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University of Texas M.D. Anderson Cancer Center Houston, Texas 77030
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Introduction |
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Thyroid follicular epithelial cells have two unique differentiated functions that allow the sensitive and specific detection of papillary and follicular thyroid carcinomas (DTC): the uptake and organification of iodine, and the production of thyroglobulin. Both of these functions are enhanced by increased serum levels of thyrotropin, another marker of thyrocyte differentiation. The ability to quantitate and image thyroid tissue, both normal and neoplastic, with tracer amounts of radioiodine also leads to a mode of specific therapy with higher quantities of radioiodine, usually in the form of 131I. However, false negative results occur in up to 15% of diagnostic radioiodine scans in patients with detectable thyroglobulin levels after thyroid ablation. On the basis of a high frequency of post-therapy scans that demonstrate foci of radioiodine uptake combined with subsequent decrease in the serum thyroglobulin level, it has been proposed that patients with elevated serum thyroglobulins and negative diagnostic radioiodine scans after thyroidectomy and ablative treatment should receive empiric 131I therapy with 100–300 mCi. Although such therapy can be administered and may be associated with a degree of response, as measured by both thyroglobulin levels and radioiodine uptake, it is far from clear that this approach to patient management should be widely adopted. Instead, the dictum of needing to balance evidence of potential benefit against the evidence of potential risk must be considered on a case-by-case basis, and empiric therapy may not be appropriate for most such patients.
First, it is necessary to consider the causes of morbidity and mortality due to DTC. Patients develop troubling symptoms due to disease affecting critical structures in the neck, bones, and central nervous system, and less commonly due to large tumor bulk in the lungs and mediastinum. Similarly, disease-related mortality is generally related to overwhelming tumor bulk, invasion into cervical structures, or central nervous system metastases (1). The risk for disease-related morbidity or mortality in patients with scan-negative, thyroglobulin-positive disease is not well defined. This may be particularly true for patients without evidence of tumor mass by other current imaging modalities such as high-resolution neck ultrasound or chest computed tomography. Patients with nonpalpable locoregional recurrence of papillary carcinoma large enough to be detected by ultrasound have been reported to have survival rates similar to those with disease only detected scintigraphically. As the resolution of cervical ultrasound commonly approaches 2 mm, failure to demonstrate disease in the thyroid bed or paratracheal regions by this method, even if detectable by thyroglobulin measurements, likely indicates that conservative observation would not be deleterious. This consideration may be even more important for patients whose thyroglobulin level following thyroid hormone withdrawal is no more than 12 ng/mL, which in the commonly cited NIH study was the cutoff that excluded extracervical uptake on post-therapy scanning (2). With time, mild thyroglobulin elevations may even diminish without specific intervention (3).
Second, there is no evidence whatsoever that either partial reductions in serum thyroglobulin levels or elimination of radioiodine uptake, visible only on post-therapy scans, are associated with improved patient outcome. Only a minority of patients in the NIH report achieved thyroglobulin (Tg) levels of less than 5 ng/mL, and radioiodine uptake rarely was completely ablated when present on post-treatment scans in extracervical sites. In fact, it has been argued that 131I itself is not the most appropriate radioisotope to treat the micronodular foci of disease often found on post-therapy imaging (4). Instead, 125I, with a shorter pathlength of radiation and greater delivery of effective radiation dose to small lesions, may be the more effective treatment.
Consistent with the philosophy of primum non nocere, the potential risks of empiric therapy must be considered as well. The decision to treat until all uptake has resolved on post-therapy imaging implies a need for at least two administrations of high-activity radioiodine, one to "treat" and one for a follow-up scan. Assuming that a patient has previously undergone radioiodine ablation, a total activity of at least 400–500 mCi will have been administered by this approach, likely increasing the risk of chronic sialoadenitis and xerostomia, and introducing the potential for impaired marrow function if careful blood dosimetry is not performed. Although the evidence for secondary malignancies from radioiodine administration is far from definitive, recent reports of increased rates of colorectal, bladder, breast, and salivary tumors should be taken into consideration as well, especially in younger patients who are otherwise more likely to live long enough to develop secondary malignancies (5, 6).
With these concerns in mind, it seems reasonable to consider empiric radioiodine therapy of Tg positive, scan negative disease as experimental and of unproven benefit. In that sense, prospective, randomized clinical trials should be undertaken to determine whether such therapy is beneficial. For those patients with evidence of progressive metastatic disease, it may be reasonable to consider a therapeutic trial of radioiodine before embarking on other treatment modalities. But, for younger patients with stable albeit elevated thyroglobulin levels and no radiographic evidence of disease otherwise, there does not appear to be sufficient evidence of benefit to warrant such therapy.
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This article has been cited by other articles:
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  R. T. Kloos Approach to the Patient with a Positive Serum Thyroglobulin and a Negative Radioiodine Scan after Initial Therapy for Differentiated Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1519 - 1525. [Abstract] [Full Text] [PDF]
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 C. Ma, J. Xie, and A. Kuang Is Empiric 131I Therapy Justified for Patients with Positive Thyroglobulin and Negative 131I Whole-Body Scanning Results? J. Nucl. Med., July 1, 2005; 46(7): 1164 - 1170. [Abstract] [Full Text] [PDF]
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 M. E. Spieth, S. B. Standiford, M. E. Starkman, and J. Gough Recombinant TSH-Stimulated, Radioguided Differentiated Thyroid Carcinoma Surgery Clin. Med. Res., January 1, 2003; 1(1): 53 - 56. [Abstract] [Full Text] [PDF]
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