.38 to 3.49, P=0.018) in those who had been treated with radiation before age 2 years.
The type of cancer also was a strong factor, with the highest incidence of diabetes at age 45 occurring among patients having had nephroblastoma, at 14.7% (95% CI 9.6 to 22.2) compared with 3.1% (95% CI 2.1 to 4.6) for other malignancies. The study cohort did not include leukemia survivors, who are at high risk of obesity and diabetes, the authors said.
Chemotherapy overall did not appear to influence diabetes risk, nor did radiation exposure to organs other than the pancreas.
Still, radiation does have other potentially relevant abdominal effects, such as damage to subcutaneous adipose tissue, according to Kevin C. Oeffinger, MD, and Charles A. Sklar, MD, of Memorial Sloan-Kettering Cancer Center in New York City.
"We hypothesize that with the loss of the normal abdominal subcutaneous depot, fat accumulation occurring with aging is preferentially stored in the deep viscera," Oeffinger and Sklar wrote in an accompanying commentary.
"Because visceral adiposity is strongly linked to insulin resistance, we speculate that this preferential increase in visceral adiposity might contribute to relative beta-cell insufficiency with insufficiency with insulin resistance developing in adulthood," they noted.
Limitations of the study included the chance of reporting bias, the exclusion of patients who died, and reliance on the less accurate radiation dose estimations than those used today.
Nonetheless, when children with cancer are being treated with radiation, exposure to the pancreas should be as minimal as possible and should not exceed "a few Gy," de Vathaire and colleagues cautioned.
The study was funded by the Ligue Nationale Contre le Cancer, the Institut de Recherche en Santé Publique, the Programme Hospitalier de Recherche Clinique, the Institut National du Cancer, the Agence Française de Sécurité Sanitaire et des Produits de Santé, and the Fondation Pfizer pour la santé de l'enfant et de l'adolescent.
The authors declared no conflicts of interest.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Lancet OncologySource Reference: de Vathaire F, et al "Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study" Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70323-6.
Lancet OncologySource Reference: Oeffinger K, Sklar C "Abdominal radiation and diabetes: one more piece in the puzzle" Lancet Oncol 2012; DOI: 10.1016/S1470-2045(12)70340-6.