A first study (phase I/II), completed in 1994 in 19 patients after a recent thyroidectomy for differentiated thyroid cancer (DTC), demonstrated the safety and the efficacy of rhTSH in promoting 131I uptake . Based on previous dose-finding studies the dose of rhTSH was fixed at 0.9mg for 2 consecutive days.
The encouraging results of this limited study were confirmed in a larger multicenter phase III study conducted between 1992 and 1995 in the USA in 127 patients . Using a single daily injection of 0.9 mg of rhTSH for 2 consecutive days, the 131I whole-body scan was equal to that obtained after thyroid hormone withdrawal in 86% of the patients and inferior in the remaining patients. This study had some methodological limitations, including the use of non-uniform 131I doses (74-148MBq, 2-4mCi), different scanning times and techniques, and the inclusion of only a few patients with metastatic disease. Furthermore, serum Tg testing was not a study endpoint.
To overcome these limitations, a second multicenter phase III trial, including US and European centers, was designed . The study included the comparison of two arms receiving different regimens of rhTSH given at a fixed dose of 0.9mg (once daily injection for 2 consecutive days versus 3 injections, 3 days apart), a fixed tracer dose of radioiodine (148 MBq, 4 mCi) and the analysis of serum Tg as a marker of disease. Serum Tg testing and 131I-WBS obtained after rhTSH and after thyroid hormone withdrawal were compared: 131I -WBS were similar in more than 90% of the patients, and serum Tg responses were comparable between the two methods. Among patients with persistent or recurrent disease, 80% had concordant scans, 4% had superior rhTSH scans, and 16% had superior withdrawal scans. Serum Tg was detectable (>2ng/mL) in only 80% of these patients during L-T4 therapy and was detectable in 100% following both rhTSH and withdrawal. The peak serum Tg was usually observed 2-3 days after the last injection of rhTSH. The shorter duration of stimulation with rhTSH is likely to have an impact on Tg levels and radioiodine uptake. In fact, the serum Tg level attained following rhTSH stimulation was usually lower than following withdrawal, but Tg was still detectable in all patients with persistent or recurrent disease investigated; this underlines why a sensitive IRMA method should be used and why all detectable serum Tg levels should be taken into account, even low levels. Furthermore, radioiodine uptake was also lower with rhTSH, and this was attributed both to a shorter duration of stimulation and to decreased bioavailability of radioiodine after rhTSH (euthyroid status) than following withdrawal (hypothyroid status). In fact, hypothy-roidism decreases the renal clearance of iodine and increases its body retention, thus increasing its bioavailability for thyroid cells but also the body radiation dose. This underscores the need for a diagnostic dose of 131I of 4mCi and not less and for scanning 2 days after the dose using standardized procedures.
In conclusion, the combination of serum Tg and of 131I-WBS was more informative than 131I-WBS alone and even more important, rhTSH-stimulated Tg detected all patients with persistent or recurrent disease.
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