title: Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiotherapy, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Köln, Germany. martin.kocher@medizin.uni-koeln.de
authors.forename: Martin
authors.initials: M
authors.lastname: Kocher
authors.forename: Hans-Theodor
authors.initials: HT
authors.lastname: Eich
authors.forename: Robert
authors.initials: R
authors.lastname: Semrau
authors.forename: Semi Aykut
authors.initials: SA
authors.lastname: Güner
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Müller
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary*; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012074:Remission Induction; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I