www.thelancet.com/oncology Published online August 23, 2012 http://dx.doi.org/10.1016/S1470-2045(12)70323-6 1 Articles Published Online August 23, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70323-6 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(12)70340-6 Radiation Epidemiology Group, INSERM U1018, Villejuif, France (F de Vathaire PhD, C El-Fayech MD, N Haddy PhD, C Guibout PhD, C Veres MSc, A Jackson MSc, I Diallo PhD, O Oberlin MD, C Thomas-Teinturier MD); Institut Gustave Roussy, Villejuif, France (F de Vathaire, C El-Fayech, N Haddy, C Guibout, C Veres, A Jackson, I Diallo, F F Ben Ayed MD, Prof M Schlumberger MD, O Oberlin); Université Paris-Sud, Villejuif, France (F de Vathaire, C El-Fayech, N Haddy, C Guibout, C Veres, A Jackson, I Diallo, O Oberlin); Centre for Childhood Cancer Survivor Studies, School of Health and Population Sciences, University of Birmingham, Birmingham, UK (D Winter HNC, Prof M Hawkins PhD); Hôpital Bicêtre, Le Kremlin Bicetre, France (C Thomas-Teinturier); and Institut Curie, Paris, France (H Pacquement MD) Correspondence to: Dr Florent de Vathaire, Radiation Epidemiology Group, Unit 1018 INSERM, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif, France florent.devathaire@igr.fr Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study Florent de Vathaire, Chiraz El-Fayech, Faten Fedhila Ben Ayed, Nadia Haddy, Catherine Guibout, David Winter, Cécile Thomas-Teinturier, Cristina Veres, Angela Jackson, Hélène Pacquement, Martin Schlumberger, Mike Hawkins, Ibrahima Diallo, Odile Oberlin Summary Background Children and young adults treated with total body or abdominal radiotherapy have an increased risk of insulin resistance and diabetes mellitus. However, little is known of the efect of pancreas irradiation on the risk of diabetes. We assessed the relation between radiation exposure and occurrence of diabetes in a large cohort of long- term childhood cancer survivors. Methods We sent a questionnaire to 3468 survivors of a childhood cancer treated in eight centres in France and the UK between 1946 and 1985, of which 2520 were returned. Each self-declaration of diabetes was conirmed by contacting the patients’ medical doctors. We estimated the radiation dose received by the tail, head, and body of the pancreas and 185 other anatomical sites during each course of radiotherapy from 1990 to 1995 for each child after reconstruction of the conditions in which irradiation was delivered. We investigated the relation between radiation dose to the pancreas and the risk of a subsequent diabetes diagnosis. Findings 65 cases of diabetes were validated. The risk of diabetes increased strongly with radiation dose to the tail of the pancreas, where the islets of Langerhans are concentrated, up to 20–29 Gy and then reached a plateau for higher radiation doses. The estimated relative risk at 1 Gy was 1·61 (95% CI 1·21–2·68). The radiation dose to the other parts of the pancreas did not have a signiicant efect. Compared with patients who did not receive radiotherapy, the relative risk of diabetes was 11·5 (95% CI 3·9–34·0) in patients who received 10 Gy or more to the tail of the pancreas. Results were unchanged after adjustment for body-mass index, despite its strong independent efect (p<0·0001), and were similar between men and women. Children younger than 2 years at time of radiotherapy were more sensitive to radiation than were older patients (relative risk at 1 Gy 2·1 [95% CI 1·4–4·3] vs 1·4 [95% CI 1·1–2·2] in older patients; p=0·02 for the diference). For the 511 patients who had received more than 10 Gy to the tail of the pancreas, the cumulative incidence of diabetes was 16% (95% CI 11–24). Interpretation Our study provides evidence of a dose-response relation between radiation exposure of pancreas and subsequent risk of diabetes. Because of the risks observed and the frequency of diabetes in general population, this inding raises important public health issues. The pancreas needs to be regarded as a critical organ when planning radiation therapy, particularly in children. Follow-up of patients who received abdominal irradiation should include diabetes screening. Funding Ligue Nationale Contre le Cancer, Institut de Recherche en Santé Publique, Programme Hospitalier de Recherche Clinique, Institut National du Cancer, Agence Française de Sécurité Sanitaire et des Produits de Santé, Fondation Pizer pour la santé de l’enfant et de l’adolescent. Introduction Little is known of the possible relation between radiation exposure and occurrence of diabetes mellitus. 1 In radiation epidemiology, diabetes has been considered as a possible confounding factor only in studies of cardiovascular outcomes. 2 To our knowledge, diabetes has never been studied as a radiation-induced outcome with accurate radiation dosimetry. However, it has been considered by the International Commission for Radiation Protection as one factor involved in multifactorial diseases that potentially afect the ofspring of populations exposed to ionising radiation. 3 One reason for this lack of knowledge is that diabetes mellitus is rarely a fatal disease, although it can lead to life-threatening complications. Furthermore, the disease is not routinely registered as a contributing cause of death in oicial statistics. Therefore, it cannot be satisfactorily investigated by studies based exclusively on causes of death. The Childhood Cancer Survivor Study 4 reported that patients who received radiation treatment for childhood cancer were 1·8 times more likely than their siblings to develop diabetes. This increased risk was 7·2 times greater after total body irradiation and 2·7 times greater after abdominal irradiation. The investigators also reported that increased diabetes incidence was unrelated to body-mass index (BMI), but was higher with younger age at diagnosis of childhood cancer. 4 We report the incidence of diabetes and its risk factors in a large cohort of childhood cancer survivors treated before 1986, and followed up for an average of 30 years.