Rico Braun
High-Dose Tamoxifen and Thyroid Suppression in Recurrent Malignant Glioma Patients.
Lav K Goyal, Aleck A Hercbergs, John H Suh, Robert M Fine, Bruce Cohen, David Peerboom, Glen Stevens, Manjula Gupta, Sethu Reddy, Chandana Reddy, Paul G Elson, Gene Barnett, Cleveland Clin Fdn, Cleveland, OH.
Experimental, clinical, and epidemiological studies suggest that thyroid hormone deprivation (hypothyroidism) attenuates growth rates of solid neoplasms and prolongs survival in advanced cancer. Possible mechanisms include down-regulation of triiodothyronine (T3) modulation of the tumorigenic insulinlike growth factor-1 (IGF-1) and EGF-r (epidermal growth factor receptors) signaling systems. IGF-1 is mitogenic and antiapoptotic in various tumor cell systems and inhibition of tamoxifen induced apoptosis of glioma cells by IGF-1 in a dose dependent manner has been demonstrated in the WITG2 human glioma cell lines which might potentially limit therapeutic efficacy of high dose tamoxifen in malignant gliomas. Since significant reduction of IGF-1 blood levels is observed in hypothyroidism, we studied the induction of subclinical (biochemical) hypothyroidism and high-dose tamoxifen therapy in patients with recurrent gliomas. Hypothyroidism was induced with propylthiouracil and Lugol´s solution. Tamoxifen was initiated when free T4 < 0.7 ng/dL or TSH of >10 uU/ml was achieved. Tamoxifen doses were escalated from 80 mg up to 240 mg /day. Twenty patients have entered the trial thus far with 16 currently evaluable (GBM: 11, AA: 2, Anaplastic oligo: 1, Gliosarcoma: 1, High grade NOS: 1). Eleven of the 16 patients had suffered at least 2 recurrences before initiating the protocol. Of the 9 patients where adequate thyroid suppression was maintained, 6 are still alive with a median survival from the start of protocol of 6.5 months (range 1.3-9.5 mo.) compared to 2 out of 7 patients still alive with a median survival from the start of protocol of 3.2 months (range 1.8-8.1 mo.) in the group with inadequate thyroid suppression. There were no patients with greater than grade 2 toxicity. The results suggest that this treatment is well tolerated and may prolong survival in certain patients.
ASCO 2000