Belani C P, Aisner J, Hiponia D, Engstrom C
Department of Medicine, University of Pittsburgh School of Medicine, PA 15213, USA.
Semin Oncol. 1995 Aug;22(4 Suppl 9):7-12.
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.
紫杉醇（泰素；百时美施贵宝肿瘤公司，新泽西州普林斯顿）和顺铂各自对非小细胞肺癌均显示出活性，且它们在体外具有协同作用。因此，我们设计了一项I期研究，以确定联合使用和不使用非格司亭支持时的最大耐受剂量和剂量限制性毒性。初始固定剂量的紫杉醇135mg/m²通过24小时静脉输注给药，基于使用卡尔弗特公式计算的浓度-时间曲线下面积（AUC）为5、7、9或11的目标值，以三名患者为一组逐步增加顺铂剂量：剂量（mg）=目标AUC×（肾小球滤过率+25）。剂量递增基于I疗程毒性。仅在前一剂量水平的三名患者中有两名出现4级中性粒细胞减少后，才在第一个周期给予非格司亭5μg/kg。已对26例患者进行了105个疗程的紫杉醇和顺铂治疗。在2级（I周期）时，两名患者出现剂量限制性毒性（4级中性粒细胞减少）。此后，在接下来的四个剂量水平的I周期中使用非格司亭。在4级时出现4级血小板减少；因此，在下一个剂量水平降低顺铂剂量，但增加紫杉醇剂量。该方案耐受性良好。一名患者完全缓解，12名患者部分缓解，总缓解率为50%。紫杉醇和顺铂均有剂量反应效应的迹象。紫杉醇和顺铂联合方案对非小细胞肺癌有活性，在不使用非格司亭支持时，该联合方案的推荐II期剂量为紫杉醇175mg/m²通过24小时静脉输注给药，顺铂剂量基于目标AUC为7。在继续增加紫杉醇剂量时，将确定使用非格司亭支持的II期剂量。
