title: Paclitaxel and carboplatin with and without filgrastim support in patients with metastatic non-small cell lung cancer.
abstract: Paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) and carboplatin have each shown activity against non-small cell lung cancer and they are synergistic in vitro. We thus designed a phase I study to define the maximum tolerated dose and dose-limiting toxicity of the combination with and without filgrastim support. With an initial fixed dose of paclitaxel 135 mg/m2 given as a 24-hour infusion, carboplatin was administered in escalating doses in cohorts of three patients, based on a target area under the concentration-time curve (AUC) of 5, 7, 9, or 11 using Calvert's formula: dose (mg) = target AUC x (glomerular filtration rate + 25). Dose escalations were based on course I toxicities. Filgrastim 5 micrograms/kg was administered with the first cycle only after grade 4 neutropenia occurred in two of three patients at the prior dose level. One hundred five courses of paclitaxel and carboplatin have been administered in 26 patients. Dose-limiting toxicity (grade 4 neutropenia) occurred in two patients at level 2 (cycle I). Filgrastim was instituted thereafter with cycle I for the next four levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated in the next level, but the paclitaxel dose was escalated. The regimen has been well tolerated. One patient had a complete response and 12 had partial responses, for an overall response rate of 50%. There is a suggestion of a dose-response effect with both paclitaxel and carboplatin. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II doses for the combination without filgrastim support are paclitaxel 175 mg/m2 as a 24-hour infusion with the carboplatin dose based on a target AUC of 7. The phase II dose with filgrastim support will be defined as dose escalation of paclitaxel continues.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, PA 15213, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Belani
authors.forename: J
authors.initials: J
authors.lastname: Aisner
authors.forename: D
authors.initials: D
authors.lastname: Hiponia
authors.forename: C
authors.initials: C
authors.lastname: Engstrom
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary*; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D000069585:Filgrastim; D005919:Glomerular Filtration Rate; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012074:Remission Induction; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003404:Creatinine; D016190:Carboplatin; D017239:Paclitaxel; D000069585:Filgrastim