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Purpose: Topotecan has demonstrated exceptional central nervous system penetration as well as radiosensitizing properties in glioblastoma xenografts [Chastagner et al., Int J Radiat Oncol Biol Phy 50: 777–782, 2001]. This phase I trial was performed to determine the maximum tolerated dose and the recommended dose of topotecan continuous infusion administered together with concomitant radiotherapy in patients with glioblastoma. Patients and methods: A total of 20 patients were treated in this trial. Twenty one day topotecan continuous infusion was escalated from 0.3 mg/m2/d in increments of 0.1 mg/m2/d and cohorts of 3–6 patients until maximum tolerated dose was reached; Three-dimensional (3d) conformal radiotherapy was applied concurrently twice daily with a fraction size of 1.75 Gy up to 57.75 Gy total dose. Three additional cycles of maintenance topotecan chemotherapy were scheduled. Results: Fifty-three courses were performed in 5 dose levels (0.3 mg/m2/d: 12 cycles, 0.4 mg/m2/d: 6 cycles, 0.5 mg/m2/d: 10 cycles, 0.6 mg/m2/d: 6 cycles, 0.7 mg/m2/d: 19 cycles). Maximum tolerated dose was reached at dose level 5 (0.7 mg/m2/d), because 3/7 patients suffered from dose limiting toxicity. These were febrile sinusitis, bacterial sepsis and grade 4 thrombocytopenia. Neutropenia of grade 4 was encountered in 2 cycles (0.5 and 0.7 mg/m2/d). Response data were available in 17 patients, 3 of which (18%) achieved partial remission, 12 (71%) stable disease throughout the observation period and 2 (11%) progressive disease. Conclusion: The recommended dose for further trials will be 0.6 mg/m2/d topotecan administered as 21 days continuous infusion in combination with accelerated 3d conformal radiation.