title: Myelotoxicity of oral topotecan in relation to treatment duration and dosage: a phase I study.
abstract: Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m(2) for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m(2) and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m(2) daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m(2) for 3 days, 2.0 and 2.3 mg/m(2) for 4 days, and 2.3 mg/m(2) for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46-77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m(2) for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m(2) 3-day treatment developed grade 3-4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m(2) developed grade 3-4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3-4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m(2) for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m(2) for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m(2).
authors.affiliation: Department of First Oncology, Errikos Dunant Hospital, Semitelou 2A, Athens 115 28, Greece. dr-gps@ath.forthnet.gr
authors.forename: George P
authors.initials: GP
authors.lastname: Stathopoulos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Ardavanis
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakotoulas
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.forename: George
authors.initials: G
authors.lastname: Papadopoulos
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Antoniou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Athanasiadis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trafalis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: John
authors.initials: J
authors.lastname: Koutantos
authors.forename: Michael
authors.initials: M
authors.lastname: Vaslamatzis
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced*; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced*; D013997:Time Factors; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan