Abstract
Dunhill did not give a rationale for treating his thyroid cancer patients with thyroid hormone. However, thyroid extracts had been used to treat other thyroid conditions for some time. The first reports on the treatment of myxedema appeared in the l890s and in 1894 there were several reports of patients whose goiters shrank or disappeared when given raw sheep or calf thyroid (3).
Parenthetically, in 1894 von Eiselberg reported evidence that a thyroid cancer metastasis could produce thyroid hormone. His patient was a 38-year-old woman who developed myxedema following a total thyroidectomy for thyroid cancer. Growth of her sternal metastasis was associated with a return to euthyroidism (4). In his Lettsomian Lectures Dunhill said in apparent reference to von Eiselberg's patient, “a metastatic deposit from a malignant thyroid can function sufficiently to supply the body's needs after the thyroid gland has been extirpated, and that subsequent removal of the deposit has resulted in myxoedema. Metastatic carcinoma of the thyroid has also shown physiological activity in the tadpole test” (1).
By the 1930s the ability of pituitary thyrotropin (TSH) to stimulate the thyroid was well understood and both crude preparations of TSH and bioassays for TSH were available (5). Dunhill was aware of this evidence. Possibly, in vague reference to a relationship between thyroid hormone status and thyroid carcinoma, he speculates that “papilliferous hyperplasia” (which he believed might be a precursor of “papilliferous adenocarcinoma”) might be due to stimulation of the thyroid by “ordinary physiologic demands” and that such changes might not occur if the physiologic demands of the body could be kept at a lower level (1).
The availability of radioiodine in the early 1940s led to rapid advances in the diagnosis and treatment of thyroid disease. It was soon discovered that some thyroid cancers concentrated radioiodine and that others could be induced to do so by rendering the patient hypothyroid or injecting TSH (6 –8). It became common practice to subject patients with metastases to prolonged periods of hypothyroidism, and it was observed that this often caused the metastases to grow more rapidly (2,9). In the early 1950s Greer and Astwood studied the effect of TSH suppression on thyroid function and growth. In 1951 Greer reported that 3–5 grains of desiccated thyroid suppressed the thyroidal uptake of radioiodine to less than 10% in most normal volunteers (10), and in 1953 Greer and Astwood reported a series of 50 patients with thyroid enlargement or nodules who were treated with 2–3 grains of desiccated thyroid daily with complete regression in 40% (3). They hypothesized that “thyroid…will decrease the secretion of TSH and, in turn, the size of the goiter.” However, no patients with known thyroid cancer were included in their study.
In 1954 Balme published the first well-documented case in which function and growth of metastatic thyroid cancer was suppressed by administration of thyroid hormone (11). The patient was a 37-year-old woman with diffuse pulmonary metastases. She was treated with 100 mCi of iodine 131 (131I) and retained 46% in her chest. Nine months later an 131I study showed a chest uptake of 56%. She was then placed on
The chief advocate of a major role for TSH suppression in the treatment of thyroid cancer was also a surgeon, George Crile, Jr. In his initial report in 1955 (12), he described seven patients treated with 3–4 grains of desiccated thyroid for 1–5 years. Five with pulmonary metastases showed improvement in their chest X-ray and two with solitary bone metastases (who were also treated with X-ray) remained stable and showed recalcification. He was inspired by a patient who had both lung metastases from Hürthle cell thyroid cancer and severe hyperthyroidism. During a 2-year period while she remained hyperthyroid the lung metastases were stable. After she was treated with radioiodine and became hypothyroid the lung metastases grew rapidly and she died a few months later. Crile realized that “It was the increased output of thyroid-stimulating hormone from the pituitary that made the cancer grow” and began to treat all his metastatic thyroid cancer patients with desiccated thyroid. He refers to the 1953 paper by Greer and Astwood (3) and the l954 paper by Balme (11) and notes that “similar dependency on hormones has been observed in certain cancers of the prostate and breast.”
Between 1957 and 1988 Crile continued to publish on his experience with TSH suppression at the Cleveland Clinic (2,13 –15). The best responses were in papillary carcinoma, while undifferentiated cancers failed to respond. The responders were younger and almost all had pulmonary metastases. Some of the responders were treated with 131I before being placed on thyroid but none had shown regression. He observed a close correlation between the ability of the cancer to concentrate 131I and regression during treatment with desiccated thyroid. He advocated near total thyroidectomy and TSH suppression without 131I ablation for patients under age 45 unless there was extensive local disease. He believed that treatment of younger patients with thyroid hormone was as effective as treatment with 131I, although not more effective. He was opposed to prolonged hypothyroidism. He routinely placed all of his surgical cures on 2–3 grains of desiccated thyroid daily and reported that the recurrence rate decreased by 50%.
Another early proponent of TSH suppression was also a surgeon, Colin G. Thomas, Jr. In l957 he published an article on a series of nine thyroid cancer patients treated with 120 to 300 mg (2–5 grains) of desiccated thyroid daily (16). In two patients there was inhibition of growth and in an additional two there was clear-cut regression. He also referred to the endocrine dependency of breast and prostate cancer and opposed prolonged TSH stimulation (16). In 1991 Thomas published a thorough review of the role of TSH suppression in the management of thyroid cancer, which included a discussion of the possible role of TSH in induction of thyroid cancer based on animal studies (17).
Crile's recommendation that TSH suppression should be first line treatment for metastatic thyroid cancer in younger patients never caught on. However TSH suppression is now universally recommended for all patients with thyroid cancer (18), in large part due to the work of Ernest Mazzaferri, whose studies showed a significant reduction in the risk of recurrence for patients given thyroid hormone after thyroidectomy (19,20). More recently interest has shifted to possible adverse effects from the subclinical hyperthyroidism, which is associated with TSH suppression, and we have begun to tailor the degree of suppression to the extent of disease and risk of recurrence (21).