No Excess Cancer Risk from Radioactive Iodine Treatment in Hyperthyroidism

Despite conflicting findings, new data refuting any discernible link between increased risk of all cancers gains the endorsement of endocrine community.

with Naomi Gronich, MD, Anca M. Avram, MD, and Brian Haugen, MD

Concerns about whether radioiodine (radioactive iodine, RAI) treatment for hyperthyroidism confers an increased risk of cancer persist given results of recent large-scale studies that have yielded conflicting results.

Findings from a large-scale cohort study on this topic by a team of Israeli researchers,1and published in the journal Thyroid, may offer a clearer answer for your patients. The authors found no significant associations between radioiodine treatment and increased risk of overall cancer.1   

Latest study refutes worries of increase cancer risk with RAI treatment for hyperthyroidism.

No Link Evident from Radioactive Iodine for Hyperthyroidism and Future Risk of Cancer

After evaluating data gathered from more than 16,000 patients in the Clalit healthcare database encompassing 123,166 person‐years of follow‐up,1 Gronich et al reported no increased risk among individuals with thyroid disease who received RAI as compared with those who received other forms of treatment for overactive thyroid disease. This is a substantial population-based study as the database represents more than half of the Israeli population.1

All adults identified with a new diagnosis of hyperthyroidism between 2002 and 2015 who were treated with RAI or thionamides (propylthiouracil, thiamazole) were included in the analysis whereas patients with prior history of cancer were excluded,1 according to lead author Naomi Gronich, MD, assistant professor of clinical pharmacology and internal medicine at Lady Davis Carmel Medical Center in Haifa, Israel.

Among the participants, about one in five (21%) presented with obesity and 13% had a diagnosis of type 2 diabetes (13%) but those factors were not evaluated as risk factors for cancer in this study,1 Dr. Gronich told EndocrineWeb.

Solid Study Refutes Increased Cancer Risk with RAI Therapy

The results stand in stark contrast to those of another cohort study,2 published in JAMA Internal Medicine, in which the authors reported: "greater organ-absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer."2

This second study was a multicenter, 24-year extension of the data from the Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFS), involving 18,805 patients (mean age at study 49 years; 78% women; 93.7% had Graves’ disease; 34.1% had multiple RAI treatments).2

The authors concluded that, for every 1,000 patients treated with RAI at the age of 50, an estimated lifetime excess of 18 to 31 solid cancer deaths would occur (including 4 to 6 breast cancers), most occurring more than 20 years after treatment with radioactive iodine.

"Greater organ-absorbed doses appear to be modestly positively associated with risk of death from solid cancer," according to Cari M. Kitahara, PhD, MHS, and colleagues

For patients with hyperthyroidism who opt for radioiodine treatment, the risk of developing cancer is ''very low," according to the study findings.

Endocrine Society Calls Cancer Scare "Unjustified"

Findings from the CTTFS sparked renewed concerns in the endocrinologist community and among patients, promoting an editorial,7 "Association of Radioactive Iodine Treatment of Hyperthyroidism with Cancer Mortality: An Unjustified Warning?"

This commentary was published in the Endocrine Society's Journal of Endocrinology and Metabolism,to call attention to significant design flaws in the Kitahara-led study:

  • The analysis assessed whether greater absorbed RAI doses to specific organs were associated with increased mortality risk from specific cancers, with the dose to the stomach used arbitrarily as the reference.
  • CTTFS included patients treated between 1946 and 1964 with follow-up after 1968, and many patients were lost to follow-up.
  • The study was initially designed to compare cancer risk between RAI-treated patients and those treated differently. An original report of the CTTFS data (mean 21-year follow-up) concluded that RAI was not linked to cancer deaths (except thyroid cancer, with the underlying thyroid disease appearing to play a role). In this early analysis, increased risk of breast and lung cancer were found in patients treated with surgery but not in those treated with RAI.4

Comparing the CTTFS study design with that of study conducted by the Israeli team, the senior author of the editorial, endocrinologist Anca M. Avram, MD, professor of radiology, and director of the Nuclear Medicine Therapy Clinic at the University of Michigan in Ann Arbor, told EndocrineWeb:

"The CTTFS study used data collected in the 1960s, when even smoking was not a known confounder of cancer risk. While Gronich reported on actual observed cancer rates, Kitahara's findings were based on a hypothetical model and derived cancer mortality," she said.

"Conversely, the Gronich paper is performed with adjustment for multiple variables and confounders, using modern data collection, and thus is a much better basis for discussions of cancer risks following radioiodine therapy."

In addition, Dr. Avram called attention to three previous studies, all concluding that RAI does not contribute to increased cancer risk.4-6

Is the Univariate Analysis Finding of Lymphoma Risk Important?

In the Israeli-based study,1 the univariate analysis identified a small association between radioactive iodine and non-Hodgkin lymphoma (NHL) but this was not seen in the multivariable analysis.

"The univariate analysis is always flawed in a retrospective clinical observational study, because there is never just one variable and always confounders. On that basis, the lymphoma finding is not significant," Dr. Avram told EndocrineWeb since a statistical (Bonferroni) adjustment is needed to analyze the findings of a univariate analysis among 20 cancer types (requiring a P value of < 0.0025 to gain statistical significance).

"There is no significant risk after Bonferroni adjustment even for the univariant P value. Endocrinologists should not make any clinical decisions based on this insignificant mention," said Dr. Avram. In fact, in the Israeli population prior use of thionamides was associated with higher mortality rates than RAI treatment using both the univariate and multivariable Cox proportional hazards models.1

Clinical Implications, Management of Hyperthyroidism

Dr. Avram added that the article by Kitahara et al "has the potential to influence clinical choices and cause unwarranted distress," in patients receiving RAI for hyperthyroidism.2  

For worried patients, here's a consumer-focused article on RAI.

A concern that patients may reject the use of RAI therapy as the preferred treatment to manage hyperthyroidism, prompted a statement from the British Thyroid Association, in which the authors concluded: "...it would be unfortunate if patients were deprived of the option of rapid, effective control of their hyperthyroidism with radioiodine due to concerns of cancer risk." This is in line with guidelines for treating hyperthyroidism issued by the American Thyroid Association 

"Current evidence shows no excess cancer risk, [so] it would be reasonable to continue with current approaches to the management of hyperthyroidism,"  Both the British statement and the Endocrine Society's statement encourage further study on this subject to help settle the debate of radioactive iodine and cancer risk.

For patients with hyperthyroidism getting the radioiodine treatment, the study suggests that the cancer risk is ''very low,"

These results [of the Gronich-led study are reassuring, said Bryan Haugen, MD, FACP, professor of medicine and pathology and head of the division of endocrinology, University of Colorado School of Medicine in Aurora, who reviewed the study for EndocrineWeb but was not involved in the research.

None of the cited authors had any financial conflicts with regard to this work.

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