Paclitaxel by 1-h infusion in combination with carboplatin in advanced non-small cell lung carcinoma (NSCLC)

In our previous study, FCCC 93-024, paclitaxel by 24-h infusion combined wi th carboplatin yielded a response rate of 62% and median survival of 54 wee ks in advanced non-small cell lung cancer (NSCLC). Myelosuppression proved dose-limiting, requiring the routine use of granulocyte-colony stimulating factor (G-CSF). Based on the reported activity of l-h paclitaxel infusion i n NSCLC and minimal myelosuppression at doses of 135 and 200 mg/m(2) every 3 weeks and the suggestion of a dose-response relationship, we launched an intrapatient dose escalation trial of combination carboplatin and l-h pacli taxel. Chemotherapy-naive patients with advanced NSCLC received paclitaxel 175 mg/m(2) I-h and carboplatin dosed to a fixed targeted area under the co ncentration-time curve (AUC) of 7.5 at three weekly intervals for six cycle s. In the absence of grade 3 myelosuppression, paclitaxel was escalated by 35 mg/m(2)/cycle on an intrapatient basis to a maximum dose of 280 mg/m(2) by cycle 4. G-CSF was not routinely used. 57 patients (pts) were accrued fr om November 1994 through to April 1996. 44 pts (77%) had Eastern Cooperativ e Oncology Group (ECOG) performance status 1. Median age was 64 (range: 34- 50) years. Cumulative peripheral sensory neuropathy proved dose-limiting an d prohibitive in the first 20 evaluable patients (cohort A): grade greater than or equal to 1 in 15 patients (75%)1 grade 3 in 6 (30%), generally occu rring at paclitaxel doses greater than or equal to 215 mg/m(2) and obligati ng 3 patients to have treatment hailed in the absence of disease progressio n. The protocol, therefore, was revised and the initial paclitaxel dose red uced to 135 mg/m(2) with intrapatient dose escalation of 40 mg/m(2)/cycle t o a maximum dose of 215 mg/m(2), recapitulating the original dosing schema used in FCCC 93-024. 35 patients were enrolled in this second cohort (B): 3 3 proved evaluable. Whilst 17 (52%) experienced peripheral sensory neuropat hy, grade 3 neurotoxicity developed in only 3 (9%). Myelosuppression also w as less pronounced, with 42% exhibiting grade 4 granulocytopenia and 30%' g rade greater than or equal to 3 thrombocytopenia in cohort B compared with 70% and 50%, respectively in cohort A. Of the first 22 patients accrued to cohort A, 12 (55%) had major objective responses. Median survival was 38.5 weeks, 1-year survival rate 45% and 2-year survival rate 18%. Of 33 evaluab le patients in cohort B, 9 (27%) had major objective responses. Median surv ival was 46 weeks, 1-year survival rate 47% and 1-year survival rate 12%. C ombination paclitaxel by I-h infusion and carboplatin at a fixed targeted A UC of 7.5 is active in advanced NSCLC. Neurotoxicity, not myelosuppression, proved dose-limiting at paclitaxel doses exceeding 215 mg/m(2). Lower dose s may be associated with lower response rates but do not appear to compromi se survival. (C) 2000 Published by Elsevier Science Ltd. All rights reserve d.