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 ...effect 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 confirmed 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 significant effect. 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 effect (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 difference). 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 finding 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 Pfizer pour la santé de l'enfant et de l'adolescent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke ...after treatment of childhood cancer.
We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT.
Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval CI: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients.
The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer.
We analyzed data from a case-control study with 35 cases and 140 ...controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis.
Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trend became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m(2).
Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
To present a method for calculating dose-volume histograms (DVH's) to the active bone marrow (ABM) of patients who had undergone radiation therapy (RT) and subsequently developed leukemia.
The study ...focuses on 15 patients treated between 1961 and 1996. Whole-body RT planning computed tomographic (CT) data were not available. We therefore generated representative whole-body CTs similar to patient anatomy. In addition, we developed a method enabling us to obtain information on the density distribution of ABM all over the skeleton. Dose could then be calculated in a series of points distributed all over the skeleton in such a way that their local density reflected age-specific data for ABM distribution. Dose to particular regions and dose-volume histograms of the entire ABM were estimated for all patients.
Depending on patient age, the total number of dose calculation points generated ranged from 1,190,970 to 4,108,524. The average dose to ABM ranged from 0.3 to 16.4 Gy. Dose-volume histograms analysis showed that the median doses (D50%) ranged from 0.06 to 12.8 Gy. We also evaluated the inhomogeneity of individual patient ABM dose distribution according to clinical situation. It was evident that the coefficient of variation of the dose for the whole ABM ranged from 1.0 to 5.7, which means that the standard deviation could be more than 5 times higher than the mean.
For patients with available long-term follow-up data, our method provides reconstruction of dose-volume data comparable to detailed dose calculations, which have become standard in modern CT-based 3-dimensional RT planning. Our strategy of using dose-volume histograms offers new perspectives to retrospective epidemiological studies.
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5.
Thyroid adenomas after solid cancer in childhood Haddy, Nadia; El-Fayech, Chiraz; Guibout, Catherine ...
International journal of radiation oncology, biology, physics,
10/2012, Volume:
84, Issue:
2
Journal Article
Peer reviewed
Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after ...childhood cancer.
A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose received at other anatomical sites of interest.
After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently.
The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
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