Patients with Differentiated Thyroid Carcinoma Benefit from Radioiodine Remnant Ablation

Bryan R. Haugen

Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262

Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Room B151, 420 East Ninth Avenue, Denver, Colorado 80262. E-mail: bryan.haugen{at}uchsc.edu.

The initial treatment of differentiated thyroid cancer (DTC) includes surgery, radioiodine (for remnant ablation and/or therapy), and levothyroxine. Surgery and levothyroxine are generally accepted therapies, but the use of radioiodine, especially for patients with low risk for disease recurrence and mortality, remains controversial. Potential risks of radioiodine treatment include sialadenitis, xerostomia, bone marrow suppression, diminished reproductive function, and secondary malignancies. Potential benefits of radioiodine treatment include destruction of microscopic thyroid cancer, facilitation of sensitive monitoring for disease persistence or recurrence, reduction of disease-specific and overall mortality, and reduction in disease recurrence. These last two benefits on reduction of mortality and recurrence have been the topic of much debate for decades. The issue may be resolved with an appropriately designed, randomized, controlled clinical trial, but this has yet to be performed. Wong et al. (1) estimated that 1000 patients followed over 25 yr would be required to detect a significant reduction in disease mortality of 20%, and 4000 patients would be required to detect a more realistic 10% difference. A more recent study suggests that the number of patients needed to show a 30% reduction in disease recurrence would be less than 600 (2). A recent review of the existing literature suggested that patients with very low risk for disease recurrence (solitary tumor <1–1.5 cm, no invasion or lymph node involvement) did not benefit from radioiodine therapy (3). Patients with a high risk for disease recurrence [American Joint Committee on Cancer (AJCC) classification stages III and IV] clearly benefited from radioiodine therapy, and this was supported by a prospective, multicenter, nonrandomized trial (4). Patients in the low-risk group (stages I and II, 70–80% of patients with DTC) appear to have a reduction in disease recurrence in many but not all studies, and the effects of radioiodine on mortality are mixed (3). One problem with most studies that address the issue of recurrence is the definition of recurrence, which is not clearly stated in a majority of these studies. As technology advances, the definition of recurrence has evolved from symptomatic or palpable disease to radiographic evidence of disease, to identification of small, diseased lymph nodes on sensitive neck ultrasonography, to elevated serum thyroglobulin with or without TSH stimulation. The clinical relevance of this detected disease is also hotly debated.

In the absence of a randomized, controlled, clinical trial, which may never be performed, the current study by Sawka et al. (5) in this issue of JCEM attempts a careful review of the existing cohort studies and metaanalysis to evaluate the role of radioiodine remnant ablation/therapy on disease-related mortality and recurrence in patients with DTC. The authors reviewed 1543 references related to this subject and performed analysis on 23 unique references that met inclusion criteria (patients with low-risk DTC or completely resected disease, bilateral thyroid resection, and ≥5 yr mean or median outcome data on disease recurrence and/or disease-specific mortality). Ten studies were identified that were adjusted for prognostic factors and cointerventions. Only one of six studies examining cancer-related mortality showed a significant reduction (50%) in mortality with radioiodine treatment (6). Although this study appears to be the outlier, it was one of the largest studies and was the study with the longest median follow-up, both of which may account for the differences between this and the other studies. Causespecific mortality (10 yr) was low in these studies (1.3–7%), confirming the overall good prognosis in most patients with DTC. Three of six adjusted studies evaluating recurrence showed a significant reduction in tumor recurrence with radioiodine treatment. Of note, two of these studies were the largest studies with the longest median follow-up, which would suggest a benefit of radioiodine therapy. These same authors performed pooled analyses from 20 unadjusted studies that were published between 1985 and 2002. These studies included 8280 patients, 3459 (42%) receiving radioiodine, and 4821 (58%) receiving no radioiodine. These retrospective, nonrandomized, compiled data reflect the diversity of individual patient and physician choices in the use of radioiodine for DTC. Of note, the study that showed benefit of radioiodine for both mortality and disease recurrence, which is the most highly quoted study by proponents of radioiodine, used radioiodine in only 23% of patients (6). Another study that is highly quoted by opponents of radioiodine for patients with low-risk disease, showing no benefit of radioiodine, used radioiodine in 43% of patients (7). Pooled analyses on 10-yr disease-specific mortality was not able to be performed due to the heterogeneity of data in these 20 studies. The 10-yr disease-specific mortality in patients with papillary (or papillary/follicular) carcinoma was 2.6%, emphasizing the excellent prognosis in this low-risk group of patients. The one study that showed decreased disease-specific mortality in an adjusted analysis demonstrated a reduction in disease-specific mortality from 2.2 to 0.4% with the use of radioiodine in low-risk patients (mean AJCC stage 1.4) with tumors more than 1.5 cm (6). Opponents of the use of routine remnant ablation in these patients would agree with the quote that the use of radioiodine in these individuals is "the illogical pursuit of a perfect outcome" (8). Proponents would argue that no one with "low-risk" thyroid cancer should die from this disease and the use of radioiodine is justified if the data supports benefit. The data in this study will not settle that debate.

Pooled analysis did show a significant 69% reduction in locoregional recurrence with radioiodine therapy for all DTC, but the benefit of radioiodine for any recurrence could not be analyzed for all DTC, and subtype analysis showed no benefit. These data are somewhat confusing and may reflect treatment bias, the relatively short (10 yr) duration of follow-up, or ascertainment bias. Patients who were not treated with radioiodine may have had less rigorous monitoring (radioiodine scans, anatomic imaging, thyroglobulin measurement), resulting in less early detection of disease recurrence. Nevertheless, the reduction in locoregional recurrence in the pooled analysis is impressive. The overall effect of radioiodine on distant metastatic disease at 10 yr is an even more compelling argument for radioiodine remnant ablation in these patients. The authors of this study demonstrated a 50% reduction in distant metastatic disease in patients treated with radioiodine in the pooled analysis. Again, skeptics could argue that the absolute risk is very low (4% in patients not treated with radioiodine), and a reduction in metastatic disease from 4 to 2% may not be clinically relevant. This is a reasonable point, but these data from this carefully performed metaanalysis must be considered when deciding on the use of radioiodine for remnant ablation in patients with low-risk DTC.

Taken together, these data would suggest that patients with low-risk DTC may benefit from radioiodine remnant ablation by decreased risk of locoregional recurrence (69%) and decreased risk of distant metastatic disease (50%). One could argue that, based on these data, all patients with low-risk DTC should receive remnant ablation. Although this is a carefully performed pooled analysis on a large number of patients from many different centers, this study has many limitations, which the authors acknowledge. This is a pooled analysis of nonrandomized studies, the definition of recurrence and methods used to detect recurrence is lacking in most studies, there is a mixture of higher risk patients (albeit small) in many of the studies, and the overall follow-up is relatively short in this analysis. Some of these limitations would bias toward benefit of radioiodine therapy, and other limitations would bias against this therapy. Still, the data are suggestive that radioiodine therapy is beneficial in this group of patients with DTC.

Finally, the risks of radioiodine therapy must be considered. Most of our knowledge about the risks of radioiodine on secondary primary malignancies is based on case reports and small series, which suggest that cumulative administered doses of radioiodine (131I) below 600 mCi are relatively safe (9, 10). More recently, studies have suggested that lower cumulative doses of radioiodine may be associated with increased risk of chronic myelogenous leukemia (10, 11). A recent multicenter cohort study analyzed the risk of secondary malignancies in 6841 patients with DTC (62% were treated with radioiodine) (12). The investigators observed a significant 30% increased risk of second primary malignancies in patients treated with radioiodine, and there appeared to be a linear relationship between the cumulative dose and solid tumors (4% increased risk/GBq 131I). These authors calculated that 3.7 GBq (100 mCi) would be associated with an excess of 53 solid malignant tumors and three leukemias per 10,000 patients over a 10 yr follow-up. Although these data are estimates from an extrapolation of higher cumulative doses of radioiodine and not actual data from patients receiving 100 mCi 131I, they should provoke us to consider that there may be risks (however small) associated with single doses of radioiodine for remnant ablation. Another recent randomized clinical trial examined the effectiveness of eight different administered doses of radioiodine (15–50 mCi 131I) for remnant ablation in patients with low-risk thyroid cancer (13). The investigators found that 131I doses of at least 25 mCi were equally effective (≥80%) at successful remnant ablation. The study did not assess or discuss iodine intake or excretion in these patients, and pretreatment remnant uptake of radioiodine was higher (8–10%) than is commonly seen in many centers in the United States. Despite these differences, the two recent studies suggest that administered doses of radioiodine lower than 100 mCi 131I may decrease risks of second primary malignancies without compromising successful remnant ablation.

While we wait for the definitive, randomized, controlled clinical trial, we need to treat, manage, and monitor our patients with DTC. The value of the current study is that it provides the strength of a carefully performed literature review and metaanalysis. This study suggests that there is benefit to using radioiodine for remnant ablation in patients with low-risk DTC. We must individualize radioiodine therapy, use the lowest effective dose of radioiodine, and carefully discuss the risks and benefits of this potential therapy with our patients. Older patients with larger tumors and patients with lymph node involvement may significantly benefit from radioiodine remnant ablation. The benefit of radioiodine in younger patients with smaller tumors is less clear, and potential risks of therapy need to be thoroughly considered.

Footnotes

Abbreviation: DTC, Differentiated thyroid cancer.

Received May 14, 2004.

Accepted May 21, 2004.

References

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