Recommendations for the Use of Levothyroxine in Thyroid Cancer

The consensus recommendation currently is that TSH suppressive therapy should be given postoperatively to all patients with differentiated thyroid cancer. The exact definition of appropriate TSH suppression to suppress tumor growth adequately remains unclear. Studies with very large numbers and follow-up would be required to detect significant differences. The true efficacy of ablative 131I has never been established in a controlled clinical setting.228,229 In the postoperative setting in the cases believed to be high risk (the older male patient with a tumor larger than 4 cm with either capsular or angioinvasion if follicular or extensive lymphadenopathy if papillary), T4 replacement therapy is avoided for 4 to 6 weeks. This allows maximal TSH stimulation to occur and permits a valuable assessment of postoperative thyroglobulin levels (because thyroglobulin levels increase as serum TSH levels increase in patients with remnant normal thyroid tissue or metastatic thyroid cancer after thyroidectomy).230 In some patients with rapidly growing metastases, it may be critical to minimize TSH stimulation of the tumor after thyroidectomy or 131I scanning or ablation, and this is best achieved by the use of T3, which, because of its shorter half-life, needs to be discontinued for only about 2 weeks to stimulate TSH for diagnostic or therapeutic purposes.231

It can be seen that radioiodine scanning and ablation are not trivial undertakings. The need to stop replacement therapy and to render the patient at least subclinically hypothyroid, along with the precautions necessary in the use of radiopharmaceuticals, must be coordinated by a nuclear medicine physician with a specific interest and experience in thyroid tumor treatment. The timing of the first scan, the indications for remnant removal or ablation, and the interval between scanning are all matters of controversy.

Serum thyroglobulin determination is also comparable to or more sensitive than 131I scanning in the follow-up of patients with differentiated carcinoma. Thyroglobulin is a large glycoprotein synthesized by thyroid follicular cells and stored in colloid, providing the tyrosyl groups for iodi-nation and coupling to form both T3 and T4. TSH stimulates thyroglobulin release, and thus serum thyroglobulin is elevated in any disease associated with an increased mass or activity of the gland. As a result, it is elevated in endemic and sporadic goiter, thyroiditis, and benign and malignant thyroid neoplasms.232 Its use in the assessment of patients after total thyroidectomy is roughly equivalent to that of radioiodine scanning.233"238 In 8% to 22% of cases of differentiated thyroid carcinoma, thyroglobulin measurement is difficult, however, because of circulating antithyroglobulin antibodies leading to spuriously high levels,239 although the newer use of monoclonal antibodies to thyroglobulin and immunometric assays will lessen this problem.240 A serum concentration suppressed according to a second-generation assay with a TSH of less than 0.1 mU/L may be readily detectable by a third-generation assay with a limit of 0.01 mU/L. The term "undetectable" then becomes obsolete when assessing TSH suppression and is relative to the assay used.

Equally, in a small group of patients with nonfunctioning but differentiated metastases (particularly elderly patients with invasive Hurthle cell tumors), both thyroglobulin measurement and sestamibi or thallium scanning or technetium pyrophosphate bone scanning, or a combination, are superior to diagnostic 13II scans.241'242

TSH suppression has been shown to reduce recorded levels of thyroglobulin in patients with proven functional metastases, and thus thyroglobulin levels are best assessed with the patient not receiving replacement thyroid hormone.243-244 An elevated thyroglobulin concentration with a normal 13'I diagnostic scan without thyroid hormone should alert the clinician to the possibility of nonfunctioning osseous or pulmonary metastases and result in careful clinical assessment with standard radiologic methods for detecting metastatic disease, such as computed tomography scanning, skeletal surveys, and magnetic resonance imaging. When treated with therapeutic doses of 13'I, some of these patients have their thyroglobulin levels decrease to below 3 ng/mL, and metastatic tumor is seen on a follow-up scan (approximately 5 days after treatment). The value of thyroglobulin measurement after simple lobectomy in thyroid cancer is clearly debatable, but if it is elevated after such surgery in patients receiving levothyroxine suppression (i.e., above the normal range for an intact thyroid lobe), a search for metastatic disease should be initiated.232-245 An algorithm for the use of TSH suppression therapy, based on data from Schlumberger and colleagues,245 is shown in Figure 8-2.

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