title: Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies.
  
  
  METHODS
  Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery.
  
  
  RESULTS
  Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs.
  
  
  CONCLUSIONS
  Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.
authors.affiliation: Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Australia. M.Millward@petermac.unimelb.edu.au
authors.forename: M J
authors.initials: MJ
authors.lastname: Millward
authors.forename: J
authors.initials: J
authors.lastname: Zalcberg
authors.forename: J F
authors.initials: JF
authors.lastname: Bishop
authors.forename: L K
authors.initials: LK
authors.lastname: Webster
authors.forename: A
authors.initials: A
authors.lastname: Zimet
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: G C
authors.initials: GC
authors.lastname: Toner
authors.forename: J
authors.initials: J
authors.lastname: Laird
authors.forename: W
authors.initials: W
authors.lastname: Cosolo
authors.forename: M
authors.initials: M
authors.lastname: Urch
authors.forename: R
authors.initials: R
authors.lastname: Bruno
authors.forename: C
authors.initials: C
authors.lastname: Loret
authors.forename: R
authors.initials: R
authors.lastname: James
authors.forename: C
authors.initials: C
authors.lastname: Blanc
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives; D043823:Taxoids; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel; D002945:Cisplatin