Gainesville, Florida 32608-4653
Address all correspondence and requests for reprints to: E. Mazzaferri, M.D., M.A.C.P., 4020 SW 93rd Drive, Gainesville, Florida 32608-4653. E-mail: mazz01{at}bellsouth.net
What Is the Controversy All About?
There is little dispute that 131I is highly effective in the treatment of differentiated thyroid cancer (DTC). Yet, some 50 yr after its proposed use in destroying ostensibly normal thyroid remnants (1), controversy continues to swirl around the exact role and efficacy of remnant ablation in the management of DTC. This is partly fueled by the significantly different outcomes of patients with papillary, follicular, and Hürthle cell cancers; the 10-yr cancer-specific mortality rates for the three were about 7, 15, and 25%, respectively, among 53,856 patients managed in the United States between 1985 and 1995 (2). Embedded in this controversy is the fact that remnant ablation plays a major role in ensuring the accuracy of long-term follow-up. This is a major issue. Because most patients tend to survive for long periods, the prevalence of DTC survivors has swollen to almost 300,000 in the United States1 and 200,000 in Europe (3). Each needs lifelong surveillance. Tumor recurrence, sometimes decades after initial treatment, is often signaled only by a high serum thyroglobulin (Tg) level (4). Without 131I remnant ablation, this is usually not possible.
What Does the Study by Sawka et al. (5) Tell Us about the Efficacy of Remnant Ablation?
In this issue of JCEM, Sawka et al. (5) present the results of a systematic review and metaanalysis of the literature on remnant ablation. The main conclusions are that it may be beneficial in decreasing recurrence of DTC, but the results are inconsistent and the benefit of remnant ablation remains unclear in low risk patients treated with bilateral thyroidectomy and thyroid hormone suppression of TSH.
The 10-yr cause-specific mortality rates among the studies in this analysis were very low, i.e. 1.7% for papillary cancer and 3.4% for combined papillary/follicular thyroid cancer studies. The treatment effects of 131I ablation were significantly different among the studies, perhaps because the amount of 131I administered for remnant ablation ranged from 28 to 200 mCi and the mean or median follow-up period was longer than 10 yr in only a few studies. In the follicular cancer studies, there was less heterogeneity, and the 10-yr cause-specific mortality rate was 10% with or without remnant ablation. Overall, the 10-yr cancer-specific mortality rates were considerably lower than those in the U.S. study mentioned above, perhaps because the studies in the Sawka analysis (5) were generally smaller than the huge U.S. study (2) and included patients treated long before 1986. It is not surprising that Sawka et al. (5) found no treatment effect of remnant ablation on cancer-specific mortality, which often occurs years after treatment, making it impossible to know without decades of follow-up of large patient cohorts (6). On the other hand, the 10-yr event rates of new metastases from all histologies combined after treatment with or without 131I ablation were 4 and 10%, respectively, for locoregional recurrences, and 2 and 4% for distant metastases. For remnant ablation, the pooled relative risk of locoregional recurrence was 0.31 (95% confidence interval, 0.2, 0.49), and the pooled risk of distant metastases decreased by 3% (95% confidence interval, 1% to 4%).
Why Perform Thyroid Remnant Ablation and What Are the Downsides to Doing It?
Remnant ablation is performed for several reasons in addition to destroying occult microscopic cancer. It facilitates follow-up with whole body 131I scans and TSH-stimulated serum Tg measurements, both of which undergo substantial interference from residual normal thyroid tissue. Persistent disease and tumor stage cannot be identified shortly after surgery when there is a large thyroid remnant (3). Without remnant ablation, for example, half of the lung metastases in children cannot be identified (7). The greatest downside to remnant ablation is exposure of a person to radiation that might be unnecessary. As a practical matter, however, the main problems caused by 131I remnant ablation are transient loss of taste, acute and chronic radiation-induced parotitis, and sialadenitis that may produce chronic xerostomia (8). It also may cause transient testicular damage (9). To some extent, these risks can be reduced or eliminated by using smaller amounts of 131I. A recent randomized prospective study of 509 patients concluded that any activity of 131I between 25 and 50 mCi appears to be adequate for remnant ablation (10).
What Bearing Does the Sawka Study Have on the Current Management of DTC?
Treatment of DTC in the United States (4) and Europe (3) usually comprises total or near-total thyroidectomy and remnant ablation, although some still advocate less surgery and no 131I therapy for the majority of patients, arguing that mortality rates are so low that such aggressive treatment is unnecessary (11). If so, why do so many patients and physicians opt for near-total thyroidectomy (12) and 131I remnant ablation (13, 14)? I think it is concern about tumor recurrence, the rates of which are high, ranging up to 30% in some studies (4). In the past, persistent tumor was often not recognized until many years after treatment. For example, in our studies, 15% of locoregional tumors and 24% of distant metastases were first identified more than two decades after initial therapy (15). Many of the metastases were undoubtedly present at the time of initial therapy but had gone unrecognized for lack of sensitive Tg tests and modern high-resolution ultrasonography and for failure to appreciate the importance of postablative 131I scans in identifying residual tumor. Micrometastases in lymph nodes (16) and lung (4, 7, 17, 18) that routinely evade diagnostic imaging studies are common in patients with papillary thyroid cancer, a problem that has been greatly alleviated by newer follow-up paradigms that rely heavily upon thyroid remnant ablation (3, 19). Indeed, the Sawka study (5) found reasonably good evidence that 131I ablation reduced the risks of locoregional and distant recurrences, the main source of death from DTC.
Is There a Risk of Late Tumor Identification?
The composition of patients with DTC in the United States (see Footnote 1) and Europe (3) has been slowly changing over the years, probably as a result of earlier diagnosis and effective therapy. Malignant thyroid tumors are being identified at an earlier stage by the extensive use of imaging studies and fine-needle biopsy (4). The result is that more patients are at lower risk of dying of cancer than was so in the past. In fact, mortality rates for thyroid cancer in the United States have declined nearly 50% in the past three decades, but only in women (see Footnote 1). In men, thyroid cancer is identified much later in life and at a more advanced stage than it is in women (see Footnote 1). Compared with women, men have twice the rate of distant metastases at the time thyroid cancer is diagnosed and experience nearly twice the cancer mortality rate (see Footnote 1). As a result, thyroid cancer has become the most rapidly rising cause of cancer death among men in the United States (see Footnote 1). It is difficult to know why this is, but I think it is simply because men undergo fewer annual medical examinations than do women and because obstetricians and primary care physicians often examine a womans neck to identify thyroid nodules, whereas urologists seem less inclined to do so. I cannot recall having had a referral from an urologist to evaluate a mans thyroid nodule, but I see many women with thyroid nodules referred by gynecologists. This supports the notion that early diagnosis, including early recognition of the tumor and metastases, along with prompt therapy, has an important impact on outcome. Nowadays, sensitive follow-up strategies identify patients with persistent tumor shortly after they have undergone total thyroidectomy and 131I remnant ablation, enhancing the opportunity for effective treatment.
How Important Is Remnant Ablation to Current Follow-Up Paradigms?
The main objectives of follow-up are to identify tumor at the earliest possible time while simultaneously distinguishing patients who are free of disease. This ensures that treatment will have the greatest potential to extend survival in the first group while avoiding unnecessary treatment in the latter, especially levothyroxine suppression of TSH with its associated adverse cardiac effects and loss of bone mineral density. To achieve these goals, follow-up strategies have undergone substantial evolution. We now rely heavily on TSH-stimulated Tg levels, post-131I treatment whole body scans (RxWBS), and neck ultrasonography to identify patients with persistent tumor (3, 19), which diagnostic whole body 131I scans (DxWBS) and baseline Tg measurements (during TSH suppression) commonly fail to identify (3, 4). DxWBS has thus been largely replaced by RxWBS (3, 19, 20, 21).
Postoperatively, patients are now classified as showing no evidence of disease if they have had complete tumor resection, they show no uptake outside the thyroid bed on the post-remnant ablation RxWBS, and they have a negative neck ultrasound examination and serum Tg levels below 1 ng/ml with TSH suppression and after recombinant human TSH- (rhTSH) administration or thyroid hormone withdrawal (3, 19).
Tumor is often present when a baseline serum Tg below 1 µg/liter rises above approximately 2 to 5 ng/ml with rhTSH administration or above approximately 5 to 10 ng/ml with levothyroxine withdrawal (19, 22, 23). Conversely, the risk of developing a recurrence is below 0.5% (3) when there is no clinical evidence of tumor and the TSH-stimulated serum Tg level remains undetectable and neck ultrasonography is negative. In this case, patients can be reasonably assured that they are free of tumor and that TSH suppression should be stopped (3, 19, 20, 24). Yet none can be so assured in the presence of a large thyroid remnant; the serum Tg is not reliable (25), and few metastases can be visualized by 131I scanning (7, 26). As a practical matter, accurate tumor staging is impossible without total or near-total thyroidectomy and 131I remnant ablation. One study found that without TSH stimulation, approximately 20% of patients with lymph node metastases and 5% of those with distant metastases were missed by a baseline Tg below 1 ng/ml (3). In our study, 21% of 784 patients with no clinical evidence of tumor and baseline Tg levels usually below 1 ng/ml had, in response to rhTSH, a rise in serum Tg to more than 2 ng/ml (19). When this occurred, 36% of the patients were found to have metastases, 36% of which were at distant sites. DxWBS after either rhTSH or thyroid hormone withdrawal identified only 19% of the cases of metastases. Combined with ultrasonography, TSH-stimulated Tg identifies nearly all patients with persistent tumor early in the first year or two of follow-up.
Is a Randomized Trial of Remnant Ablation Feasible Using Current Follow-Up Paradigms?
Most agree that a randomized trial of remnant ablation using thyroid cancer mortality as an endpoint will likely never be performed because of the low number of events (6). Still, Dragoiescu et al. (27) recently suggested that using tumor recurrence as the endpoint, a randomized trial of adjuvant 131I therapy in DTC is feasible. A model was constructed using age, N and T stage to identify a subset of patients with papillary thyroid carcinoma treated at several institutions who were considered to be at substantial risk of relapse. A patient was considered to be free of disease if, after having undergone total thyroidectomy, the Tg (usually during TSH suppression) was not measurable and there was no clinical evidence of disease, including a negative DxWBS (performed in 90% of the patients). However, in one participating institution DxWBS was performed with 1 mCi 131I, making it even less sensitive than usual. Mean follow-up was 129 months, and follow-up was 6 yr or more in 80%. During the observation period, 48 (14%) patients had a recurrence, and 60% of them died compared with 8% of the patients without recurrences. A test set of patients validated the model. Still, follow-up in this group was likely too brief to identify all the patients with tumor, and failure to use TSH-stimulated serum Tg measurements as the gold standard likely missed a considerable number of patients with residual tumor.
It would be nice to think that a randomized trial might be done to settle once and for all the differences of opinion concerning the therapeutic efficacy of 131I remnant ablation. Such a trial, however, must use sensitive follow-up paradigms, a problem that seems nearly insurmountable given the current information about TSH-stimulated serum Tg measurements and the use of RxWBS in the follow-up of patients with DTC. How this dilemma might be reconciled poses a major problem that is likely to baffle any quest for the elusive goal of a prospective randomized trial of remnant ablation.
Footnotes
Abbreviations: DTC, Differentiated thyroid cancer; DxWBS, diagnostic whole body 131I scan; rhTSH, recombinant human TSH-; RxWBS, post-131I treatment whole body scan; Tg, thyroglobulin.
1 Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Cleeg L, Mariotto A, Fay MP, Feuer EJ, Edwards BK 2003 SEER Cancer Statistics Review, 19752001. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2001/results_single/sect_25_table.12.pdf.
Received April 20, 2004.
Accepted May 21, 2004.
References