title: A phase I clinical trial of topotecan given every 2 weeks in patients with refractory solid tumors.
abstract: OBJECTIVE
  Topotecan, a potent inhibitor of the enzyme topoisomerase I, has shown an interesting activity against several types of solid tumors, most notably small cell lung cancer (SCLC) and ovarian cancer. We conducted a phase I study to evaluate the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of topotecan given in a novel schedule of administration in patients with refractory solid tumors.
  
  
  METHODS
  Twenty-six patients with histologically confirmed diagnosis of solid tumors refractory to all known forms of effective therapy were enrolled. The patients' median age was 61 years, 15 were male, and 18 had a performance status of (WHO) 0-1. Seven patients suffered from ovarian cancer, 11 from SCLC, 4 from non-SCLC, 2 from melanoma and 2 from cervical cancer. Topotecan was given for 3 consecutive days as a 30-min intravenous infusion, at doses ranging from 0.75 to 1.2 mg/m2. Treatment was repeated every 2 weeks.
  
  
  RESULTS
  At dose level 5 with topotecan 1.2 mg/m2, both study patients presented DLTs (1 patient grade 4 neutropenia and the other grade 3 fatigue), and the recommended doses for future phase II studies are topotecan 1.1 mg/m2 for 3 consecutive days every 2 weeks. A total of 60 treatment cycles were administered, with a median of 2 cycles per patient. Grade 3/4 neutropenia was observed in 11 (18%) cycles and 2 of them were complicated by fever requiring patient hospitalization. Grade 3/4 thrombocytopenia was seen in 2 (3%) cycles and grade 3 anemia in 3 (5%). Although non-hematologic toxicity was generally mild, grade 2/3 fatigue complicated 12 (20%) cycles and grade 4 one (1.5%) requiring treatment interruption in 4 patients. Among 18 evaluable patients, no objective response to treatment was observed.
  
  
  CONCLUSIONS
  This phase I study demonstrates that topotecan given at the dose of 1.1 mg/m2 for 3 consecutive days every 2 weeks is a safe and tolerable regimen and possibly permits the combination of the drug with other cytotoxic agents at clinically relevant doses.
authors.affiliation: Department of Clinical Oncology, University General Hospital of Heraklion, Heraklion, Greece. georgoul@med.uch.gr
authors.forename: S
authors.initials: S
authors.lastname: Kakolyris
authors.forename: C
authors.initials: C
authors.lastname: Kouroussis
authors.forename: J
authors.initials: J
authors.lastname: Souglakos
authors.forename: D
authors.initials: D
authors.lastname: Mavroudis
authors.forename: S
authors.initials: S
authors.lastname: Agelaki
authors.forename: K
authors.initials: K
authors.lastname: Kalbakis
authors.forename: N
authors.initials: N
authors.lastname: Androulakis
authors.forename: N
authors.initials: N
authors.lastname: Vardakis
authors.forename: L
authors.initials: L
authors.lastname: Vamvakas
authors.forename: V
authors.initials: V
authors.lastname: Georgoulias
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019772:Topotecan