Epithelial Cell Thyroid Cancer and Thyroid Stimulating Hormone—When Less is More1

Charles H. Emerson and Raffaella Colzani

Lewis E. Braverman University of Massachusetts School of Medicine Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Lewis E. Braverman, Department of Medicine, Division of Endocrinology and Metabolism, University of Massachusetts School of Medicine, Worcester, Massachusetts 01655.


    Introduction
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 Introduction
 References
 
Endocrinologists, who have the most experience in the diagnosis and treatment of epithelial thyroid cancer, also should serve as the oncologist for patients with this disorder. These tumors are usually not completely dedifferentiated and therefore retain many TSH-regulated responses, including those related to iodide uptake and organification. The tumors are often sensitive to radioactive iodine, but almost always resistant to conventional radiation and chemotherapy, the mainstays for most malignancies. Unlike most neoplasms, treatment of thyroid cancer entails years of surveillance and titration of hormone replacement (1).

Surgery, administration of therapeutic doses of 131I (RAI), and suppression of endogenous TSH are the cornerstones for managing thyroid cancer. Surgery for suspected thyroid cancer is not only diagnostic, but is also therapeutic. There is general agreement that total or near total thyroidectomy is best for stage III and IV tumors (1). Although less extensive surgery is advocated by some for lower grade disease, even the most conservative approach should include resection of the affected lobe and isthmus. In fact, the overwhelming majority of thyroidologists currently employ total or near total thyroidectomy for Stage II papillary thyroid cancer (2). We share this preference because, even for this stage of thyroid cancer, more extensive resection of thyroid tissue is associated with a lower tumor recurrence rate (1, 3, 4).

RAI is employed to ablate recurrent tumor, metastatic disease, and tissue that remains in the thyroid bed after surgery. RAI treatment is associated with an approximately two-fold decrease in the recurrence rate of stage II and III tumors and at least a two-fold lower mortality rate (3). Thyroid hormone administration is the only method currently available for suppressing endogenous TSH secretion. In animal models, TSH suppression inhibits growth and formation of epithelial cell thyroid cancers (5). In humans, controlled studies are lacking, in part because the practice of not treating thyroid cancer patients with thyroid hormone has been abandoned for many years. In one setting, namely radiation-induced thyroid cancer, the addition of thyroid hormone after initial surgery for nodular disease did reduce the recurrence rate of benign thyroid nodules but not the recurrence of thyroid cancers (6). Nonetheless, the use of TSH suppressive doses of thyroid hormone in thyroid cancer patients is strongly supported by the animal studies and by human studies, including the early work by Mazzaferri and his colleagues (7), the observation that about 15 percent of primary thyroid cancers regress after thyroid hormone treatment, and case reports describing an amelioration of primary and metastatic disease with thyroid hormone treatment alone (1, 5, 7).

The combination of surgery with RAI is efficacious, as more extensive surgery enhances the ability of RAI to ablate residual tissue (8). With regard to TSH suppression and RAI treatment, it is unfortunate that an important feature of the current method for RAI administration is in diametric opposition to the principle of TSH suppression. This is the practice of withholding thyroid hormone for several weeks before RAI therapy to achieve the markedly elevated serum TSH concentrations thought to be required for optimum delivery of the RAI radiation dose. Elsewhere in this issue of JCEM (see page 11) Rudavsky and Freeman (9) describe a patient with advanced papillary thyroid cancer in whom recombinant human TSH (rhTSH) rather than thyroid hormone withdrawal was used to prepare the patient for RAI therapy. An important reason for this approach, it appears, was because several years earlier there had been rapid growth and substernal extension of the tumor after thyroid hormone was discontinued in preparation for whole body scanning.

This patient already had advanced thyroid cancer when he first presented. After thyroidectomy his initial RAI scan revealed uptake in both lung fields as well as in the thyroid bed. An ablative dose of 170 mCi RAI was given but a post-therapy scan was not performed, so the full extent of tumor metastases at that time is not known. RAI scans in subsequent years failed to show uptake in the lung metastases. Bone scan, bone biopsy, and MRI, however, demonstrated that thyroid cancer was present in the left femur, spine, and sacroiliac region. Two daily doses of 0.9 mg rhTSH were used to prepare the patient for RAI treatment. Twenty-four hours after the last injection of rhTSH, the patient received 515 MCi RAI, an extremely large dose. Post-treatment studies revealed concentration of the therapeutic dose in lungs and skeletal lesions. After a stormy course complicated by pneumonia, there was resolution of bone pain, increase in strength, and an improved sense of well-being. The serum thyroglobulin also decreased markedly but remained substantially elevated. Although rhTSH followed by RAI therapy was not curative for this patient, there was definite improvement in the clinical course.

This report, as well as the early studies in which bovine TSH (bTSH) was used to prepare patients with thyroid cancer for RAI treatment (10, 11, 12), raises the question of whether, insofar as TSH and thyroid cancer are concerned, less is more. There is no doubt, as attested to by the recent use of rhTSH in a patient with hypopituitarism (12), that TSH stimulation is needed to deliver a meaningful dose of RAI to thyroid cancer tissue. When either bovine or human TSH is administered, serum TSH concentrations at the time of RAI administration are comparable to or even higher than those achieved by thyroid hormone withdrawal (13). Integrated serum TSH concentrations during the month before RAI treatment, however, are far less after rhTSH administration than during the period of thyroid hormone withdrawal. It is not clear that the chronically elevated serum TSH concentrations obtained by thyroid hormone withdrawal are needed to obtain satisfactory iodide uptake (14). In fact, there is some evidence that two weeks of thyroid hormone withdrawal resulting in mild hypothyroidism are as effective as four weeks in this regard (15). Moreover, although early studies suggested that thyroid hormone withdrawal was better than bTSH in stimulating thyroid iodide uptake in metastatic tissue (16), a difference of this magnitude is not suggested by studies comparing thyroid hormone withdrawal and rhTSH in the preparation of thyroid cancer patients for RAI whole body scans (13, 17, 18). It is likely that chronically elevated serum TSH concentrations, as occur with current whole body RAI scans and RAI treatment protocols, are more than a trivial stimulus for tumor growth. Prolonged hypothyroidism in intact animals is one of the most potent promoters of tumor growth (5); in cell culture "prolonged and continuous" TSH exposure is said to be a prerequisite for cellular proliferation (19).

Although it is too soon to determine whether rhTSH administration is preferable to thyroid hormone withdrawal as a means of preparing thyroid cancer patients for RAI treatment, there is little doubt that less is more when the minimal side effects of rhTSH are compared with those of thyroid hormone withdrawal or bTSH administration. Unlike thyroid hormone withdrawal, rhTSH administration has not caused any effects that are detrimental to quality of life except for mild nausea in a minority of patients (17). Administration of bTSH, which is no longer available for clinical use, is associated with far more side effects than rhTSH, such as severe allergic reactions including anaphylaxis (19, 20). Furthermore, whereas rhTSH does not induce the formation of anti-TSH antibodies, this occurred in some patients who received bTSH, causing unreliable serum TSH assays and even suppressed thyroid function (21, 22, 23).

In their concluding remarks, Rudavsky and Freeman (9) call for controlled clinical studies to evaluate the safety and efficacy of rhTSH in the RAI treatment of thyroid cancer. We agree that every effort should be made to obtain objective information in this area but caution that the natural history of thyroid cancer and its diverse behavior will make it very difficult to design efficient and ethical protocols. The current focus in this field is on the use of rhTSH for diagnostic procedures. Thus, a study is in progress to determine the optimum rhTSH dosing schedule needed to prepare surgically and RAI ablated thyroid cancer patients, with and without metastatic disease, for whole-body scanning and monitoring of the serum thyroglobulin response. When the time comes to design protocols for using rhTSH to prepare thyroid cancer patients for RAI treatment, the concept that less is more may be useful. One important and concrete goal would be to determine the least dose of rhTSH that achieves satisfactory uptake and retention of the RAI therapy dose in cancer or residual thyroid bed tissue.


    Footnotes
 
1 This work was supported in part by NIH Grant DK18989, NIDDK, Bethesda, Maryland. Back

Received September 30, 1996.

Accepted October 1, 1996.


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 Introduction
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