title: Phase I trial of intravenous cisplatin-topotecan chemotherapy for three consecutive days in patients with advanced solid tumors: parallel topotecan escalation in two fixed platinum dosing schemes.
abstract: OBJECTIVE
  We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor.
  
  
  METHODS
  40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity.
  
  
  RESULTS
  The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting.
  
  
  CONCLUSIONS
  The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.
authors.affiliation: Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Pentheroudakis
authors.forename: E
authors.initials: E
authors.lastname: Briasoulis
authors.forename: V
authors.initials: V
authors.lastname: Karavassilis
authors.forename: D
authors.initials: D
authors.lastname: Mauri
authors.forename: E
authors.initials: E
authors.lastname: Tzamakou
authors.forename: D
authors.initials: D
authors.lastname: Rammou
authors.forename: N
authors.initials: N
authors.lastname: Pavlidis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy; D011994:Recombinant Proteins; D019772:Topotecan / Q000008:administration & dosage
chemical_list: D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D000068817:Epoetin Alfa; D019772:Topotecan; D002945:Cisplatin