BY0000301 Thyroid Cancer Following Diagnostic Iodine-131 Administration Per HALL,* John D. BOICE, Jr.,* and Lars-Erik HOLM* ^Department of General Oncology, Radiumhemmet, and $Epidemiology andBiostatistics Program, Division of Cancer Etiology, National Cancer Institute, Bethesda, MD 20892, USA Abstract. To provide quantitative data on the risk of thyroid cancer following 1 3 1 I expo- sure, 34,104 patients administered 131 I for diagnostic purposes were followed for up to 40 years. Mean thyroid dose was estimated as 1.1 Gy, and 67 thyroid cancers occurred in con- trast to 49.7 expected [standardized incidence ratio (SIR) = 1.35; 95% confidence interval (CI) 1.05-1.71]. Excess cancers were apparent only among patients referred because of a suspected thyroid tumor and no increased risk was seen among those referred for other rea- sons. Further, risk was not related to radiation dose to the thyroid gland, time since expo- sure, or age at exposure. The slight excess of thyroid cancer, then appeared due to the un- derlying thyroid condition and not radiation exposure. Among those under age 20 years when 131 I was administered, a small excess risk (3 cancers vs 1.8 expected) was about 2- 10 times lower than that predicted from A-bomb data. These data suggest that protraction of dose may result in a lower risk than acute x-ray exposure of the same total dose. 1. Introduction Thyroid cancer has been convincingly linked to ionizing radiation only after childhood exposure [1-5]. Despite some reports that adult exposure might increase the risk, the evidence is weak [6- 8]. In the most recent follow-up of A-bomb survivors, thyroid cancer risk was significantly in- creased only among individuals under age 20 years at exposure [9]. Other than radiation dose, age at exposure appears to be the most important determinant of future risk, and differences in reported risk estimates might merely reflect differences in age distribution. 2. Material and Methods The patients were less than 75 years of age when examined with 131 I during the period 1950-69 and characteristics are given in Table I. A total of 2,408 individuals were exposed before 20 years of age and 316 before the age of 10 years. - 807 - 10,785 14/86 44 (1-75) 6 23 (5-38) 40(0-96) 2.4 (0.04-37) 1.3 (0.0-25.7) 23,319 22/78 42(1-75) 8 24(5-39) 40(0-96) 1.6(0.04-37) 0.9 (0.0-40.5) 34,104 20/80 43 (1-75) 7 24 (5-39) 40(0-96) 1.9 (0.04-37) 1.1 (0.0-40.5) Table I. Characteristics of patients exposed to 1 3 1 Iin relation to reason for referral. The first 5 years after expo- sure were excluded. Reason for referral Suspicion of thyroid tumor Other reasons All No. of patients Males/Females, % Mean age at exposure (range), years Patients <20 years of age at exposure, % Mean follow-up period (range), years Mean 24-hour thyroid uptake (range), % Mean administered activity (range), MBq Mean dose to the thyroid (range), Gy The individual absorbed thyroid dose was estimated from the amount of 131 I administered, the physical half-life of 1 3 1 I, the 131 I uptake in the thyroid gland, and the thyroid gland size. The follow-up period started at the time of first 131 I administration or if examined prior to 1958, at January 1, 1958. The end of follow-up was the date of thyroid cancer diagnosis, death, emigration, or December 31,1990. The cohort was matched with the Swedish Cancer Register for the period 1958-90 to identify thyroid carcinomas. The expected number of thyroid cancers were calculated using incidence data from this register and indirect standardization with adjustment for sex, attained age at expo- sure, and calendar period. Thyroid cancers occurring during the first 5 years of follow-up were excluded because any thyroid cancer occurring shortly after examination would be likely related to referral or increased medical surveillance and not 131 I exposure. 3. Results Between 1958 and 1990,67 thyroid cancers were identified more than 5 years after 131 I admin- istration. Forty-two of the 67 patients who developed thyroid cancer were referred because of clinical indications that a thyroid tumor might be present. The mean time after 13 lj administra- tion to the diagnosis of thyroid cancer was 15 years. There were 36 papillary, 18 follicular, 11 anaplastic or giant cell thyroid cancers found, and one sarcoma of the thyroid gland. In one case the exact histopathology was not given. The significant overall risk for thyroid cancer more than 5 years after exposure was 1.35 (Table II). A significantly higher risk was seen for the 10,785 patients referred under the sus- - 808 - picion of a thyroid tumor (SIR=2.86) compared to those referred for other reasons (SIR=0.75; Table U). Table II. Observed number of cases (Obs.) and thyroid cancer risk (SIR) in relation to estimated thyroid dose. The first 5 years after exposure were excluded. Dose, Gy All 50.25 0.26-0.50 0.51-1.00 >1.00 All Referredfor suspicion of thyroid cancer <0.25 0.26-0.50 0.51-1.00 >1.00 AH Referredfor other reasons 50.25 0.26-0.50 0.51-1.00 >1.00 All Obs. 11 16 9 31 67 6 12 4 20 42 5 4 5 11 25 SIR 1.03 1.84 0.46 1.60 1.35 3.57 4.30 1.39 2.72 2.86 0.55 0.68 0.47 1.04 0.75 95% CI 0.51-1.83 1.05-2.98 0.38-1.57 1.09-2.27 1.05-1.71 1.31-7.77 2.22-7.51 0.38-3.56 1.66-4.20 2.06-3.86 0.18-1.29 0.18-1.73 0.20-1.46 0.52-1.86 0.48-1.10 No dose-response relationship was noticed regardless of the reason for referral The highest risks were seen during the period 5 to 9 years after 131 I administration. Only 3 thyroid cancers occurred among the 2,408 patients exposed before the age of 20 years (SIR=1.69; 95% CI 0.35-4.93). Men had a significantly higher relative risk than women among those with a suspi- cion of a thyroid tumor. No cases of thyroid cancer were found among men referred for other reasons. 4. Discussion The thyroid gland of children appears to be one of the organs most susceptible to radiation car- cinogenesis with relative risk estimates at 1 Gy ranging from 4 to 12 [10]. Since 93% of the - 809 - 34,104 patients were over age 20 years when l^lj W as administered, the apparent absence of an overall effect might be attributable in part to the lower sensitivity of the adult thyroid gland. Iodine-131 delivers nearly all its radioactivity within the first 6 weeks of exposure and it is conceivable that this time was sufficient to allow repair of DNA damage to occur. Lifetime ex- posure to elevated levels of natural background radiation in China has not been associated with an increase in thyroid tumors [11]. A recent parallel analysis of most major studies of thyroid ir- radiation concluded that spreading dose over time may lower the risk of subsequent thyroid cancer [12]. The influence of the underlying thyroid condition, real or suspected, could influence the ob- servations in several ways. Persons under surveillance for a suspected thyroid condition might be more likely to have a thyroid cancer detected because of increased medical surveillance. We attempted to address these possibilities by excluding all thyroid cancers that were reported within 5 years of the initial 13*1 administration. The decreasing risk of thyroid cancer with time after 131 I examination is consistent with the possibility that the underlying condition and medi- cal screening contributed to some of the early thyroid cancers. On the other hand, exclusion of individuals who had been examined because of a suspected thyroid tumor may have depleted the exposure group of persons who would likely have developed thyroid cancer. To address this possibility, we conducted dose-response and time-response evaluations. No trend of in- creasing risk with increasing dose or time since exposure was suggested. A recent report from cancer registry data in Belarus purports high rates of thyroid cancer to be associated with radioactive fallout, mainly radioactive iodine, including 1 31 1 from the Cher- nobyl accident [13], This opinion was shared by an expert panel formed by the Commission of the European Communities, although they emphasized that the influence of screening should be carefully considered in assessing the results [14]. The time between exposure and appearance of the thyroid cancer is remarkably short and the dramatic increase in thyroid cancers most likely is, at least in part, related to the intense screening, increased awareness and changed referral routines [15]. Ongoing studies with estimated thyroid doses to individuals should help clarify the causal factors associated with the increase. References [1] C J. Fiirst et al.. 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