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Meta-Analysis Reviews Risk of Subsequent Malignancies After Thyroid Cancer

Darcy Lewis
Published Online:3:55 PM, Fri June 28, 2019
An updated systematic review and new meta-analysis of the incidence of subsequent malignant neoplasms (SMN) following thyroid cancer has found that there was no significant increased relative risk of breast cancer, salivary cancer, or combined hematologic malignancies based on whether or not patients had received radioactive iodine (RAI).1

The meta-analysis, published in Thyroid and written by a team of authors in Canada, also found that although relatively rare, the risk of subsequent leukemia was increased, but the risk of multiple myeloma was reduced in patients with thyroid cancer who had been treated with radioactive iodine.

“RAI use was associated with an increased risk of subsequent leukemia but reduced risk of subsequent multiple myeloma. Yet, each of these outcomes is relatively rare,” Yu et al wrote. “The heterogeneity of results within the outcome of any SMN and variability in effects observed among various specific SMNs suggest that it may be preferable for future studies to examine the risks of respective second primary cancers, rather than the composite outcome of any SMN.”

The authors reviewed 93 full-text papers published in English that examined whether the risk of SMN was different in thyroid cancer survivors treated with RAI compared to those not treated with RAI. Eligible studies included published clinical trials, systematic reviews and meta-analyses, and observational studies with at least 50 thyroid cancer patients. They ultimately included 17 studies, 3 of which were reviews. The remaining 14 studies were original clinical research.

In examining the 10 studies that reported data on the rate of any subsequent malignant neoplasm by treatment status, the authors found that the percentage of affected patients ranged from 2.5% to 12.0%, with a risk ratio of 0.98 (CI, 0.76-1.27), based on data from 65,539 thyroid cancer survivors. This included 5053 SMN events. The mean or median follow-up periods varied from 5 to 16 years, and the mean or median cumulative iodine-131 (131I) activity varied from 3700 to 5550 MBq (100-150 mCi).

The authors also examined the 7 original studies that reported on the risk of subsequent breast cancer in thyroid cancer survivors based on RAI treatment status and found that the risk of subsequent breast cancer varied from 1.2% to 2.5%. Breast cancer was the most commonly reported type of secondary malignancy in 6 of these studies. The study authors’ pooled analysis found that the relative risk of subsequent breast cancer in thyroid cancer patients based on RAI-treatment status was 0.80 (CI, 0.53-1.21; P = .281). Their analysis, which they cautioned was subject to a high degree of statistical heterogeneity, used data from 68,481 thyroid cancer survivors. This included 1276 subsequent breast cancer events. The mean or median follow-up period for studies reporting later breast cancer ranged from 7 to 13 years.

Yu et al also reported on the 4 studies that studied the risk of any type of subsequent leukemia. They found that the cumulative incidence rate of subsequent leukemia varied from 0.03% to 0.26%, with a mean or median follow-up period varying from 2 to 13 years. Their pooled analysis found that the relative risk of subsequent leukemia in patients with thyroid cancer treated with RAI was 1.6 (CI, 1.30-1.96; P <.001). This included data from 367,369 patients with 384 subsequent leukemia events. They noted that this yielded an estimated absolute excess risk of 0.05% in RAI-treated patients during subsequent follow-up.

The investigators also found a reduced risk of subsequent multiple myeloma in RAI-treated patients with thyroid cancer. They cautioned that their meta-analysis was dominated (94.1% weight) by one large Surveillance, Epidemiology, and End Results study.2 They estimated the baseline risk for RAI-naïve patients to be 0.11%, while the relative risk in patients with thyroid cancer who received treatment with 131I was 0.60.

“Explanations for these findings are not clear, although some credence is lent to the finding of increased leukemia risk after RAI, with the concurrent observation of increased risk of chronic myeloproliferative neoplasms (which may transform to AML),” the study authors wrote. “The observation of a reduced relative risk of multiple myeloma in RAI-treated [patients with] thyroid cancer certainly requires confirmation, as it is largely based on the findings of one large study, and it is possible it could be spurious.”

Overall, the authors believe that the strength of their study hinges on its control comparison group, which consisted of patients with thyroid cancer who did not receive RAI, rather than general population controls. They also note the limitations include relatively limited follow-up periods and any methodological limitations in the primary studies. They also identified a potential publication bias related to fewer than expected studies showing a potential positive effect of RAI treatment on subsequent malignancy outcomes.

Yu et al concluded that the body of evidence on whether 131I treatment of thyroid cancer is associated with any subsequent malignant neoplasm is highly heterogeneous and complex. “More research examining the long-term risk of specific SMNs after 131I treatment is needed,” they wrote.
  1. Yu CY, Saeed O, Goldberg AS, et al. A systematic review and meta-analysis of subsequent malignant neoplasm risk after radioactive iodine treatment of thyroid cancer. Thyroid. 2018;28(12):1662-1673. doi: 10.1089/thy.2018.0244.
  2. Molenaar RJ, Sidana S, Radivoyevitch T, et al. Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol. 2018;36(18):1831-1839. doi: 10.1200/JCO.2017.75.0232.

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