Department of Medicine, Washington Hospital Center, Washington, D.C. 20010-2975
Address all correspondence and requests for reprints to: Dr. Leonard Wartofsky, Department of Medicine, Washington Hospital Center, 110 Irving Street NW, Washington, D.C. 20010-2975. E-mail: . leonard.wartofsky{at}medstar.net
On the basis of recent data, the frequency of diagnosis of new thyroid cancer cases appears to be increasing, with projections of about 18,800 new cases in 2001 and perhaps 1,500 deaths (1). Optimal management of thyroid cancer patients includes performance of the appropriate surgical procedure, usually total or near total thyroidectomy, followed by radioiodine ablation and careful, periodic follow-up with suppression of TSH by T4 administration (2, 3). Subsequent evaluation generally requires discontinuation of T4 to elevate serum TSH sufficiently to perform a whole body scan survey to detect residual or metastatic disease (2, 3, 4, 5, 6, 7). Longer term follow-up also includes employing a variety of monitoring methods such as careful physical examination, high resolution ultrasound of the neck, chest x-ray or computed tomography scan, 131I total body scans and serum Tg measurements, and other imaging modalities such as [18F]fluorodeoxyglucose positron emission tomography, thallium or sestamibi scans, and magnetic resonance imaging (6, 7).
Traditionally, diagnostic radioiodine scanning has been performed after withdrawal of T4 therapy, but unfortunately, thyroid hormone withdrawal can be associated with profound symptoms of hypothyroidism and reduced quality of life. Recent availability of recombinant human TSH (rhTSH, Thyrogen, TSH alfa for injection) has altered follow-up evaluations for residual or recurrent disease of patients after their initial management (8, 9). Phase III studies have indicated that in most patients rhTSH preparation for diagnostic whole body scans and Tg measurement is as efficacious as withdrawal (10, 11). These studies have demonstrated that administration of rhTSH improves sensitivity of Tg testing to detect residual disease. Indeed, one recent retrospective study suggested that there may be little need to do withdrawal and that rhTSH scanning and Tg measurement are sufficient in virtually all patients (12).
Given the costs of scanning and the desire to avoid additional isotope exposure, patients often are monitored with only measurements of serum Tg. In addition, to avoid the morbidity of hypothyroidism, Tg is often assayed while the patient is on TSH-suppressive therapy (THST) with T4. Detection of thyroid tumor by measurement of Tg is most sensitive when the TSH is elevated (13, 14), a state that, until recently, was only achieved after rendering patients hypothyroid by T4 withdrawal. An elevated serum Tg in a patient on THST indicates recurrent or residual disease, but an undetectable serum Tg may not adequately rule out disease.
Although serum Tg measurements have a lower false negative rate than whole body scanning (11, 15), it remained to be determined whether patients can be adequately evaluated by elimination of THST withdrawal and diagnostic scanning and performance of only rhTSH-stimulated serum Tg measurement. This question has now been answered, at least in large part, by the study of Mazzaferri and Kloos (16), appearing in this issue of JCEM, that explored whether measurement of Tg after administration of rhTSH might be sufficient to detect residual disease and thereby eliminate the necessity for 131I scanning. A rhTSH-stimulated Tg approach would identify those patients demonstrating a significant increment in serum Tg who then would be candidates for further evaluation such as ultrasound, magnetic resonance or PET imaging, or withdrawal and 131I scanning.
The study by Mazzaferri and Kloos (16) is retrospective and examined the necessity for 131I diagnostic scanning for detection of residual or recurrent thyroid carcinoma in 107 patients when rhTSH is administered and serum levels of Tg are measured after rhTSH. There were 11 patients who showed no evidence of disease by scan but had positive stimulation of serum Tg by rhTSH. The data indicate that scanning adds little additional information other than perhaps evidence of residual thyroid bed. Remarkably, a stimulated cut-off value for serum Tg of less than 2 ng/ml after rhTSH had a 100% negative predictive value, indicating that a serum Tg greater than 2 ng/ml after rhTSH is a strong indicator of residual or recurrent disease. Indeed, none of 87 patients whose serum Tg was less than 2 ng/ml were seen to have a positive whole body scan, although 8% of patients with a Tg greater than 2 ng/ml had negative scans, suggesting a greater sensitivity of rhTSH-stimulated Tg than diagnostic scanning. Thus, in the absence of interfering anti-Tg antibodies, scanning will add little to the results of rhTSH-stimulated Tg measurement. These conclusions perhaps are best considered viable in the context of low-risk thyroid cancer patients. Although the authors state that half of their patients were at high risk for recurrence, the inclusion of patients with an often rather long interval of up to 35 yr of their initial treatment may have weighted the expected results with more of these long-term patients, showing a negative response of Tg to rhTSH and consequently less disease being detected.
The observations of Mazzaferri and Kloos (16) are fully consistent with those of a preliminary report of a multicenter study that was undertaken to ascertain prevalence and significance of rhTSH-stimulated increases in Tg levels in thyroid cancer patients who were felt to be at low risk for recurrence (17). The 300 patients who were studied had undergone near-total or total thyroidectomy and remnant ablation between 1 and 10 yr before enrollment; they had received THST and had basal TSH levels of less than 0.5 mU/liter and Tg levels equal to or less than 5 ng/ml while on THST. Patients with Tg antibodies, distant metastases, or suspected residual disease were excluded. After baseline TSH, Tg (Nichols Chemiluminescence assay), and anti-Tg antibody levels were measured, 0.9 mg rhTSH was injected on days 1 and 2, and Tg was measured on day 5. After rhTSH, 53 of 300 patients (18%) had elevations in Tg of at least 2 ng/ml, including 33 patients (11%) with increases of more than 5 ng/ml from baseline. Individual and median levels of serum Tg at baseline on day 1 and on day 5 following rhTSH stimulation are depicted in Fig. 1. Patients who initially had a more advanced stage of disease were more likely to display elevations in Tg after rhTSH, because almost one third of those with stage III disease displayed elevations in Tg of at least 2 ng/ml. Thus, as was seen in the study by Mazzaferri and Kloos (16), these data suggest that rhTSH-stimulated Tg testing without scan may be a useful tool in follow-up of patients with low-risk thyroid cancer and may serve to identify patients previously thought free of disease on the basis of undetectable Tg levels while on THST. Indeed, from the follow-up data available to date in both our studies and that of Mazzaferri and Kloos (16), it appears that many patients with positive Tg responses to rhTSH had earlier negative isotopic scans or may even have subsequent negative follow- up scans. This suggests that rhTSH may indeed improve the sensitivity of detection of some patients with disease not identified by scanning.
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Generally, the aggressiveness or frequency of follow-up evaluations must be linked to risk stratification of the patients. The recent studies reviewed above indicate that latent residual disease might be uncovered earlier by studying the Tg responses to rhTSH in patients with immeasurable Tg on THST. Although definitive studies that would indicate that earlier detection and ablation of residual tumor are more likely to prolong life or cure the cancer are still lacking or inconclusive, it is difficult to deny the possibility, based on the nature of other malignancies. Using periodic assessment of low-risk patients by rhTSH-stimulated Tg could permit the earlier identification of a smaller mass of tumor burden that would be more readily eradicated by radioiodine therapy.
Finally, whereas we believe that the serum Tg response to rhTSH may prove very useful in the follow-up of low-risk patients, the data of Mazzaferri and Kloos (16) appear to be applicable to higher risk patients as well. Thus, an undetectable serum Tg in virtually any patient with well differentiated thyroid cancer on THST should not be interpreted to rule out the presence of residual disease that may be uncovered in 18% of low-risk patients and almost 35% of high-risk patients by simply measuring a serum Tg level 72 h after rhTSH injections. Although Mazzaferri and Kloos (16) report a zero false negative rate for rhTSH-stimulated Tg levels greater than 2 ng/ml, it should be borne in mind that much more weight may be placed on a positive response to rhTSH than on a negative one, with a positive test result with stimulation of Tg likely to signify disease, whereas a negative result may not. Patients with a positive response could be withdrawn from THST and treated with 131I directly without performance of a diagnostic scan as proposed by Cailleux et al. (19) or could be evaluated by ultrasound or [18F]fluorodeoxyglucose positron emission tomography to determine the location and potential resectability of the Tg source.
Although we focused on a cut-off value of less than 2 ng/ml in our study (17), the results in patients with Tg levels less than 1.0 ng/ml as well as those reported recently by Robbins et al. (21) (see below) lead us to suggest that it would be clinically useful in low-risk patients to consider a baseline serum Tg level of more than 1 ng/ml (and not more than 2 ng/ml) as the trigger point for further testing. This level of Tg is consistent with the recently reported results of Fatemi et al. (20) that indicated that it may not be necessary to monitor low-risk patients with serum Tg less than 1.0 ng/ml by TSH-stimulated Tg measurements, and moreover that patients with serum Tg below 1 ng/ml on THST by their second postsurgical year have an extremely low rate of ultimate recurrence (14).
Recently reported results of a retrospective review by Robbins et al. (21) suggest some caution should one consider a cut-off value of serum Tg of less than 2.0 ng/ml on THST as indicating absence of disease. They examined rhTSH-stimulated Tg testing in 114 low-risk patients, and subsequent evaluation by scanning disclosed either residual disease or thyroid bed activity in approximately 13% of the patients. All of the patients who had scan evidence of residual disease had a prior positive diagnostic scan, so that a negative prior scan coupled with failure of Tg stimulation by rhTSH would be associated with a negative predictive value of 100%. Thus, these observations support a set point or cut-off Tg value for potential clinical significance of 1 ng/ml on T4 suppression. Given the increasing sensitivity and specificity of Tg assays, I would favor adopting this restrictive a cut-off, assuming one is basing the decision on a highly sensitive and valid assay. This concept could form the basis for a revised algorithmic approach to these patients (Fig. 2). Performing a diagnostic scan after rhTSH, as indicated in the algorithm for patients having a Tg of 0.52.0 on THST, might be considered optional based on the observations of Mazzaferri and Kloos (16), but is included because 13% of the above-mentioned patients of Robbins et al. (21) were found to have positive scans. Although a rhTSH-based system of monitoring could be clinically effective for disease detection, the frequency with which we should perform rhTSH stimulation for Tg remains to be determined. The method avoids both the inconvenience of withdrawal and the inconvenience, radiation exposure, and costs of isotopic scanning. However, longer term follow-up of a larger number of patients with both positive and negative Tg responses to rhTSH will be necessary to determine false positive and false negative rates, respectively.
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Acknowledgments
Footnotes
Abbreviation: THST, T4 suppressive therapy.
Received January 25, 2002.
Accepted January 25, 2002.
References