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Dose-finding and sequencing study of paclitaxel and carboplatin in non-small cell lung cancer

G Giaccone, M Huizing, P E Postmus, W W ten Bokkel Huinink, M Koolen, N van Zandwijk, J B Vermorken, J H Beijnen, O Dalesio, H M Pinedo
Seminars in Oncology 1995, 22 (4): 78-82
A dose-finding study was set up to identify the optimal dose of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin for phase II studies in patients with advanced chemotherapy-naive non-small cell lung cancer (NSCLC). The influence of drug sequence on the toxicity and pharmacokinetics of both agents was also assessed. To develop an ambulatory regimen for palliation of advanced NSCLC, paclitaxel was infused over 3 hours with standard premedication and carboplatin over 30 minutes. Cycles were repeated every 4 weeks. At each dose level, at least six patients were randomized to receive either paclitaxel followed by carboplatin or the reverse sequence. In the second and following cycles the alternate sequence was administered. The pharmacokinetics of both paclitaxel and carboplatin were compared in the first two cycles in at least two patients per dose level. Sixty-two patients have been entered in this study. Paclitaxel was increased from 100 mg/m2 in 25 mg/m2 increments up to a maximum of 225 mg/m2 combined with a fixed carboplatin dose (300 mg/m2). Thereafter, the drug doses were increased to a maximum of 400 mg/m2 carboplatin and 250 mg/m2 paclitaxel. In 243 cycles, the most frequent side effects were neutropenia, alopecia, and mild emesis. Only one patient developed a major hypersensitivity reaction to paclitaxel. Bone pain, myalgia, and peripheral neurotoxicity occurred more frequently at paclitaxel doses above 200 mg/m2. No significant differences in toxicity or in the pharmacokinetics of either drug were observed between the two drug sequences. The pharmacokinetics of paclitaxel were nonlinear and consistent with saturation. At the highest paclitaxel dose (250 mg/m2 with carboplatin 350 mg/m2) a toxic death due to severe leukopenia, thrombocytopenia, and hemorrhage occurred. Safe doses for phase II trials in untreated NSCLC are 200 mg/m2 paclitaxel with 300 mg/m2 carboplatin. Of 50 evaluable patients, five of the six major responses were observed at paclitaxel doses of 175 mg/m2 and above, which suggests a dose-response relationship for paclitaxel in NSCLC.


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