Radioiodine/Cancer Link in Hyperthyroidism Study Sparks Debate

Recent research suggesting a dose-dependent link between radioiodine therapy for hyperthyroidism and an increased risk of death from solid cancers has prompted a joint statement from two UK-based endocrine societies advising caution in interpreting the findings.

"We felt the need to issue a statement because we saw that this research caused an uproar among colleagues, as well as patients, who were concerned that a treatment being recommended to them could cause cancer," Kristien Boelaert, MD, PhD, of the Clinical Committee for the UK-based Society for Endocrinology, told Medscape Medical News.

The cohort study in question, published in July in JAMA Internal Medicine, as reported by Medscape Medical News, showed a statistically significant dose-response relationship for mortality in all solid cancers among 18,805 patients with hyperthyroidism who were treated with radioactive iodine.

The source for the conclusions was a 24-year extension of the multicenter Cooperative Thyrotoxicosis Therapy Follow-up Study, which specifically showed a 6% increase in risk of death for all solid cancers for each 100-mGy dose of radioiodine to the stomach, with a 12% increase in risk of death for breast cancer per 100-mGy dose to the breast.

No Control Group, Model Not Validated, and Confounders Not Adjusted For

In their joint statement, published in Clinical Endocrinology, the Society for Endocrinology and British Thyroid Association argue that critical aspects of the study leave many questions unanswered.

Among the most prominent limitations is that the study did not include a control group of patients with hyperthyroidism, they stress.

"The lack of a hyperthyroidism control group makes it difficult to ascertain if the increase in cancer risk is a consequence of hyperthyroidism and poor disease control, or of radioiodine per se," the joint statement points out.

Furthermore, the study used a novel but complex mathematical model, which has not been validated, for estimating the absorbed radioiodine dose based on a series of "assumptions on thyroid gland weight and radioiodine uptake in a small preliminary sample of patients," and needs further replication for validation, the statement asserts.

And importantly, the study did not control for key confounders such as smoking, obesity, alcohol intake, and biochemical disease severity. "Without correcting for these factors, it becomes problematic to attribute mortality to the effects of radioiodine," according to the statement.

The groups further add that the observed effects, while statistically significant, have a generally modest, and in some cases only marginal, magnitude.

And, importantly, other studies have shown no excess solid cancer risk following the administration of substantially higher doses of radioiodine in patients with thyroid cancer.

Although Uncertainties Exist, Don't Deprive Patients of Effective Therapy

Although the development of secondary cancers has been reported in patients with radioiodine-treated thyroid cancer administered cumulative iodine-131 activity in the 1400 to 7400 MBq range, a recent meta-analysis of 17 studies showed no increased risk of second malignancies among thyroid cancer patients treated at the usual dose, with mean iodine-131 activity ranging from 3700 to 5500 MBq.

A small leukemia risk was observed at those doses but the analysis showed no significant increase in breast cancer or other solid malignancies.

By comparison, the mean administered radioiodine activity in the new study was 375 MBq for Graves disease and 488 MBq for toxic nodules — representing only about 10% of the doses administered to the patients with thyroid cancer.

"Thus, given the uncertainties in the radioiodine dose estimates, the potential for unexplored confounding by indication, and the lack of patient control groups, these marginal risks will need to be interpreted with caution," the joint statement concludes.

Boelaert underscored that the known benefits of radioiodine treatment need to be given strong consideration in the context of the new data.

"We do need to take heed of the findings; we agree that patients need to be followed up and there should be registries for this, but the findings also need to be taken in the right context," she urged.

"It's been proven that radioiodine is an important treatment of hyperthyroidism, and depriving patients of an effective treatment for a condition that can have significant long-term cardiovascular disease consequences would be unfortunate," she added.

Cautious Interpretation Also Urged by Others

The American Thyroid Association (ATA) has not issued any similar statement on the research, but a review of the same JAMA Internal Medicine study was published in the August issue of Clinical Thyroidology, one of the ATA's journals, and underscores most of the same limitations raised in the joint statement — as well as the concerns about the influence of the findings on clinicians and patients.

"Conveying a nuanced interpretation of these data to patients considering treatment options for hyperthyroidism (as well as those previously treated with radioiodine therapy) will be challenging for clinicians," writes author Daniel J. Toft, MD, of the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago.

"Additional studies are needed to test the hypothesis that even low doses of radioactive iodine, such as those examined in this study, confer an increased risk of mortality," he noted.

Angela M. Leung, MD, who is editor-in-chief of Clinical Thyroidology and on the board of directors of the ATA, also agrees that scrutiny of the JAMA Internal Medicine study is warranted.

"The points raised in the response statement by the Society of Endocrinology and the British Thyroid Association are valid and important," she told Medscape Medical News.

"Although the findings of the original study are provocative and address an important clinical issue, its limitations as described (in the joint statement) should be carefully considered in the interpretation of the authors' findings," added Leung, of the UCLA David Geffen School of Medicine, Los Angeles, California.

She added that, based on the study's limitations, "it would be premature to adjust how we counsel hyperthyroid patients who may otherwise be good candidates for radioiodine therapy."

In addition to the review and joint statement, two other groups of researchers published letters to the editor along with the study in JAMA Internal Medicine, citing many of the same concerns.

Study Authors Respond: Risk Is "Small"; "We Never Said Change Treatment"

In responding to the concerns about the lack of a control group with hyperthyroidism but no exposure to radioiodine, lead author Cari M. Kitahara, PhD, of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, in Bethesda, Maryland, said it is important to note that this was an observational cohort study — not a randomized trial.

"If this were a randomized trial, this criticism could be justified, as any differences in risk of cancer death could be attributed to the treatment," she told Medscape Medical News.

"However, in this observational study, patients who were not treated with radioiodine were substantially different from patients who were treated with radioiodine in several important ways, including those described by the authors of the joint statement: underlying diagnosis — Graves vs toxic nodular goiter — age, sex, reproductive history, general health and comorbidities, smoking status, etc," Kitahara said.

The inclusion of patients who were not treated with radioiodine as a comparison group could have, in fact, biased the results, she said.

"Thus, we disagree that focusing the analysis on the patients exposed to radioiodine treatment was a 'substantial limitation' of our study. On the contrary, this was one of the major strengths," she noted.

Regarding the issue of a lack of reports of solid cancer risk seen with much higher doses of radioiodine in thyroid cancer, Kitahara said research on the issue is lacking.

"Studies that evaluate the risk of cancer following radioiodine therapy for either hyperthyroidism or thyroid cancer have been limited — so the issue is far from settled," she said.

Most prior studies have compared patients treated with radioiodine versus those not treated, and few have evaluated whether risk increases with greater treatment doses. Meanwhile, "no other study before ours included estimates of organ doses," Kitahara said.

"Clearly, more studies are needed to better understand the long-term risks associated with radioiodine treatment for thyroid cancer and hyperthyroidism, especially for younger patients, who could be more vulnerable to the carcinogenic effects of radiation exposure," she commented.

In a response to comments published with the study, Kitahara and colleagues further elaborate on other issues, including the magnitude of risk.

They underscore that "in the article, we emphasized that the magnitude of the risk associated with current typical treatment doses is small (20 to 30 lifetime excess cancer deaths per 1000 patients treated with radioiodine)."

They further note that their intention was not to recommend practice changes.

"Nowhere in our article did we state or imply the need to change current hyperthyroidism treatment guidelines based on results of a single observational study," they emphasize.

"Additional studies are needed to more rigorously assess the full spectrum of risks and benefits for each major treatment option for hyperthyroidism," they conclude.

Clin Endocrinol (Oxf). Published online December 1, 2019. Full text

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