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. Author manuscript; available in PMC: 2020 Dec 3.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2020 Oct;27(5):323–328. doi: 10.1097/MED.0000000000000561

Cancer incidence and mortality following treatment of hyperthyroidism with radioactive iodine

Josh M Evron 1, Nazanene H Esfandiari 2, Maria Papaleontiou 2
PMCID: PMC7714219  NIHMSID: NIHMS1649427  PMID: 32773569

Abstract

Purpose of Review:

Hyperthyroidism is a commonly encountered clinical issue. Radioactive iodine is one of the treatment modalities employed over the last 80 years. Prior studies are conflicting as to whether radioactive iodine is associated with an increased risk of subsequent malignancy and associated mortality. This article reviews recent publications on this subject.

Recent Findings:

Two recent studies make meaningful contributions to the existing literature; however, data remain inconsistent. The first, conducted using the Clalit Health Services database, evaluated solid tumor incidence after radioactive iodine and found no association with increased risk of solid tumor malignancy. The second, which is an updated analysis of the Cooperative Thyrotoxicosis Therapy Follow-up Study, concluded that there is a dose-dependent increased risk of solid tumor mortality using a novel method of estimating organ-specific radiation exposure.

Summary:

In patients with hyperthyroidism, radioactive iodine is a popular and effective treatment option. Prior studies reach conflicting conclusions on the potential relationship between radioactive iodine and both subsequent cancer incidence and mortality. We review recent publications that add to our understanding of this important clinical question.

Keywords: radioactive iodine, hyperthyroidism, malignancy, mortality

INTRODUCTION

Radioactive Iodine (131I) was first evaluated as a therapeutic modality for hyperthyroidism by Dr. Saul Hertz in 1941[1, 2]. By 1990, it had become the preferred treatment method for Graves’ disease in the United States (U.S.), with a survey of American Thyroid Association members suggesting that nearly 70% of respondents considered radioactive iodine their first-line therapy (survey response rate 62%) [3].

On the other hand, the possibility of an increased risk of secondary malignancies in physicians exposed to ionizing radiation has been of significant concern since the early 1900s [4] and increased risk of leukemia was demonstrated in Japanese survivors of the atomic bombings [5]. Additionally, several studies have concluded that the higher activities of radioactive iodine used in the treatment of differentiated thyroid cancer are associated with a small, dose-dependent increased risk of leukemia and solid cancers [6–8].

Multiple prior studies have evaluated whether the lower activities of radioactive iodine used in the treatment of hyperthyroidism might also be associated with an increased risk of subsequent malignancies and associated mortality with conflicting results [9–17]. Two papers, published within the last 18 months, make significant contributions to this body of literature. The goal of this review is to briefly summarize important historical papers and then to provide a more detailed overview of these recent publications, including their strengths and limitations. Table 1 provides a summary of studies to date on the association between radioactive iodine use for hyperthyroidism and subsequent risk of malignancy and associated mortality.

Table 1.

Summary of studies evaluating risk of secondary malignancies and mortality following radioactive iodine treatment in patients with hyperthyroidism.

Study (Year) Primary Outcome Evaluated Cohort Size (N) Control Group Duration of Follow Up Primary Result
Dobyns et al. [10]a (1974) Post-treatment thyroid cancer incidence and mortality 34,684 Hyperthyroid patients treated with thyroidectomy
*No statistical analyses performed		 8 years (mean) Incidence rate of 0.09% vs 0.03% (RAI vs surgery)

Mortality rate of 0.03% vs 0.02% (RAI vs surgery)
Hoffman et al. [17] (1982) Post-treatment cancer incidence 3,146 Hyperthyroid patients treated with thyroidectomy 15 years (mean) Cancer incidence: RR 1.0 (95% CI 0.7–1.3)
Holm et al. [13] (1991) Post-treatment cancer incidence 10,207 Population-based age, sex and year-specific controls 15 years (mean) SIR 1.06 (95% CI 1.01–1.11)
Hall et al. [12] (1992) Post-treatment cancer mortality 10,552 Population-based age, sex and year-specific mortality data 15 years (mean) SMR 1.09 (95% CI 1.03–1.16)
Ron et al. [14] (1998) Post-treatment cancer mortality 35,593 Population-based age, sex and year-matched mortality data 21years (mean) SMR 1.02 (95% CI 0.98–1.07)
Franklyn et al. [11] (1998) Post-treatment cancer mortality 7,209 Population-based age, sex, and year-matched mortality data Not reported Cancer mortality was not increased (numbers not provided)
Metso et al. [16] (2007) Post-treatment cancer incidence 2,793 Population-based age and sex-matched controls 9.8 years (median) RR 1.25 (95% CI 1.08–1.46)
Ryodi et al. [15] (2015) Post-treatment cancer incidence and mortality 6,148 Hyperthyroid patients treated with thyroidectomy 10 years (median) Cancer incidence: HR 1.03 (95% CI 0.86–1.23)
Cancer mortality: HR 1.05 (95% CI 0.80–1.39)
Kitahara et al. [25]** (2019) Dose-response relationship between radioactive iodine and cancer mortality 35,593 None 26 years (mean) RR for breast cancer mortality 1.12 (95% CI 1.00–1.32) at 100-mGy

RR for solid cancer mortality 1.06 (95% CI 1.02–1.10) at 100-mGy
Gronich et al. [18]** (2020) Post-treatment cancer incidence 16,637 Hyperthyroid patients treated with thionamides 7.3 years (mean) Cancer incidence: HR 1.01 (95% CI 0.83–1.21)
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SIR = Standardized incidence ratio, SMR = Standardized mortality ratio, RR = Relative risk, HR = Hazard ratio

a

Cohort used for thyroid cancer analysis

OLDER STUDIES

Cooperative Thyrotoxicosis Therapy Follow-Up Study

The Cooperative Thyrotoxicosis Therapy Follow-Up Study was initiated in 1961 and followed 36,050 patients treated for hyperthyroidism at 26 U.S. and one British medical center between 1946 and 1964. The first report of these data with regards to solid malignancies was performed by Dobyns et al. in 1974. This study evaluated the risk of thyroid cancer following treatment of hyperthyroidism. The authors report that the study was limited by a number of factors including low rates of thyroid malignancy, significant within-group heterogeneity, and different lengths of follow up [10]. Post-occurring (≥ 1 year after treatment) malignant thyroid neoplasms were seen in 0.03% (4/11,732) of those treated with thyroidectomy, 0.09% (19/21,714) of those treated with radioactive iodine, and 0.32% (4/1,238) of those treated with antithyroid drugs. Death from malignant thyroid neoplasms occurring ≥ 1 year after treatment occurred in 0.02% (2/11,732) of patients treated surgically and 0.03% (6/21,714) of patients treated with radioactive iodine.

In 1998, Ron et al. conducted a follow up evaluation of this cohort examining cancer mortality rates [14]. Overall, in patients treated with radioactive iodine, there was no increased risk of solid cancer mortality (standardized mortality ratio [SMR], 1.02; 95% confidence interval (CI), 0.98–1.07), compared to age, sex, race, and year-matched U.S. mortality rates. There was a significantly increased risk of thyroid cancer-specific mortality (SMR, 3.94; 95% CI, 2.52–5.86), and the risk was higher in those with toxic multinodular goiter (SMR, 6.53; 95% CI, 2.80–12.82).

Notably, Ron et al. attempted to evaluate the possibility of a dose-response relationship for hematopoietic and lymphoproliferative neoplasms by estimating bone marrow exposure, and for thyroid cancer using administered activity of radioactive iodine. The authors found no relationship between estimated bone marrow dose and death from any hematopoietic or lymphoproliferative neoplasm. As above, there was an association between radioactive iodine and increased thyroid cancer mortality, and a significant dose-response relationship was found using standardized mortality ratios. The dose-response trend was not significant in Poisson regression analyses using internal comparison.

Other Studies

Cancer incidence and mortality risk in patients receiving radioactive iodine for hyperthyroidism were also evaluated retrospectively in Sweden. This cohort included 10,552 patients treated with radioactive iodine for hyperthyroidism between 1950 and 1975. A total of 1,543 cancers were identified between 1958–1985, occurring ≥1 year after radioactive iodine treatment. Overall, compared with the general population, there was a slightly increased incidence for any cancer (standardized incidence ratio [SIR], 1.06; 95% CI, 1.01–1.11) with a specific increased risk of lung (SIR, 1.32; 95% CI, 1.07–1.59) and kidney cancer (SIR, 1.39; 95% CI, 1.07–1.76) [13]. In a complementary study using the same cohort (mean follow-up 15 years), cancer mortality was also increased (SMR, 1.09, 95% CI, 1.03–1.16) with a specific increase in death from cancer of the digestive tract, lung, and thyroid [12]. There was a non-significant increase in SMR with increasing radioactive iodine dose. A population-based study in the United Kingdom utilizing the Birmingham Thyroid Follow-Up Register (N=7,209), found no increased risk of death from cancer in patients with hyperthyroidism treated with radioactive iodine [11].

In a 2007 study using data from the Finnish Cancer Registry (N=2,793), which assessed the long-term cancer risk from radioactive iodine treatment for hyperthyroidism (median follow-up 9.8 years), overall cancer incidence was increased (SIR, 1.25; 95% CI, 1.08–1.46) compared with age- and sex-matched controls. Significant increases in the incidence rates of kidney, breast, and gastric cancer were observed [16]. On the contrary, findings from a more recent Finnish study (N = 6,148) did not demonstrate a significantly increased overall cancer incidence (relative risk (RR), 1.05; 95% CI, 0.96–1.15) or cancer mortality (RR, 1.09; 95% CI, 0.95–1.26) in treated hyperthyroid patients compared with age and sex-matched controls. Additionally, cancer mortality was not higher in those treated with radioactive iodine versus surgery (hazard ratio [HR] 1.05; 95% CI 0.80–1.39) [15].

RECENT STUDIES

Radioactive Iodine and Cancer Incidence

In early 2020, Gronich et al. published the results of their study evaluating the post-treatment incidence of malignancy in hyperthyroid patients ≥18 years of age treated with either radioactive iodine or thionamides [18]. This was a population-based cohort study utilizing records from Clalit Health Services, the largest health services provider in Israel, between 2002 and 2015. This database contains health information including comorbid conditions, smoking status and socioeconomic status, as well as whether the patient has been adherent with routine cancer screening. Notably, this study directly compares cancer incidence in those treated with radioactive iodine with those treated only with thionamides. To account for the fact that many patients treated with radioactive iodine were treated with thionamides first, this period of time was added to the follow-up time of those treated with thionamides. Follow-up started one year after study entry and ended with the first diagnosis of cancer, death or at the conclusion of the study period.

The cohort consisted of 16,637 patients followed for a mean of 7.3 years. Overall, 2,829 were treated with radioactive iodine, and 13,808 were treated with thionamides. Compared with those treated with thionamides, there was no association between radioactive iodine administration and subsequent cancer diagnosis in either univariate (HR, 0.99; 95% CI, 0.83–1.19) or multivariable (HR 1.01; 95% CI, 0.83–1.21) analyses. There was an increased incidence of non-Hodgkin’s lymphoma, but this association did not reach statistical significance in multivariable analysis. In those treated with radioactive iodine, there was a significantly decreased risk of thyroid cancer incidence in multivariable analysis (HR, 0.45; 95% CI, 0.21–0.99). Interestingly, thionamide treatment was associated with an increased risk of death in multivariable analysis (HR, 1.21; 95% CI, 1.05–1.39).

This study has several strengths. First, it is a large cohort of hyperthyroid patients. Second, as noted in a previous review of this manuscript, unlike many prior studies, the control group consists of hyperthyroid patients treated with thionamides rather than non-hyperthyroid matched controls [19]. Third, the health database used includes important information on comorbid health conditions and socioeconomic factors that might be sources of confounding. Fourth, the study period was recent, which may mean that patients received higher doses of radioactive iodine. These doses have a higher likelihood of being curative, and are more consistent with current practice guidelines [20].

On the other hand, there are certain limitations that merit consideration. First, like many previously published studies [10–12, 21, 13–16], these data come from a single country and results may not be generalizable to other regions and populations. Second, this is a retrospective cohort study, and while the authors attempt to account for several sources of confounding, there are inherent limitations when using a health database. Third, the length of follow up is relatively short. Fourth, while the number of radioactive iodine treatments is known, cumulative dose is not. Fifth, no information is available on the underlying etiology of hyperthyroidism, thus no comparisons can be made between those with Graves’ disease, those with toxic multinodular goiter and those with other etiologies. Sixth, information is lacking on the percentage of patients that achieved a euthyroid state. This is relevant given the prior finding that higher mortality rates in thionamide-treated patients may be driven by those who fail to achieve biochemical control [9]. Lastly, this study does not include details on how post-treatment medical care, such as the frequency of doctor visits or imaging studies, compares between the two groups. This is an important study limitation in view of recent data supporting increased health care utilization as a major driver of thyroid cancer detection [22–25].

Radioactive Iodine and Cancer Mortality

In August 2019, Kitahara et al. published a study evaluating cancer mortality in patients treated for hyperthyroidism with radioactive iodine [26]. This study utilized the multi-center Cooperative Thyrotoxicosis Therapy Follow-up Study cohort described above and extended the mortality follow-up period by 24 years, through the end of 2014. Importantly, the primary objective of this study was distinct from prior analyses of this cohort in that the focus was entirely on those patients treated with radioactive iodine. Specifically, the authors evaluated site-specific malignancy dose-response relationships.

In contrast to the prior study utilizing this cohort [14], the authors employed a novel method of estimating organ-specific absorbed radiation doses based on a biokinetic model created from 197 patients from the Cooperative Thyrotoxicosis Follow-up Study who had measurements of radioactive iodine in the blood, thyroid and urine [27]. All patients who received at least one dose of radioactive iodine were included, regardless of other treatments used (i.e., surgery or antithyroid drugs). A latency period of five years from the last radioactive iodine treatment was used to calculate person-years at risk. Multivariable linear regression models were used to estimate excess relative risks and the results were normalized per 100-mGy organ or tissue dose to allow direct comparison. The estimated stomach dose was used as a whole-body dose surrogate in the models evaluating combined solid cancer mortality. The 2014 Surveillance, Epidemiology, and End Results (SEER) mortality data were used to determine baseline age-specific total and cancer-specific death rates.

A total of 18,805 eligible patients with hyperthyroidism were included in the study cohort. Patients with a history of cancer at the time of the first treatment were excluded. Overall, 78.0% of included patients were women and 93.7% had Graves’ disease. Of these patients, 38.2% were treated with radioactive iodine only, while the remainder were also treated with antithyroid drugs, surgery, or both. At the time of this study, 82.3% (N = 15,484) of study participants were deceased and, of those cases, cancer was the primary cause of death in 15.3% (N = 2,366).

In evaluating post-treatment cancer mortality, a statistically significant dose-response relationship was identified for female breast cancer (relative risk [RR], 1.12; 95% CI, 1.00–1.32). A statistically significant dose-response relationship was not seen for mortality from any other individual cancer. When combining the incidence of all solid malignancies, there was a statistically significant dose-response relationship, regardless of whether female breast cancer was included (RR, 1.06; 95% CI, 1.02–1.10) or excluded (RR, 1.05; 95% CI, 1.01–1.10). Neither the breast cancer mortality nor the combined solid cancer mortality relationship changed when analysis was restricted to the subgroup that received only radioactive iodine. Based on these findings, the authors estimated that 14.0% of breast cancer deaths and 8.0% of all solid cancer deaths were attributable to radiation exposure.

This study has significant strengths. First, it utilizes long-term mortality data from the largest cohort of hyperthyroid patients currently available, which includes treatment centers across the U.S. and one center in the United Kingdom. Second, it is unique in that it estimates organ-specific radiation exposure using a novel biokinetic model so that dose-response relationships can be evaluated. This method, if valid, would provide a more meaningful assessment of dose-dependent relationship compared with prior studies. Third, by focusing only on the subset of patients treated with radioactive iodine, it avoids major sources of confounding that may occur when retrospectively comparing treatment groups or when comparing a treatment group with the general population.

Importantly, this study also has limitations [28–33]. First, while the authors are very methodical and use a novel model to estimate organ-specific radiation exposure, important uncertainties remain in regards to key components and assumptions of this model [28–32]. Additionally, the use of the absorbed stomach dose as a surrogate for whole body exposure is of uncertain validity [21, 31]. Notably, in personal discussion with the first author, Dr. Kitahara, the findings did not change when weighted organ doses were used (Kitahara CM, personal communication). Third, the standard deviations on estimated organ doses are large. Because relative risks are normalized to 100-mGy organ doses, it is difficult to know how the findings apply to individual patients. Fourth, this study, like many prior studies, relies on cancer mortality data, which is a particular limitation in evaluating dose-response relationships in cancers with low mortality rates. Lastly, this is an historical cohort treated between 1946 and 1964. How the significant progress in both diagnostic testing and therapeutics used in the management of both hyperthyroidism and cancer would impact these findings is unknown.

CONCLUSION

Radioactive iodine has been an effective and important therapy in the treatment of hyperthyroidism since it was first introduced in the 1940s. There has been concern over time about the possibility of an increased risk of post-treatment hematologic and solid tumor malignancies and associated mortality. Several large, population-based studies have attempted to evaluate this relationship, primarily through a comparison of cancer incidence or mortality rates with matched controls. In general, these studies suggest the possibility of a small increased risk of subsequent malignancy in hyperthyroid patients treated with radioactive iodine. On the other hand, findings on cancer mortality are more variable, demonstrating either no increased risk or a very small absolute increased risk.

Two recent studies published within the last year, make meaningful contributions to the existing literature. The first, by Gronich et al., found no increased risk of post-treatment solid malignancy in patients treated with radioactive iodine compared with those treated with thionamides. The second, by Kitahara et al., found a positive dose-response relationship between radioactive iodine therapy and risk of both breast cancer and cumulative solid cancer mortality. Importantly, as noted by Dr. Korevaar in a recent review, these studies are not directly comparable for a number of reasons including significant differences in statistical methods, outcome measures, and latency periods between treatment and outcome [19].

The true relationship between radioactive iodine therapy for hyperthyroidism and the risk of subsequent malignancy and cancer mortality remains challenging to definitively delineate due to the retrospective nature of the studies and heterogeneous populations evaluated. Future studies should build upon the foundation laid by prior work, and methods should continually be refined to make findings as meaningful as possible [19]. Unfortunately, retrospective studies are inevitably prone to confounding, and the risk of confounding by indication is of particular relevance given the multiple treatment modalities available for hyperthyroidism. As is true of all medical therapies, treatment decisions must weigh risks and benefits, as well as the inherent risks of the patient’s underlying disease and comorbid conditions.

KEY POINTS.

  • Radioactive iodine treatment has been an effective and safe treatment for hyperthyroidism for almost 80 years in the United States.

  • Conflicting data exist regarding the use of radioactive iodine for hyperthyroidism and risk of subsequent malignancy and associated mortality.

  • Available studies suggest the possibility of a small increased risk of post-treatment malignancy in hyperthyroid patients treated with radioactive iodine.

  • Current studies on the association of radioactive iodine use for hyperthyroidism and risk of cancer and associated mortality are limited by their retrospective nature, heterogeneity of populations studied and variable follow-up.

Acknowledgements:

We would like to acknowledge Ms. Brittany Gay who assisted with literature review and manuscript formatting and submission.

Financial support and sponsorship: Dr. Papaleontiou is supported by funding from the National Institute on Aging under award K08 AG049684.

Footnotes

Conflicts of interest: None.

REFERENCES

* of special interest

** of outstanding interest

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