Journal
STRAHLENTHERAPIE UND ONKOLOGIE
Volume 181, Issue 1, Pages 20-25Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00066-005-1242-9
Keywords
brain metastases; whole-brain radiotherapy; combined radiochemotherapy; topoisomerase I inhibitor; topotecan
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Background and Purpose: Topotecan penetrates the blood-brain barrier and sensitizes tumor cells against radiation. A phase I/II dose-escatating trial of repetitive daily i.v. topotecan application simultaneously with whole-brain irradiation (WBRT) was conducted to estimate toxicity, maximum tolerated dose and survival in patients with inoperable brain metastases. Patients and Methods: In 47 patients suffering from previously untreated brain metastases, topotecan was applied on a daily i.v. schedule simultaneously with WBRT (36 Gy/3-Gy fractions). The infusion schedule started at the beginning of WBRT and was discontinued during weekends. Each infusion was completed within 1-2 h before irradiation. In a dose-finding study, topotecan was escalated from 5 x 0.5 mg/m(2), 8 x 0.5 mg/m(2), 12 x 0.5 mg/m(2) to 12 x 0.6 mg/m(2). Results: Altogether, 38/47 patients (81%) completed the prescribed schedule. Leukopenia and thrombocytopenia were dose-Limiting. Grade 3/4 hematologic toxicity occurred in 5/32 chemonaive patients (16%) and 7/15 patients (47%) with previous chemotherapy. At 12 x 0.6 mg/m(2), 2/4 patients experienced grade 4 leukopenia/thrombopenia. Nonhematologic toxicities were generally mild to moderate and unrelated to topotecan. Response evaluation was possible in 26/47 patients, overall response rate was 58% (CR [complete remission] 5/26, PR [partial remission] 10/26, NC [no change] 8/26). Median survival amounted to 5.1 months. In 15/42 patients (36%), brain metastases were the dominant cause of death. Conclusion: For a daily topotecan schedule simultaneous to WBRT, the maximum tolerated dose is 12 x 0.5 mg/m(2) in chemonaive patients. For chemo-pretreated patients, daily doses should be reduced to 0.4 mg/m(2). A phase III trial has now been started to find out whether WBRT + topotecan increases survival compared to WBRT alone.
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