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Radioactive iodine (RAI) therapy for hyperthyroidism didn't seem to increase all-cause cancer risk by any clinically meaningful amount, a new meta-analysis suggested.

The analysis, which pooled data from 12 studies with nearly 500,000 patients with hyperthyroidism, found no significantly higher risk for any type of cancer among those exposed to RAI therapy versus other forms of therapy (standardized incidence ratio [SIR] 1.02, 95% CI 0.95-1.09), reported Won Jin Lee, MD, PhD, of Korea University College of Medicine in Seoul, and colleagues.

Patients treated with RAI also did not appear to have a significantly elevated risk for death due to all cancers either (standardized mortality ratio [SMR] 0.98, 95% CI 0.92-1.04), the researchers reported in .

However, the team said, when an analysis was done by specific type of cancer, there was a link for thyroid cancer in particular -- the only type of cancer to show this association. More specifically, patients with hyperthyroidism treated with RAI therapy had a significantly elevated risk of thyroid cancer incidence (SIR 1.86, 95% CI 1.19-2.92) and thyroid cancer-related mortality (SMR 2.22, 95% CI 1.37-3.59).

"One possible reason may be the high dose of radiation exposure on the thyroid gland," the researchers suggested, adding that one of the studies included in the meta-analysis mentioned that the mean organ dose estimate for the thyroid gland in the was about 130 Gy -- "a substantially larger dose than those administered to other organs and tissues."

"The underlying conditions of the thyroid gland could be another possible reason for the increased risk of malignant thyroid tumor after RAI for hyperthyroidism," Lee and co-authors added. "Thyroid-stimulating hormone and thyroid-stimulating antibodies, present in Graves disease [GD], may play a role in carcinogenesis and tumoral growth, and hyperthyroidism is associated with a high incidence of thyroid carcinoma."

The relationship also is not surprising, as these particular patients already had abnormal thyroid functioning, the researchers added.

The other cancer sites assessed in the analysis included cancers of the digestive organs; eye; brain/central nervous system; lip, oral cavity, and pharynx; respiratory and intrathoracic organs; breast; genital organs; urinary tract; lymphoid, hematopoietic, and related tissue. RAI therapy was not significantly tied to increased risk of malignant neoplasms at any of these cancer sites, the investigators said.

In a dose-response sub-analysis, just two of the 12 studies included in the systematic review and meta-analysis found links between a higher RAI dose with both breast cancer and solid cancer mortality (breast cancer mortality per 370 MBq: 1.35, P=0.03; solid cancer mortality per 370 MBq: 1.14, P=0.01).

The author of an , Bernadette Biondi, MD, of the University of Naples Federico II in Italy, called the results "reassuring"... and can be used to "reduce anxiety in both patients and clinicians as to the risk of cancer after RAI."

She added that future studies looking into the association should include a long-term follow-up and specifically compare RAI therapy with antithyroid drugs (ATDs), which are the primary treatment of hyperthyroidism caused by GD.

"In Europe, approximately two-thirds of the members of the European Thyroid Association prefer a first approach with ATDs ... However, RAI is the preferred first-line therapy for GD in the United States and the United Kingdom because it is associated with a higher cure rate and lower relapse rate compared with ATDs," Biondi explained.

And when comparing these outcomes from the three main treatment options currently available for hyperthyroidism -- ATDs, RAI therapy, and surgery -- Biondi suggested special attention be placed on subgroup analyses, considering the underlying etiology of the hyperthyroidism, severity of disease, and cumulative dose of RAI.

Lee's group performed a search of articles from the PubMed, Cochrane, and Embase databases. A total of 12 studies were identified -- representing a total of 479,452 patients -- conducted in North America and Europe; nine were deemed of high and moderate quality, while three were considered relatively low or very low quality. Patients were treated between 1946 and 2015.

To be included in the meta-analysis, the studies needed to include patients treated for hyperthyroidism with RAI who were followed up until cancer diagnosis or death. The studies also needed to include a minimum of one comparison group of patients not exposed to RAI treatment -- for example, the general population, those treated for hyperthyroidism with thyroidectomy or ATDs, or those exposed to different administered doses of RAI.

Among the study limitations, the team said, were that the individual studies included patients who were not randomized to the treatments received, and such observational studies may be vulnerable to confounding bias; and that the number of studies included in the quantitative synthesis was relatively small for pooling risks of relatively uncommon cancer types despite the large sizes of the cohorts and only three studies had information about dose-response associations.

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