Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme.

METHODS AND MATERIALS: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used.

RESULTS: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis.

CONCLUSIONS: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.