Although several studies (both population-based and cohort) have reported an elevated risk of SPM from the use of RAI therapy for thyroid cancer,11-14
to our knowledge, no reports have specifically addressed this issue in patients with low-risk WDTC, for whom the benefits of RAI are less clear. Therefore, the objective of the current study was to specifically determine trends in RAI use and the associated risk of SPM in patients with low-risk WDTC. These patients account for the majority of the increased incidence of thyroid cancer observed in the United States over the past decade.
There are limited data indicating any efficacy of RAI as adjuvant treatment to prevent recurrences or prolong survival in patients who fall into the low-risk WDTC category, which led the ATA to revise their guidelines for RAI ablation in 2009.7
These recommendations now advise that there are no data to support the routine use of RAI in patients with intrathyroid tumors with or without multifocality that measure <1 cm. Because there is conflicting evidence on the benefits of RAI for patients who have tumors that measure >1 cm, the ATA suggests limiting its use to patients who have intermediate-risk or high-risk features, such as extrathyroid extension, aggressive histologic variants, or the presence of cervical lymph adenopathy. On the basis of the guidelines outlined above, there is probably minimal valued-added benefit to the use of adjuvant RAI in young patients with low-risk tumors; ie, patients aged <45 years with intrathyroid T1 tumors (<2 cm) and without extrathyroid extension or lymph node metastasis. These patients are considered “low risk” in the current ATA guidelines7
and were categorized as “very low risk” in a recent systematic analysis of the literature.21
Despite this, 38% of patients who fall into this low-risk category currently receive adjuvant RAI in the United States. For patients with microcarcinomas, the presence of microscopic multicentricity in recent years nearly tripled the likelihood of RAI use; although, currently, this factor is not considered an indication for adjuvant RAI.7
More important, time trends demonstrate that the receipt of RAI by low-risk patients continues to increase with time in an almost linear manner despite the absence of any evidence for an impact on survival. It has been suggested that RAI should be used in all but the most microscopic of tumors, and some have advocated adjuvant RAI for tumors that measure >0.5 cm.22
However, these statements are based on “expert opinion” and, thus, should be viewed with scrutiny. Furthermore, many of these tumors are incidental, subclinical tumors that probably would remain asymptomatic and, in an earlier era, would have been diagnosed only at autopsy.2
The decision to use RAI should be based on a balance between its risks and benefits. The side-effect profile of RAI has been underplayed as minor compared with external-beam radiation, and this view often is passed on to patients. Short-term side effects of RAI include salivary gland dysfunction (sialadenitis, altered taste), which is observed in >40% of patients; xerophthalmia (25%); transient fertility reduction (20%); transient leukopenia; and thrombocytopenia.8-10,23,24
Fortunately, life-threatening, short-term risks, such as acute bone marrow failure, are rare. Delayed toxicities are less well appreciated and are not mentioned routinely, such as xerostomia (40% partial, 4% complete) or reduced pulmonary function secondary to radiation pneumonitis (6%). In a quality-of-life analysis, Almeida et al reported that, in patients with low-risk thyroid cancer, treatment with RAI was the only factor on multivariate analysis associated with poorer quality-of-life scores.25
The development of SPM attributable to RAI is viewed as 1 of the most serious sequelae of treatment.9,26
However, it is generally believed that this is a rare outcome; therefore, it is not emphasized when recommending adjuvant treatment. Several studies, both cohort and population-based, have demonstrated a significant increase in the incidence of SPM among patients with WDTC who received RAI compared with their counterparts who did not receive RAI.11-14
It is estimated that this increased risk ranges from 20% to 30% compared with a matched population. Undoubtedly, in patients who have high-risk or metastatic disease, there are limited options available, and the comparatively low SPM risk can be justified. Although some authors suggest that low-dose RAI does not increase SPM risk, our data may not be consistent with that suggestion. In our current study cohort, most patients deemed as low-risk would have received a lower cumulative dose of RAI compared with patients who had recurrences or distant metastasis, yet this low-risk cohort experienced a 21% excess SPM risk attributable to the receipt of RAI. The SPM sites at elevated risk encompassed diverse malignancies, but hematologic cancers carried the most pronounced elevation in risk.
There are important limitations to our data that deserve mention. Although few patients had missing data, the SEER Program does not record certain covariates of interest, such as completeness of resection, tumor multicentricity (before 2004), or data from postoperative thyroglobulin or whole-body scanning, some of which potentially may explain the decision to use adjuvant RAI. RAI administration is recorded reliably in the SEER Program only in the adjuvant setting, as outlined above (see Statistical Methods), and may not be recorded if RAI is given at a later date for recurrent or new disease. This may lead to misclassification of RAI-positive patients into the RAI-negative cohort, attenuating the measured differences between cohorts, and leading to an under estimation of the elevated risk attributable to RAI. Second, the SEER Program does not include information on RAI dose; therefore, we were unable to correlate RAI dose with the risk of SPM.
Nonetheless, we report a striking increase in the risk of all malignancies and hematologic cancers among patients with WDTC in parallel with the increasing receipt of RAI by low-risk patients. There may be a mechanistic explanation with regard to cancers arising from the salivary glands, hematologic system, and kidney, because it is known that RAI concentrates in the salivary glands and bone marrow and is excreted through the kidneys. There are data to suggest that expression of the Na+
symporter in extrathyroid tissue, like that of the salivary gland, may be responsible for concentrating RAI in these cells, driving carcinogenesis.27
To our knowledge, our finding of an increase in the incidence of melanoma has not been reported previously, and we know of no mechanistic explanation for this. The incidence of both melanoma and renal cell cancers has been increasing in recent years, and both have been described by Welch and Black as cancers subject to overdiagnosis in the setting of increased surveillance. Therefore, it is possible that the elevated risk of second cancers in these sites simply may represent increased ascertainment in a population undergoing rigorous cancer surveillance.28
Similarly, using data from the SEER database, previous studies have demonstrated an association between thyroid cancer and breast cancer in women.29
Although we did observe a significant increase in the number of breast cancers as SPMs in patients with thyroid cancer (all patients and low-risk patients), our analyses indicated no difference in the rates between the RAI-positive and RAI-negative patients (SIR of breast cancer after WDTC: RAI-positive cohort, 1.12 (95% CI, 0.97-1.29); RAI-negative cohort, 1.15 (95% CI, 1.06-1.25).
Previous data have suggested that younger patients are unlikely to develop hematologic malignancies after RAI, which is a critical consideration given the excellent prognosis for these patients, who essentially have no mortality risk from low-risk WDTC. In our analysis, the EAR was 4.6 patients per 10,000 PYR, approximating an incidence of 0.05% per year. It is worth noting that this risk is similar to rates of radiation-induced sarcomas attributed to external-beam radiation therapy, which is estimated between 0.03% and 0.2% per year.30-32
The latter attributable risk has always been included in decision-making algorithms by radiation oncologists when advocating adjuvant treatment for young patients, in whom a balance needs to be struck between the estimated benefits of adjuvant external-beam radiation versus the risk of a radiation-induced second cancer. Perhaps it is worthwhile to consider a similar decision-making algorithm in low-risk patients with WDTC and to ask whether existing data on the benefit of RAI in these low-risk patients justify the elevated risk of an SPM across the lifetime of young patients. Clearly, these data should be incorporated into future recommendations of RAI treatment, especially when dealing with low-risk patients who are unlikely to die from WDTC. In conclusion, the increased risk of a second primary cancer in patients with low-risk WDTC, along with the lack of any data demonstrating improved survival outcomes with adjuvant RAI, provides a compelling argument for rationing the use of RAI in this patient population.