Gainesville, Florida 32608-4653
Address correspondence to: Ernest L. Mazzaferri, M.D., MACP, 4020 SW 93rd Drive, Gainesville, Florida 32608-4653. E-mail: mazz01{at}bellsouth.net.
To the editor:
We thank Dr. Menzel and associates for their thoughtful letter and are happy to know that they agree that diagnostic whole body scans (DxWBS) have very limited value in the follow-up management of patients with differentiated thyroid cancer (DTC), which is a major point of our article. Their letter questions the composition of our consensus group, suggesting that we did not have input from nuclear medicine specialists. Dr. Braverman is certified in nuclear medicine. Our group is comprised of individuals who have done in-depth research on the follow-up management of DTC. In the past decade, many were investigators in the only two prospective large-scale randomized studies evaluating recombinant human TSH (rhTSH) and DxWBS in the follow-up of patients with DTC (1, 2). Our article explicitly states that it represents the consensus of 15 experts in the field.
The general thrust of the rest of the letter by Menzel et al. is that more studies should be done than are suggested in our algorithm. They also believe that we should have categorized patients according to the 2003 AJCC/UICC classification that was introduced around the time our manuscript was submitted for publication. Because the new classification categorizes tumors 2 cm or less as T1, tumors 24 cm as T2, and tumors 4 cm and larger as T3, even more patients are now categorized as being at low risk, and many more would thus be candidates for study according to our algorithm. Menzel et al. also object to using a thyroglobulin (Tg) cutoff of 2 µg/liter to identify metastases, yet this is the Tg level that has been substantiated by prospective international multicenter studies to identify all patients with metastases (1, 2). Our recommendations are based on the findings from these studies. We agree with Menzel et al. that a few patients might have a positive DxWBS but still have a low TSH-stimulated Tg level; however, this is so uncommon that we felt it should not influence the overall algorithm. For example, only five of the 1,028 patients (<0.5%) in our study had a positive DxWBS with a stimulated Tg less than 2 µg/liter.
Menzel et al. believe that urinary iodine excretion should always be measured. We agree that it should be done in some and perhaps many patients; however, we use the test more selectively: when there is a history or even a possibility of exposure to contrast agents or other sources of iodine. They also suggest that computed tomography, magnetic resonance imaging, and positron emission tomography (PET) should be used earlier in the follow-up algorithm, yet we are aware of no studies that provide evidence to support this testing sequence. In contrast, a recent metaanalysis (3) provides consistent data on PET scanning, supporting its use explicitly for patients with elevated serum Tg levels and negative 131I scans, which is exactly where it is placed in our algorithm. This also approximates the reimbursement policy for PET scanning of thyroid cancer patients recently articulated by the Centers for Medicare and Medicaid Services in the United States (4). Moreover, computed tomography and magnetic resonance imaging studies are unnecessary if the TSH-stimulated Tg fails to rise above 2 µg/liter and there is no clinical evidence of disease. Doing otherwise would subject about 80% of patients to unnecessary imaging studies, thus substantially increasing the cost of follow-up. They also suggest that thyroid hormone withdrawal is more cost effective than rhTSH stimulation. Many patients object to withdrawal because of the subsequent symptoms of hypothyroidism that have a real cost by interfering with work and other daily activities. In response to both letters, we do not recommend follow-up without scanning; we recommend follow-up without diagnostic low-dose 131I scanning. Scans following a therapeutic dose of 131I are part of our algorithm.
Fatemi and LoPresti raise several important issues concerning our study. The general thrust of their letter is that measuring TSH-stimulated serum Tg levels is likely to have no impact on outcome, and thus fewer studies should be done. We disagree with this position and provide the following comments to support our position.
The meeting was not convened in response to the increased prevalence of DTC as stated in their letter; it was convened because of the large number of similar publications that used rhTSH-stimulated Tg to monitor DTC survivors, to see whether the recent results, taken together, impacted on traditional follow-up paradigms. The Consensus Report makes little mention of the different Tg assays used in the various centers, but this was carefully considered in preparing the report. All of the assays had a lower Tg limit of 1 µg/liter or less, and almost all reported using the international CRM 457 standard; all centers screened samples for the presence of anti-Tg antibodies and did not report Tg levels in patients with interfering Tg autoantibodies. We accordingly believe that the Tg data are reliable and reasonably consistent, reflect the reality of contemporary clinical practice, and provide meaningful information from which to draw conclusions, including the judgment that a Tg of 2 µg/liter is the most reasonable cutoff level to identify patients who require further evaluation.
Fatemi and LoPresti suggest that careful follow-up with TSH-stimulated Tg measurements may not be necessary because most patients with DTC have such a good prognosis, citing the recent study of 2,444 patients with papillary thyroid carcinoma (PTC) treated by Hay et al. (5). The latter article reports that no decline in cancer mortality rates has been observed in their institution since 1950, during which time only the extent of surgery appears to have influenced tumor recurrence or cause-specific mortality. Ten-year cancer-specific mortality rates in the Hay study for each decade from 19702000 were, respectively, 3.0, 2.2, and 2.3%. These are remarkably lower rates than those reported by Hundahl et al. (6), who found a 10-yr relative survival rate of 93% among over 43,000 patients with PTC treated in the United States between 1985 and 1995, an attributable cancer mortality rate (7%) more than 3-fold higher than that reported by Hay during the same period. Thus, the Hay survival data appear not to be applicable to the U.S. population at large. Furthermore, in contrast to Hays report of no decline in mortality rates for PTC during the past three decades, national data (7) do show a statistically significant decline (nearly 20%) in cancer mortality rates between 1973 and 1996 for all thyroid cancers. This is clearly driven by improvement in the outcome of PTC, which accounts for 80% of the thyroid cancers in the database. Lastly, Hay found a 40-yr cumulative recurrence rate of 13%, which is lower than that reported in most other series, but is the group that we believe can be identified relatively soon after surgery. Accordingly, we think it is unwise to recommend follow-up paradigms for all patients in the United States and Europe solely on the basis of the Hay mortality data (5). We suggest that a delay in treating clinical and subclinical recurrences after the initial therapy is completed might result in further tumor spread and might diminish the chance to completely ablate or resect residual metastases.
Fatemi and LoPresti believe our reference to the adverse consequences of a delay in initial treatment does not support the notion that early identification and treatment of persistent disease is worthwhile. However, there is little to support the idea that tumor found after near-total thyroidectomy and 131I ablation represents the appearance of de novo cancers. Rather, there are compelling reasons to believe that these are persistent tumors; finding and treating them after initial therapy is in most cases simply an extension of initial management. According to their assessment, early intervention in low-risk patients with occult disease is not justified, and a delay in treatment of such patients is innocuous. To support this stance, they cite the Moosa and Mazzaferri article that shows therapy was delayed an average of 16 months in pregnant women who had a good outcome, despite waiting until after delivery to undergo treatment of DTC. However, the delay in treatment was longer than 1 yr in a subgroup of only 12 pregnant patients, whereas the other 49 (80%) pregnant women underwent surgery in 1 yr or less from the time the nodule was discovered. As a result, the time lapse from discovery of the tumor to initial therapy (12.7 months) was nearly the same in the pregnant women as in the controls (10.8 months) who were not pregnant. Furthermore, women of child-bearing age represent a cohort of DTC patients who are, by definition, younger than average and, consequently, at lower risk of recurrence.
The Consensus Report shows that distant metastases were found in 21 patients and that locoregional disease was detected in 35 patients with a baseline Tg less than 1 µg/liter and a TSH-stimulated Tg greater than 2 µg/liter. The validity of this approach speaks for itself in respect to the outcome, i.e. the severity of the tumors that were discovered.
Citing their own work, Fatemi and LoPresti say that Tg alone during thyroid hormone suppression therapy (THST) is a good prognostic indicator of long-term recurrence for patients with DTC and predicts the TSH-stimulated Tg. This may be true for some patients. However, the details of their study were only presented in an abstract. Citation 6 in their letter is a report that contains clinical data on less than 15 patients and follow-up data on only three patients, and the complete data regarding this point were never published in a peer-reviewed journal. The authors cannot use this to substantiate their claim that the serum Tg on THST is a good prognostic indicator of long-term recurrence. There are numerous reports showing that the Tg level is a good indicator of recurrence and that it is more sensitive after TSH stimulation. The data in over 784 patients in the Consensus Report shows that when the THST Tg is below 1 µg/liter, one cannot predict, using current assays, when the TSH-stimulated Tg value will rise above 2 µg/liter, which occurred in over 21% of the patients in our article.
We agree with Fatemi and LoPresti that neck ultrasonography plays a major role in the surveillance of patients with DTC, but whether it is more sensitive than TSH-stimulated serum Tg levels is less certain, considering that one-third of the metastases reported in our paper were outside the neck. Nonetheless, preliminary evidence strongly supports its use during follow-up, which is generally regarded as complementary to the information provided by Tg testing.
The criticism that 93% of the patients cited in our paper were subjected to costly TSH-stimulated evaluations that simply proved they had no detectable disease but did not alter their management ignores a major issue in the follow-up care of patients with thyroid cancer: those with no rise in serum Tg after TSH stimulation are given substantial peace of mind that they are free of tumor. Furthermore, their subsequent follow-up can be appropriately modified, and the dose of L-T4 can be lowered to permit the serum TSH to rise to low normal levels (0.5 µU/liter) that avoid the consequences of subclinical hyperthyroidism. Fewer tests and imaging studies in these patients result in a lifelong cost reduction that is greater than envisioned by Fatemi and LoPresti. Only the relatively small group of patients (about 20% in our study) in whom the Tg response to TSH is greater than 2 µg/liter requires more intensive follow-up study. This can be done by a data-driven algorithm that uses low-dose 131I diagnostic WBS less frequently in lieu of other more sensitive tests such as TSH-stimulated Tg, neck ultrasonography, and post 131I treatment WBS.
In the future, using even more sensitive serum Tg assays may indeed render TSH stimulation unnecessary to identify patients with persistent tumor, but this remains to be proven by large clinical studies. We thank the authors of the two letters for voicing their concerns and providing us the opportunity to elaborate on these important issues. We hope that our paper will continue to engender robust discussion and provide a stimulus for further studies in this area.
Received June 14, 2003.
References
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