title: Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors.
abstract: BACKGROUND
  Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin.
  
  
  METHODS
  Patients with advanced cancer and performance status ECOG < or = 2. The starting dose was paclitaxel 175 mg/m2 day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m2 daily day 1-5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued.
  
  
  RESULTS
  Fifty-one patients were entered; men: women ratio 30:21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m2/carboplatin AUC 5/topotecan mg/m2 (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/ 1.0 for four days. G-CSF 5 microg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses.
  
  
  CONCLUSIONS
  The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.
authors.affiliation: Department of Internal Medicine, Saint Louis University Health Sciences Center, Missouri 63110-0250, USA. dunphyfr@aol.com
authors.forename: F R
authors.initials: FR
authors.lastname: Dunphy
authors.forename: T L
authors.initials: TL
authors.lastname: Dunleavy
authors.forename: B R
authors.initials: BR
authors.lastname: Harrison
authors.forename: C L
authors.initials: CL
authors.lastname: Cantrell
authors.forename: J L
authors.initials: JL
authors.lastname: Visconti
authors.forename: S M
authors.initials: SM
authors.lastname: Pincus
authors.forename: J M
authors.initials: JM
authors.lastname: Richart
authors.forename: P J
authors.initials: PJ
authors.lastname: Petruska
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel