Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

Patel, Shilpen; DiBiase, Steven; Meisenberg, Barry; Flannery, Todd; Patel, Ashish; Dhople, Anil; Cheston, Sally; Amin, Pradip

doi:10.1016/j.ijrobp.2010.12.053

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Volume 82, Issue 2 , Pages 739-742, 1 February 2012

Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

Presented at the 2005 American Society for radiation Oncology Annual Meeting.

Shilpen Patel, M.D.
- Department of Radiation Oncology, University of Washington, Seattle, WA
- Reprint requests to: Shilpen Patel, M.D., Department of Radiation Oncology, University of Washington, 1959 Northeast Pacific Street, Box 356043, Seattle, WA 98195-6043. Tel: (206) 598-4100; Fax: (206) 598-3786
Steven DiBiase, M.D.
- Robert Wood Johnson School of Medicine, Camden, NJ
Barry Meisenberg, M.D.
- DeCesaris Cancer Institute, Annapolis, MD
Todd Flannery, M.D.
- Princeton Radiation Oncology, Princeton, NJ
Ashish Patel, M.D.
- Division of Radiation Oncology, Abington Memorial Hospital, Abington, PA
Anil Dhople, M.D.
- MIMA Cancer Center, Melbourne, FL
Sally Cheston, M.D.
- Department of Radiation Oncology, University of Maryland, Baltimore, MD
Pradip Amin, M.D.
- Department of Radiation Oncology, University of Maryland, Baltimore, MD

Received 15 May 2010; received in revised form 22 December 2010; accepted 31 December 2010. published online 28 February 2011.

Purpose

The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas.

Methods and Materials

A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status ≥60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m² divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m² increments until the MTD was reached. When ≥2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m². A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered.

Results

A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m². One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m².

Conclusions

The MTD of tamoxifen was 100 mg/m² when given concurrently with temozolomide 75 mg/m² and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.

Glioblastoma multiforme, Tamoxifen, Temozolomide, Phase I, High-grade glioma