Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen.

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.

Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen, and hypericin: corroborating clinical response in vitro: case report.

Previous work has demonstrated the importance of protein kinase C in regulating glioma cell proliferation in vitro. Tamoxifen, a protein kinase C inhibitor when administered in high dosages, is currently being used as an adjuvant in the treatment of patients with malignant gliomas. The patient in the present study harbored a left frontal anaplastic astrocytoma adjacent to Broca's area and the paracentral region, which limited gross resection. After a subtotal resection of the tumor and after radiation, the patient was administered high-dose tamoxifen therapy for gross residual gadolinium-enhancing regions that were revealed by magnetic resonance imaging and by high glucose uptake as demonstrated by positron emission tomography. After treatment, a decrease in gadolinium enhancement on magnetic resonance images and a decrease in glucose uptake revealed by positron emission tomography were noted. A laboratory examination of the tissue obtained from the original surgical resection revealed resistance to radiation therapy but sensitivity to tamoxifen as measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide assay. The subsequent in vitro testing of the tumor that was removed after the recurrence of tumor (22 months after the initiation of tamoxifen) revealed loss of sensitivity to tamoxifen. However, the recurrent tumor remained sensitive to growth inhibition by the potent protein kinase C inhibitor, hypericin, despite loss of sensitivity to tamoxifen in vitro, suggesting the potential clinical application of this agent. This close in vitro correlation with the clinical course of the patient in the present study suggests a potential role for such in vitro radiation and chemosensitivity testing in designing a rational individualized clinical course of treatment.