Glorieux P, Ortmanns P, Marien S, Degives R, Degraeve D, Potvin M, Grauwels D, Schallier D
Clinique du Sud-Luxembourg (Site St.-Joseph), Arlon, Belgium.
Anticancer Res. 2001 Mar-Apr;21(2B):1487-94.
The efficacy and toxicity of the combination of two cytotoxic compounds that are active as single agents in non-small cell lung cancer (NSCLC), paclitaxel (Taxol) and carboplatin (Paraplatin) was investigated in a multicenter, community-based setting.
Two consecutive cohorts of chemonaive patients with stages IIIA/B and IV NSCLC received two dose levels of paclitaxel. The first cohort received 200 mg/m2 over 3 hours (HD) and the second cohort 175 mg/m2 over 3 hours (LD) in combination with a fixed dose of carboplatin. The dose of carboplatin was calculated according to the Calvert formula with an area under the concentration versus time curve (AUC) value of 6 mg/ml/minute. The carboplatin clearance, calculated by the Chatelut formula rather than the glomerulation filtration rate (GFR) +25, was introduced into the Calvert formula. The eligibility criteria were identical for both cohorts throughout the study. Treatment was administered every three weeks. The study endpoints were response rate (RR), toxicity, time to progression (TTP) and survival (S).
One hundred and thirty consecutive eligible patients from 36 Belgian institutions were fully evaluable for all study parameters (99 in the HD and 31 in the LD cohort). Myelosuppression was the most prominent side-effect of treatment with comparable results for both cohorts. The worst grade 3-4 leucopenia and neutropenia per patient in the HD versus LD cohort was 34.4 vs 19.3% and 59.2 vs 51.6%, respectively. 10.4% of patients in the HD cohort required hospitalisation for febrile neutropenia (6.2% with and 4.2% without documented bacterial infection), while in the LD cohort the respective figures were 13.7, 10.3 and 3.4%. The most prominent non-hematologic toxicities were alopecia and polyneuropathy, with no major difference between the HD and LD cohort (grade 2 alopecia in 78.1 vs. 83.9% and grade 3 neuropathy in 14.3 vs. 9.7%, respectively). The overall best clinical RR was 31 out of 130 (23.8%) with one complete (CR) and 30 partial responses (PR). The respective RR in the HD and LD cohort was 23.2 and 25.8%. Median TTP and S for all patients was 120 and 248 days, with no apparent difference between the HD and the LD cohort (119 and 254 versus 128 and 222, respectively). The one year survival was 34% in the HD cohort. The 95% confidence intervals for efficacy and toxicity parameters overlapped in both cohorts.
In this multicenter study, the combination of paclitaxel and carboplatin produced a moderate RR of 23.8% in stages IIIA/B & IV NSCLC. The therapy was generally well tolerated at both doses of paclitaxel. Myelosuppression, neurotoxicity and alopecia were the major therapy-related side-effects. The differences between the two paclitaxel dose cohorts with respect to activity and toxicity were minimal. The use of the Chatelut formula to calculate the carboplatin clearance is feasible, but might have lead to the apparent excess in myelotoxicity in our study compared to other studies which used other methods for estimating renal function.
在多中心、社区为基础的环境中，研究了两种在非小细胞肺癌（NSCLC）中作为单一药物具有活性的细胞毒性化合物紫杉醇（泰素）和顺铂（顺铂）联合使用的疗效和毒性。
连续两个队列的未经化疗的IIIA/B期和IV期NSCLC患者接受了两个剂量水平的紫杉醇。第一个队列在3小时内接受200mg/m²（高剂量组），第二个队列在3小时内接受175mg/m²（低剂量组），并联合固定剂量的顺铂。顺铂剂量根据卡尔弗特公式计算，浓度-时间曲线下面积（AUC）值为6mg/ml/分钟。将通过沙泰吕公式而非肾小球滤过率（GFR）+25计算的顺铂清除率引入卡尔弗特公式。在整个研究过程中，两个队列的入选标准相同。每三周进行一次治疗。研究终点为缓解率（RR）、毒性、疾病进展时间（TTP）和生存率（S）。
来自36个比利时机构的130例连续符合条件的患者可对所有研究参数进行全面评估（高剂量组99例，低剂量组31例）。骨髓抑制是治疗最突出的副作用，两个队列的结果相当。高剂量组与低剂量组每位患者最严重的3-4级白细胞减少和中性粒细胞减少分别为34.4%对19.3%和59.2%对51.6%。高剂量组10.4%的患者因发热性中性粒细胞减少需要住院治疗（有记录的细菌感染患者为6.2%，无记录的为4.2%），而低剂量组的相应数字分别为13.7%、10.3%和3.4%。最突出的非血液学毒性是脱发和多发性神经病变，高剂量组和低剂量组之间无显著差异（2级脱发分别为78.1%对83.9%，3级神经病变分别为14.3%对9.7%）。130例患者中总体最佳临床缓解率为31例（23.8%），其中1例完全缓解（CR），30例部分缓解（PR）。高剂量组和低剂量组的缓解率分别为23.2%和25.8%。所有患者的中位TTP和S分别为120天和248天，高剂量组和低剂量组之间无明显差异（分别为119天和254天对128天和222天）。高剂量组的一年生存率为34%。两个队列中疗效和毒性参数的95%置信区间重叠。
在这项多中心研究中，紫杉醇和顺铂联合使用在IIIA/B期和IV期NSCLC中产生了23.8%的中度缓解率。两种紫杉醇剂量下该治疗总体耐受性良好。骨髓抑制、神经毒性和脱发是主要的治疗相关副作用。两个紫杉醇剂量组在活性和毒性方面的差异最小。使用沙泰吕公式计算顺铂清除率是可行的，但与使用其他方法估计肾功能的其他研究相比，在我们的研究中可能导致明显的骨髓毒性过高。
