Background: Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy. Methods: In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14 054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000. Findings: Risk of thyroid cancer increased with radiation doses up to 20-29 Gy (odds ratio 9.8 [95% CI 3.2-34.8]). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkin's lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkin's lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkin's lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0.07). Interpretation: The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkin's lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.
Bibliographical noteFunding Information:
We thank the survivors who have contributed to the Childhood Cancer Survivor Study, the data abstractors, and the survey interviewers; the investigators of the institutions that participated in the CCSS and Pauline Mitby for her contributions to the data collection; Charles Land for advice on radiation dose-response modelling; Daniel Green and Rochelle Curtis for helpful comments; John Whitton for database and statistical input; Rita Weathers for assistance in radiation-treatment-calculation programming; and Jennifer Donaldson for graphics presentations. This work was supported by grant CA 55727 from the National Cancer Institute, Bethesda, MD, USA; grant 147149 from The Lance Armstrong Foundation, Austin, TX, USA; and by the Children's Cancer Research Fund, CA, USA.