Rising incidence of second cancers in patients with low‐risk (T1N0) thyroid cancer who receive radioactive iodine therapy

TLDR: Evaluated patterns of RAI use and elevated risk of secondary primary malignancies (SPM) in patients with low‐risk (T1N0) WDTC.

Abstract: The incidence of well differentiated thyroid cancers (WDTC) has increased substantially over the past 3 decades, and an estimated 37,200 cases were diagnosed in the United States in 2009. The majority of the increase is attributable to small (<2 cm) tumors (T1), a trend that has been ascribed mainly to improved detection of subclinical disease.1 The clinical relevance of these tumors is the subject of much debate, because a high prevalence of incidental microcarcinomas has been reported in autopsy series.2 Furthermore, the increased incidence in WDTC has not been associated with a concurrent increase in thyroid cancer mortality, suggesting that much of the disease being detected may be clinically insignificant. Despite the indolent nature of small WDTCs, few clinicians are willing to conservatively manage these malignancies. Treatment usually comprises thyroidectomy, and, when indicated, adjuvant radioactive iodine (RAI) therapy. Decision-making regarding the extent of surgery remains a subject of debate, reflecting a lack of high-quality data to support management decisions. Similar levels of controversy exist regarding the role of adjuvant RAI therapy. The administration of adjuvant RAI has 2 main objectives: first, to ablate occult microscopic foci of WDTC, reducing the risk of tumor recurrence, and, second, to ablate any remaining normal thyroid tissue, thereby facilitating surveillance with serum thyroglobulin or radioiodine whole-body scintigraphy.3 On the basis of these objectives, the decision to use RAI depends on the risk of the original thyroid cancer and the completeness of surgery in removing malignant and normal thyroid tissue. Most studies report little benefit from RAI in low-risk patients.4,5 Even in intermediate-risk patients, RAI administration confers only minor benefit in reducing the risk of recurrence or death.6 Existing guidelines from the American Thyroid Association (ATA) cite these factors.7 Notwithstanding available data and guidelines, there is widespread use of RAI in patients who have a low risk of recurrence. The decision to treat patients with RAI should be undertaken carefully. Although the side-effect profile is superior to those of other commonly used adjuvant modalities, such as external-beam radiation or cytotoxic chemotherapy, currently, there are ample data to suggest that RAI is not altogether benign.8,9 Complications range from relatively minor salivary gland dysfunction (short-term and long-term) to more serious but rare complications, such as myelosuppression and aplastic anemia.10 Furthermore, several studies have documented an increase in the incidence of second primary malignancies (SPM) in organs known to concentrate RAI.11-14 In 1 of those studies, the authors established a clear-cut dose-dependent effect, which implies causality.13 However, those analyses included patients with locally advanced and/or metastatic disease, who have few effective options apart from RAI therapy. In fact, there is no debate on the utility of RAI for patients who fall into the high-risk group, such as patients with gross extrathyroid extension or distant metastases, for whom the risk-benefit ratio favors RAI.7 However, the risk-benefit ratio may be far less favorable in low-risk patients. To our knowledge, there are no reports specifically focusing on the risk of SPM after RAI in patients with low-risk WDTC. Because this is the cohort of patients that now forms the majority of thyroid cancer cases, it is important to comprehensively define the risk of SPM caused by RAI in these patients. Therefore, the objectives of the current study were to report the use patterns of adjuvant RAI in patients with low-risk WDTC over time using a population-based registry, to determine the excess risk of SPM in the same cohort of patients, and to determine whether there is any correlation between SPM incidence and trends in RAI use.