Cancer Risk After Radioactive Iodine Treatment for Hyperthyroidism

Key Points Question Is radioactive iodine (RAI) therapy for hyperthyroidism associated with an increased cancer risk? Findings This systematic review and meta-analysis, including 12 observational studies and 479 452 participants, found that RAI therapy was not associated with a significant increase in overall cancer risk or site-specific cancer incidence or mortality, except for thyroid cancer. However, a linear radiation dose-response association between RAI therapy and solid cancer mortality was observed, based on 2 studies with information on RAI administered dose. Meaning Considering the global use of RAI therapy for hyperthyroidism, further studies are needed to provide quantitative estimates of site-specific cancer risks associated with RAI therapy, particularly at higher doses.


Moderate
The ICRP and data from Edmonds and Smith were used to estimate the radiation dose from RAI treatment to various organs. However, SIR was not shown by dose level of administered activity.

Low
There was an objective measure of outcome (SIR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, 1950-1975 and follow-up 15 years). Lag time 1 and 10 years. All patients were considered to be at risk from 1 year after the initial RAI treatment or from 1958 if first treatment occurred prior to that year.

Low
The essential covariates (age, sex, calendar year, region, dose) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.
Statistical methods (other biases)

Moderate
The statistical methods were appropriate for the available data (Poisson distribution assumption and chisuqare test). They did not provide additional sensitivity analysis results and dose-response analysis.

Low
The reported results were complete and unbiased (stratified reporting by hyperthyroidism types, all organ sites, follow-up period 1 & 10 years).

Low
The ICRP tables, the mean 24-hr uptake, and the mean administered activity of RAI were used to calculate the mean radiation dose to various organs. SMR was shown by dose level of administered activity.

Low
There was an objective measure of outcome (SMR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was resonably complete (treatment period, 1950-1975 and follow-up 15 years). Lag time 1 and 10 years. All patients were considered to be at risk from the initial RAI treatment until death or December 31, 1986 Confounder control (other biases)

Low
The essential covariates (age, sex, calendar year, region, dose) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.

Moderate
The statistical methods were appropriate for the available data (Poisson distribution assumption and chisquare test). They did not provide additional sensitivity analysis results and dose-response analysis.

Low
The reported results were complete and unbiased (stratified reporting by all organ sites, age groups, followup period, and dose level of administered activity).

Low
Doses from RAI to 17 organs were estimated for study subjects by multiplying the amount of administered activity by the dose factors (age and 24-hour thyroid uptake) provided for each organ in current ICRP tables. RR was shown by dose level of administered activity.

Low
There was an objective measure of outcome (SMR, RR and ERR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was resonably complete (treatment period, 1946-1964 and follow-up 21 years). Lag time 1 to over 10 years. The follow-up was extended until December 31, 1990.

Low
The essential covariates (age, sex, race, calendar year, time since treatment, dose) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.
Statistical methods (other biases)

Low
The statistical methods were appropriate for the available data (EPICURE software and Poisson distribution assumption used for SMR, RR, ERR calculating). They provided additional sensitivity analysis results (dose-response analysis). Reporting (other biases)

Low
The reported results were complete and unbiased (stratified reporting by all organ sites, study entry year groups, hyperthyroidism types, treatment methods, and dose level of administered activity).

Conflict of interest NI No information
Franklyn, 1999 11 Very Low

Study participants (selection bias)
Low A cohort study of UK regional cancer register population. All patients who had been treated for hyperthyroidism with RAI in the West Midlands region of the UK between 1950 and 1991. The control was UK Regional Cancer Register and the analyzed sample size was 7,417 patients.

Serious
There was no adequate explanation for the dose estimation procedure especially for individual organs. SIR and SMR were not shown by dose level of administered activity (the overall incidence of uterine cancer and bladder cancer were only described in main body, not in the regular table).

Low
There was an objective measure of outcome (SIR and SMR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, I131 for 1950-1991 & control for 1971-1991, and follow-up 9.7 years). The follow-up was computerized Birmingham Thyroid Follow-up Register.

Moderate
The essential covariates (age, sex, calendar year, period) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has not been considered.

Moderate
The statistical methods were appropriate for the available data (Poisson regression used for SIR and SM calculating). They did not provide additional sensitivity analysis results and dose-response analysis.

Moderate
The reported results were not complete and unbiased (only main outcomes of SIR and SMR were reported without stratified reporting by covariates).

Conflict of interest NI No information
Hahn , 2001 29 Moderate Study participants (selection bias) Low A cohort study of German democratic Republic's cancer registry population. Exposed and nonexposed patients were recruited from 10 German hospitals that had conducted thyroid examinations in children.
Patients were included in the RAI group (exposed group) if records existed for at least one administration of RAI for diagnostic purposes for the age of 18 years. The nonexposed group (German democratic Republic's cancer registry) consisted of patients who had been examined because of suspected thyroid disease. The analyzed sample size was 789 (RAI) and 1118 (non-exposed) Exposure (performance bias)

Low
The thyroid dose from RAI was calculated according to the biokinetic model of ICRP Report No. 53 (21). OR was shown by dose level of administered activity.

Low
There was an objective measure of outcome (SIR, RR and OR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was resonably complete (treatment period, I131 for 1958-1978 & non-expose for 1959-1986). Person-time for exposed subjects was defined as the period between the first test using RAI uptake and the study examination; person-time for nonexposed subjects was defined as the period between the initial referral for one of the examinations fulfilling the inclusion criteria for this group and the study examination. Confounder control (other biases)

Low
The essential covariates (age, sex, calendar year, time since treatment, dose) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.

Moderate
The statistical methods were appropriate for the available data (logistic regression used for SIR, RR, and OR calculating). They did not provide additional sensitivity analysis results.

Low
The reported results were complete and unbiased (stratified reporting by study entry year groups, hyperthyroidism types, and dose level of administered activity).

Low
The ICRP tables, the mean 24-hr uptake, and the mean administered activity of RAI were used to calculate the mean radiation dose to various organs. SIR was shown by absorbed thyroid dose.

Low
There was an objective measure of outcome (SIR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up period commenced at the date of first RAI administration or 1 January 1958 if the patient was first exposed prior to 1958. Accumulation of person-time at risk began 2 years after the date of first RAI administration. Person-time at risk was accumulated until the date of diagnosis of thyroid cancer, date of death, date of emigration or 31 December 1998, whichever occurred first. Lag time 2 to 20 and over 20 years.

Moderate
The essential covariates (age at first exposure, time since first exposure, absorbed RAI dose to the thyroid gland and gender) have been adjusted. However, the type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has not been considered. Statistical methods (other biases)

Moderate
The statistical methods were appropriate for the available data (EPICURE software and Poisson distribution assumption). They did not provide additional sensitivity analysis results.

Low
The reported results were complete and unbiased (stratified reporting by time since first exposure, absorbed RAI dose to the thyroid gland and gender).

Study participants (selection bias)
Low A cohort study of Finland national wide Hospital Discharge Registry population. The study population was a patient with hyperthyroidism treated between January 1965 and June 2002 at Tampere University Hospital. Choosing an age-and gender-matched control subject for each patient from the Population Register Centre formed a reference group. The analyzed sample size was 1,399 of RAI and 1,465 of thyroidectomy. Exposure (performance bias)

Moderate
There was no adequate explanation for the dose estimation procedure especially for individual organs. However, RR was shown by dose level of administered activity.

Low
There was an objective measure of outcome (RR & HR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, 1966-2003 and follow-up 9 years (RAI) & 9.4 years (control)). Lag time 3 months. The follow-up period of the control subject started at the same time as that of the corresponding patient. In both patient and control groups, the follow-up ended on the date of death, emigration, or the common closing date (December 2003) Confounder control (other biases)

Low
The essential covariates (age, sex, treatment type, etiology of hyperthyroidism, dose) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.

Moderate
The statistical methods were appropriate for the available data (Kaplan-Meier analysis with the log-rank test used for RR and HR calculating). They did not provide additional sensitivity analysis results.

Low
The reported results were complete and unbiased (stratified reporting by all organ sites, age at first treatment, etiology of hyperthyroidism, infectious diseases, endocrine diseases, cardiovascular diseases, and dose level of administered activity).

Conflict of interest Low
They provided a statement of conflict of interest to all contributors.

Ryodi, 2015 31
Low Study participants (selection bias) Low A cohort study of Finland national wide Hospital Discharge Registry population. The study population was a patient with hyperthyroidism treated between January 1986 and December 2007 in Finland from the nationwide Hospital Discharge Registry maintained by the National Institute for Health and Welfare. The reference population was formed by randomly choosing three age-and sex-matched control subjects for each patient from the comprehensive national population register. The analyzed sample size was 1,814 (1485 women and 329 men). Exposure (performance bias)

Serious
There was no adequate explanation for the dose estimation procedure especially for individual organs. RR and HR were not shown by dose level of administered activity. Outcomes (detection bias)

Low
There was an objective measure of outcome (RR & HR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was resonably complete (treatment period, 1986-2007 and follow-up 10 years). Lag time 3 months. The follow-up of the patients for cancer incidence started 3 months after the treatment, ie, thyroidectomy or the first dose of RAI, and on the same day for the corresponding controls.

Low
The essential covariates (age, sex, treatment type, etiology of hyperthyroidism) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered.
Statistical methods (other biases)

Moderate
The statistical methods were appropriate for the available data (Cox regression multivariate analysis used for RR and HR calculating). They did not provide additional sensitivity analysis results and dose-response analysis. Reporting (other biases)

Low
The reported results were complete and unbiased (stratified reporting by all organ sites, sex, etiology of hyperthyroidism).

Conflict of interest Low
They provided a statement of conflict of interest to all contributors.

Serious
There was no adequate explanation for the dose estimation procedure especially for individual organs. HR was not shown by dose level of administered activity.

Low
There was an objective measure of outcome (HR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, 1976-2000 and follow-up 16.3-22.3 years). The Patient Register is managed by the Swedish National Board of Health and Welfare, and has been validated and used for research previously. The study cohort was compiled by merging extracted data on Stockholm residents for the years 1976-2000. All individuals (both radioiodine treated and surgically treated) were then matched to the entire Patient Register for the period 1969-2000 to find other diagnoses, related to any earlier hospitalizations, that would constitute relevant baseline co-morbidity. Confounder control (other biases)

Low
The essential covariates (age, sex, smoking history, BMI, Clalit district, socioeconomic status, diabetes mellitus, hypertension, pharmacy of aspirin and of statins, and adherence to mammography) have been adjusted. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has been considered. Statistical methods (other biases)

Low
The statistical methods were appropriate for the available data (propensity score matching, inverse probability weighting, and Cox PH regression used for HR calculating). They provided additional sensitivity analysis results (by propensity score matching and inverse probability weighting, and only subjects aged 35-75 years.). Reporting (other biases)

Low
The reported results were complete and unbiased (stratified reporting by all-cause mortality, cardiovascular disease, age at treatment, year of treatment, co-morbidities at baseline, hyperthyroidism types, and treatment methods

Serious
There was no adequate explanation for the dose estimation procedure especially for individual organs. HR was not shown by dose level of administered activity.

Low
There was an objective measure of outcome (HR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, 2002-2015). Date of entry to the cohort was the date of first prescription of a thionamide or radioiodine. If a patient was treated with thionamide and later with radioiodine, time of follow-up starting at beginning of thionamides and before receiving radioiodine was added to the follow-up time of thionamide treatment to prevent immortal time bias. Thus, for this patient, follow-up time for radioiodine was started at the date of administration of radioiodine.

Moderate
The essential covariates (age, sex, smoking history, BMI, Clalit district, socioeconomic status, diabetes mellitus, hypertension, pharmacy of aspirin and of statins, and adherence to mammography) have been considered. The type of hyperthyroidism (Graves' disease and Toxic nodular goiter) has not been considered. Statistical methods (other biases)

Low
The statistical methods were appropriate for the available data (propensity score matching, inverse probability weighting, and Cox PH regression used for HR calculating). For sensitivity analysis we stratified the cohort by calendar year at cohort entry to account for difference, if it existed, in radioiodine dose over the years. Reporting (other biases)

Low
The reported results were complete and unbiased (stratified reporting by all-cause incidence, NHL only, follow-up, and treatment methods).

Conflict of interest Low
They provided a statement of conflict of interest to all contributors. Low RAI photon and electron spectra from the ICRP were used to compute the S values (mean absorbed dose in a target region per unit disintegration of RAI in a source region) on the adult reference voxel phantoms adopted by the ICRP for all important combinations of source and target regions. HR was shown by dose level of administered activity. Outcomes (detection bias)

Low
There was an objective measure of outcome (SMR and HR) which was appropriately justified and selected. No any systematic outcome measurement errors.

Low
The follow-up was reasonably complete (treatment period, 1946-1964 and follow-up 26 years). Lag time 5 years. Follow-up of US patients was recently extended through December 31, 2014.