Pooled analysis of thyroid cancer and radiation exposure in childhood cancer survivors: first results of the PIRATES project

*Lene H.S. Veiga, Institute of Radiation Protection and Dosimetry 

Keywords: Thyroid cancer, external radiation, pooled analysis, childhood cancer

Lene H. S. Veiga1,2, Jay H. Lubin1, Harald Anderson3,16, Florent de Vathaire4, Margaret Tucker1, Parveen Bhatti5, Arthur Schneider6, Robert Johansson7, Peter Inskip1, Ruth Kleinerman1, Roy Shore8, Linda Pottern9, Erik Holmberg10, Michael M. Hawkins11, M. Jacob Adams12, Siegal Sadetzki13, Marie Lundell14, Ritsu Sakata8, Lena Damber15, Gila Neta1, Elaine Ron1,17

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA; 2 Institute for Radiation Protection and Dosimetry, Brazilian Nuclear Energy Commission, Rio de Janeiro, Brazil 3 Department of Cancer Epidemiology, University Hospital, Lund, Sweden 4 Cancer Epidemiology Research Unit, National Institute for Health and Medical Research- Institut Gustave Roussy, Villejuif, France 5 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 6 University of Illinois College of Medicine, Section of Endocrinology, Diabetes and Metabolism, Chicago, IL, USA 7 Department of Oncology, University Hospital of Umeå, Sweden 8 Radiation Effects Research Foundation, Hiroshima, Japan 9 Captain, United States Public Health Service (retired), Bethesda, Maryland, USA. 10 Department of Oncology and Radiation Physics and the Oncological Centre, Sahlgrenska University Hospital, Goteborg, Sweden 11 Centre for Childhood Cancer Survivor Studies, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, United Kingdom 12 University of Rochester School of Medicine and Dentistry, Department of Community and Preventive Medicine, Division of Epidemiology, Rochester, NY, USA 13 Cancer and Radiation Epidemiology Unit, The Gertner Institute, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 14 Department of Medical Physics, Radiumhemmet, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden 15Oncology, Department of Radiation Sciences, Umeå University, Umeå, Sweden 16 Representing the Nordic Countries Childhood Cancer Survival Group 17 Deceased.

Introduction: The previous pooling study of thyroid cancer and radiation risk (1) remains the most important summary of epidemiologic information on thyroid cancer risks from exposure to external radiation. Nevertheless, questions remain regarding the risk associated with adult exposure, the shape of the dose-response curve at low and high doses, the effect of fractionated dose, the risk associated with specific thyroid cancer histologies, the effect of gender, and the relationship with attained age and time since exposure. In order to address these issues, the National Cancer Institute and investigators from throughout the world launched the second pooled effort on external radiation and thyroid cancer risk, PIRATES - Pooled International Radiation Thyroid Cancer Epidemiology Studies. PIRATES includes 14 studies from around the world (Nordic countries, France, England, Japan, US and Israel), with 1,469 thyroid cancer cases and 124,401 subjects exposed to external radiation due to medical, occupational and environmental exposures in infancy and adulthood. Childhood cancer survivors treated with radiation for their first tumor are a high risk group for thyroid cancer once the pediatric thyroid gland has been recognized as one of the most radiosensitive human organs. However, data are still limited for the evaluation of radiation dose-response at high doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. As a first effort under the PIRATES consortium and to increase understanding of treatment-related primary thyroid cancer following childhood cancer, we analyzed pooled data from four childhood cancer survivor studies.

Methods: We pooled data of two cohort and two nested case-control studies: The United States Childhood Cancer Survivors Study (2), the France and United Kingdom Childhood Cancer Survivors Study (3), the Late Effects Study Group (4) and the Nordic Countries Childhood Cancer Survivor Study (5). Individual estimated thyroid doses and detailed chemotherapy information were provided for each study. For pooled analyses, we used a likelihood function that combined binomial and Bernoulli probabilities to calculate excess relative risks (ERR) associated with radiation dose using the GMBO module of Epicure.

Results : Pooled data from the four studies included 16,757 childhood cancer survivors, 288,660 person-years of follow-up and 187 patients who developed thyroid cancer. RRs of thyroid cancer were higher in females (RR=2.2, 95% CI 1.6-3.1), decreased with greater age at first cancer (p<0.01) and increased with greater attained age (p<0.01), but were not related to type of first cancer (p=0.23). In non-radiation treated patients, RRs and 95% CIs for thyroid cancer by any alkylating agents, anthracyclines or bleomycin were 3.2 (0.9-14.9), 4.5 (1.4-17.8) and 3.2 (0.8-10.4), respectively, and decreased with increasing radiation dose category for any alkylating agents (p=0.02), anthracyclines (p=0.12) and bleomycin (p=0.01) to about 1.0 for patients receiving >20 Gy. RRs increased with radiation dose through 10 Gy, reached a plateau, then declined above 30 Gy . The fitted RR at 10 Gy was 13.7 (95% CI 8.0-24.0) for all data, with individual fitted estimates ranging from 6.8 (2.9-17.8) in the CCSS-Fr/UK study to 12.9 (1.3-499.7) in the CCSS-Nordic study. The ERR/Gy increased significantly with decreasing age at exposure (p<0.01). The ERR/Gy increased with time since exposure with an apparent peak 15-19 years after first exposure, but remained elevated 25 years and more after exposure. Gender and number of treatments did not modify the ERR/Gy estimate. We observed significant effect modification of radiation dose for treatment with alkylating agents (p=0.01), anthracyclines (p=0.01) and bleomycin (p=0.02).

Conclusions: Results from the analysis of the 14 studies in the PIRATES consortium will be the most comprehensive investigation of thyroid cancer risk due to external irradiation, providing important epidemiologic information for use by scientists and radiation protection agencies to estimate thyroid cancer risks from exposure to external, and by extension, internal radiation. Our first pooled analysis of thyroid cancer risk in childhood cancer survivors adds to the growing literature showing that certain chemotherapeutic agents can increase risks of solid tumors, but may interact with radiotherapy in complex ways. We also show that while risks decline following high dose radiotherapy, elevated risks continue for potentially many decades and therefore indicate the need for continued follow-up of childhood cancer survivors.

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