Coming of age: recombinant human thyroid-stimulating hormone as a preparation for (131)i therapy in thyroid cancer.

Recombinant human thyroid-stimulating hormone (rhTSH) was approved for diagnostic testing by the U.S. Food and Drug Administration in November 1998. It has subsequently been approved in Europe and Australia and is available in many other countries on a restricted basis. Approval was based on its ability to stimulate the uptake of radioiodine into thyroid remnants and metastases of thyroid cancer, as well as its ability to stimulate normal or neoplastic thyroid cells to produce thyroglobulin. In fact, the ability of rhTSH to stimulate the production of thyroglobulin, as judged by a rise in serum thyroglobulin above 2 ng/mL, is now recognized to be the most sensitive marker of residual thyroid cancer. The ability to visualize a thyroid remnant or a metastatic deposit of thyroid cancer cells with radioiodine depends on several factors. The first is the number of cells present in a single focus, that is, a critical mass. Another is the iodine transporting capacity, which depends largely on the sodium iodide symporter (NIS) activity. A third factor is the trapping ability of the thyroid cells, which is related to the organification of iodine by the cells that accumulate it. Finally, there are incompletely defined mechanisms (e.g., pendrin) that export or clear iodine from the cells. If there are too few cells or if they cannot sufficiently accumulate or retain the radioiodine, they will not be visible by standard imaging techniques. Haugen et al. (1) and our group (2) have independently reported, in large controlled series, that the sensitivity and specificity of whole-body radioiodine imaging is comparable whether patients are prepared by thyroid hormone withdrawal or by rhTSH. However, there is growing awareness of the poor sensitivity that a diagnostic whole-body scan has for detecting small volumes of residual disease (3–5). The ability of thyroid-stimulating hormone (TSH) to increase the expression of NIS and to enhance radioiodine uptake raises the question of whether this new agent could also substitute for thyroid hormone withdrawal as a preparation for radioiodine therapy. TSH is also known to stimulate iodine efflux mechanisms in thyroid cells; however, the time course of this effect may be different from that of the effects on uptake (6). In general, radioiodine therapy is performed with 131I and either is designed to ablate a thyroid remnant after a total thyroidectomy or is aimed at destroying metastatic thyroid cancer deposits that have demonstrated some radioiodine avidity. The therapeutic setting raises new and important issues regarding rhTSH that were not addressed in the original diagnostic paradigms. The first issue is total-body radiation exposure after therapeutic amounts of 131I. Temporary or permanent damage to bone marrow, bladder, oral mucosa, taste buds, salivary glands, gastric mucosa, and gonads has been reported after administration of 131I (7). Side effects related to 131I in the hypothyroid state occur in as many as 50% of the patients who receive large amounts of 131I (8). Furthermore, it is well established that renal blood flow and glomerular filtration are reduced in hypothyroidism (9,10). Because iodine is principally cleared by the kidney, the prolonged retention of 131I in the hypothyroid state would be expected to increase radiation to many tissues. The hypothyroid state, however, is a convenient and inexpensive means to raise endogenous pituitary production of TSH, which in turn would stimulate NIS activity in remnants or metastases. On the other hand, if patients were prepared for therapy in the euthyroid state, with rhTSH, rather than in the hypothyroid state, the renal clearance of iodine should remain intact, leading to more rapid clearance of 131I from the blood, with lower radiation of blood and tissues. This hypothesis has been tested and confirmed to be correct by several groups (11,12). This has led some investigators to administer therapeutic activities that are significantly higher than they would use in the hypothyroid state (13,14). A second issue to consider is the “dwell time,” or the duration of 131I occupancy within the thyroid (normal or neoplastic) cells. If the radioiodine also clears from the target tissue more quickly in the euthyroid state, with rhTSH, than in the hypothyroid state, then rhTSH preparation may have little therapeutic advantage. In theory, a longer dwell time will result in a higher death rate of the target cells. The trapping of radioiodine into thyroid proteins or lipids would significantly increase the dwell time of the radioisotope, with tissue-specific damage. The frequently diminished expression of NIS, thyroperoxidase, and thyReceived Mar. 13, 2003; revision accepted Mar. 24, 2003. For correspondence or reprints contact: Richard J. Robbins, MD, Endocrinology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. E-mail: [email protected]