Prolonged infusional topotecan and accelerated hyperfractionated 3d-conformal radiation in patients with newly diagnosed glioblastoma--a phase I study.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Grabenbauer
Gerhard G
GG
Department of Radiation Oncology, University Hospitals of Erlangen-Nürnberg, Erlangen, Germany. gerd.grabenbauer@strahlen.imed.uni-erlangen.de
Anders
Katharina
K
Fietkau
Rainer J
RJ
Klautke
Gunther
G
Feldmann
Horst J
HJ
Weiser
Sonja
S
Staab
Hans-Jürgen
HJ
Krauseneck
Peter
P
Sauer
Rolf
R
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016543:Central Nervous System Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy / Q000009:adverse effects; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D020266:Radiotherapy, Conformal / Q000009:adverse effects; D018805:Sepsis / Q000139:chemically induced; D012852:Sinusitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects
D000970:Antineoplastic Agents; D019772:Topotecan