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Hypothyroidism Enhances High-Dose Tamoxifen in Glioma

Hypothyroidism Enhances High-Dose Tamoxifen in Glioma

SAN FRANCISCO—Although tamoxifen (Nolvadex) kills glioma cells in culture,
it has not been effective in prolonging survival in patients with recurrent
glioma. A study presented at the 93rd Annual Meeting of the American
Association for Cancer Research (abstract 2442), however, found that
pretreating with propylthiouracil and Lugol’s solution (a solution of
potassium iodide and iodine) to induce chemical hypothyroidism prior to
high-dose tamoxifen therapy resulted in dramatic increases in survival time in
these patients.

"In research that we did at the Cleveland Clinic, we found that in cell
cultures insulin growth factor-1 (IGF-1) counteracts the cell-killing effect of
tamoxifen," said Aleck Hercbergs, MD, a radiation oncologist at the
Cleveland Clinic. Since triiodothyroxine regulates IGF-1, he continued,
"we reasoned that suppressing thyroid gland activity to a low, but
clinically tolerable, level would reduce IGF-1 levels and thus increase the
effectiveness of tamoxifen."

In the clinical study, 38 patients with recurrent glioma were treated with
up to 1,000 mg of propylthiouracil daily and 30 mg of Lugol’s solution three
times daily for 14 days to induce hypothyroidism, defined as a free thyroxine
level of less than 0.7 ng/dL. Only half of the patients developed
hypothyroidism after a median of 26 days. The other 19 remained euthyroid. Dr.
Hercbergs hypothesized that all of the 38 patients would have eventually
developed hypothyroidism if they had lived long enough. The tamoxifen dosage
was 240 mg/d.

Median survival time for the hypothyroid patients was 10.6 months, and two
of these patients were still alive after 3 years. Median survival time for the
euthyroid patients was 3.7 months, with only one patient in this group living
longer than 8 months.

Based on MRIs, five of the hypothyroid patients experienced a greater than
50% reduction in tumor size, compared with none of the euthyroid patients (see
Figure). Interestingly, one patient who became hypothyroid showed a partial
response even though he could not continue to take tamoxifen due to ataxia.

IGF-1 levels were significantly reduced in the hypothyroid group, compared
with the euthyroid group (P < .005). However, IGF-1 levels were measured in
only seven hypothyroid patients and three euthyroid patients.

Most of the reported side effects, such as deep vein thrombosis, were
typical of those seen in glioma patients. "There was one patient who
experienced possible cold intolerance, but this was in Cleveland in the
winter," Dr. Hercbergs said, so it was unclear if this was due to
hypothyroidism.

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