Chemosensitized radiosurgery for recurrent brain metastases

Abstract

Temozolomide is known to penetrate the blood-brain barrier and sensitize brain tumors to radiation and has been used clinically to sensitize fractionated external beam radiotherapy. However, there are limited prospective clinical data available on the safety of temozolomide as a chemosensitizing agent administered with stereotactic radiosurgery. This is a phase I trial of previously irradiated patients with one to four progressive brain metastases and Karnofsky performance scale score ≥60 % enrolled in three sequential cohorts: temozolomide 100, 150 or 200 mg/(m(2) day) administered for 5 days. Stereotactic radiosurgery (SRS) was administered on day 5. The SRS dose was dependent on target diameter: 15 Gy (31-40 mm), 18 Gy (21-30 mm) or 21 Gy (<20 mm). The primary endpoint was safety of increasing temozolomide doses. Secondary endpoints included local control and survival. 26 subjects were enrolled and 49 total metastatic lesions were treated. The median number of brain metastases was 1.5, with a median target diameter of 21 mm. The most common grade 1-2 adverse events irrespective of causality were vomiting (23 %), nausea (23 %), edema (12 %), seizure (8 %), psychosis (4 %) and thrombocytopenia (4 %). The frequency of nausea and vomiting did not appear to be dose-dependent. Grade 3-4 toxicities were not observed. Median overall survival was 10.2 months. Crude local control was 87.5 %, with a radiological response seen in eight of 24 evaluable patients (33.3 %), and stable disease >6 months in 13 of 24 patients (54.2 %). Temozolomide, at doses up to 200 mg/(m(2) day) × 5 days, prior to SRS is well tolerated, with no dose-limiting toxicities in patients with recurrent brain metastases. Local control of target lesions was >80 %.