Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases.

BACKGROUND AND PURPOSE

Topotecan penetrates the blood-brain barrier and sensitizes tumor cells against radiation. A phase I/II dose-escalating 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 chemonaïve 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 chemonaïve 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.