Southern California Permanente Medical Group (S.F.), Panorama City, California 91402, and University of Southern California/Keck School of Medicine (J.L.P.), Los Angeles, California 90033
Address correspondence to: Shireen Fatemi, M.D., Southern California Permanente Medical Group, 13652 Cantara St. Medical 10, Panorama City, California 91402. E-mail: shireen. fatemi{at}kp.org.
To the editor:
In the April 2003 issue of JCEM, Mazzaferri et al. (1) offer a new management paradigm for detecting recurrence in patients with low-risk differentiated thyroid cancer (DTC). They suggest that the use of recombinant human TSH (rhTSH)-stimulated thyroglobulin (Tg) is sufficiently sensitive to detect recurrence without scanning to discover residual disease and may constitute a reasonable cost-effective approach to the management of these patients.
We wish to make several comments and offer a perspective on the prognostic significance of serum Tg while on thyroid hormone suppression therapy (THST) early in the follow-up of DTC patients.
The authors emphasize that serum Tg is the keystone to the management algorithm described. Thus, the accuracy of Tg measurement is crucial and necessitates that the Tg assay used should meet the minimum performance standards of the National Academy of Clinical Biochemistry (2). However, the Consensus Report does not mention whether the different Tg assays used in the various centers from which the metaanalysis was based and from which they draw their conclusions specifically meet these standards.
The Consensus conference was convened in response to the increasing prevalence of DTC in the United States in an attempt to develop a management guideline that encompasses newer technologies. However, this may not be necessary because Hay et al. recently have shown in a large retrospective analysis that, aside from an increase in the extent of initial surgery, few other modalities have influenced tumor recurrence or cause-specific mortality (3). In the Consensus discussion, it is noted that the early detection of a tumor recurrence may affect thyroid cancer mortality (4), but the reference cited examines the delay in initial treatment, not early intervention in a low-risk patient with occult disease. A delay of initial therapy in other low-risk patients, such as postponing thyroidectomy for a mean of 16 months due to pregnancy, has not been found to be associated with an adverse outcome (5).
Although rhTSH or endogenously stimulated serum Tg may be more sensitive in detecting residual tumor or tissue than Tg on THST, as the authors speculate, its use may be overemphasized in the low-risk patient. The conclusion reached from this metaanalysis indicates that "an undetectable serum Tg measured during thyroid hormone suppression is often misleading in a large proportion of patients with residual DTC." The data of Mazzaferri et al. seem compelling when presented as a progressive breakdown in percentages, but when it is examined in comparison to the whole cohort tested, one comes to a different conclusion. Of the 784 patients with a Tg level below 1 µg/liter on THST, the number with a rise in Tg over 2 µg/liter with rhTSH administration was 168 of 784 (21.4%). Fifty-three of these patients, or 6.8% of the total group (53 of 784), were found to have metastases. Attention is given to the observation that substantial cost savings resulted from eliminating the scanning portion of the evaluation. However, it is noteworthy that approximately 93% of the group subjected to the process (multiple office visits) and expense of testing ($657,900.00 for 731 patients at approximately $900.00 for rhTSH) had no change in clinical management.
We have reported that the use of serum Tg alone on THST is a good prognostic indicator of long-term recurrence for patients with DTC (6). A low overall recurrence rate of 6.0% in Tumor Node Metastasis stage I and II patients after a median follow-up of 8 yr was observed when the Tg on THST fell to less than 2 µg/liter in the first postsurgical year. Recurrences in this group of DTC patients were nearly always preceded by a rise in Tg on THST. Others have shown that in DTC patients who underwent thyroidectomy and remnant ablation (with minimal residual bed uptake) and have a stimulated serum Tg below 10 µg/liter, the serum Tg on THST almost always became undetectable by 612 months after initial therapy when the patient was free of disease (7). Moreover, knowing that the degree of rise of Tg in relation to TSH stimulation is approximately 10-fold, one can often predict the stimulated Tg value without the necessity of rhTSH.
Given the process and expense of this paradigm using new technology, it does not seem prudent to monitor a low-risk group in this fashion when the majority of patients have no change in their clinical course. Furthermore, there is no evidence to support that earlier intervention in this group with occult cancer ultimately affects mortality. Although no guideline is suitable in all instances, periodic monitoring with a quality serum Tg on THST and annual high-resolution neck ultrasound using an experienced ultrasonographer may be used to effect the same clinical outcome.
Received May 23, 2003.
References
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