Giaccone G, Huizing M, ten Bokkel Huinink W, Koolen M, Postmus P, van Kralingen K, van Zandwijk N, Vermorken J, Beijnen J, Dalesio O
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Semin Oncol. 1994 Oct;21(5 Suppl 8):34-8.
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 24-hour infusion, and carboplatin have activity in advanced non-small cell lung cancer (NSCLC) and ovarian cancer. Two dose-finding studies were initiated to identify the optimal doses for the paclitaxel/carboplatin combination when paclitaxel is given in a 3-hour infusion. The fact that the pharmacologic interaction between paclitaxel and cisplatin increases the toxicity of paclitaxel when cisplatin is given before it also prompted an investigation of the influence of drug sequence on toxicity and pharmacokinetics in the NSCLC trial. Thirty-three patients with advanced NSCLC and 11 with advanced ovarian cancer previously untreated by chemotherapy have been enrolled to date. In the NSCLC trial escalating doses of paclitaxel were given in combination with a fixed carboplatin dose of 300 mg/m2, while both drugs were escalated in the ovarian cancer study. In both studies paclitaxel was infused over 3 hours and carboplatin over 30 minutes, and cycles were repeated every 4 weeks. The most frequent side effect has been neutropenia, although this did not result in any infectious episodes. Alopecia and mild emesis also have been frequently encountered. Mild skin reactions have been reported in a few patients. Bone pain and myalgia occur more frequently at the highest paclitaxel doses. No difference in toxicity has been observed thus far between the two drug sequences in the NSCLC study. Both studies are still accruing patients as the maximum tolerated doses of paclitaxel in combination with carboplatin have not yet been reached (carboplatin 300 mg/m2 with paclitaxel 175 mg/m2 in the NSCLC study; carboplatin 400 mg/m2 with paclitaxel 150 mg/m2 in the ovarian cancer study). An investigation of maximum tolerated doses with granulocyte colony-stimulating factor support is planned thereafter.
紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）持续输注24小时给药，与卡铂联合应用对晚期非小细胞肺癌（NSCLC）和卵巢癌具有活性。开展了两项剂量探索研究，以确定紫杉醇3小时输注时紫杉醇/卡铂联合方案的最佳剂量。紫杉醇和顺铂之间的药理相互作用表明，顺铂先于紫杉醇给药会增加紫杉醇的毒性，这也促使在NSCLC试验中研究给药顺序对毒性和药代动力学的影响。迄今为止，已有33例晚期NSCLC患者和11例既往未接受过化疗的晚期卵巢癌患者入组。在NSCLC试验中，递增剂量的紫杉醇与固定剂量300mg/m²的卡铂联合给药，而在卵巢癌研究中两种药物剂量均递增。两项研究中，紫杉醇均输注3小时，卡铂输注30分钟，每4周重复一个周期。最常见的副作用是中性粒细胞减少症，不过这并未导致任何感染性发作。脱发和轻度呕吐也较为常见。少数患者报告有轻度皮肤反应。在紫杉醇最高剂量时，骨痛和肌痛更频繁出现。在NSCLC研究中，两种给药顺序之间目前尚未观察到毒性差异。两项研究仍在招募患者，因为尚未达到紫杉醇与卡铂联合应用的最大耐受剂量（NSCLC研究中卡铂300mg/m²与紫杉醇175mg/m²；卵巢癌研究中卡铂400mg/m²与紫杉醇150mg/m²）。此后计划开展一项在粒细胞集落刺激因子支持下的最大耐受剂量研究。
