De Pas T, de Braud F, Danesi R, Sessa C, Catania C, Curigliano G, Fogli S, del Tacca M, Zampino G, Sbanotto A, Rocca A, Cinieri S, Marrocco E, Milani A, Goldhirsch A
Division of Medical Oncology, European Institute of Oncology, Milano, Italy.
Ann Oncol. 2000 Jul;11(7):821-7. doi: 10.1023/a:1008319923516.
Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naïve patients with advanced NSCLC.
Escalating doses of GEM (800-2000 mg/m2) and TAX (60-100 mg/m2) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels.
Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m2 plus GEM 1750 and, respectively, 2000 mg/m2). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hematological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of Cmax and AUC. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients.
The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m2 of GEM and 100 mg/m2 of TAX are recommended for phase II studies.
吉西他滨（GEM）和紫杉醇（TAX）是治疗非小细胞肺癌（NSCLC）的有效且无交叉耐药性的药物。我们开展了一项I期研究，以确定在初治的晚期NSCLC患者中每周给予吉西他滨和紫杉醇的最大耐受剂量（MTD）、抗肿瘤活性及药代动力学。
每4周的第1、8、15天，对35例晚期NSCLC患者给予递增剂量的吉西他滨（800 - 2000 mg/m²）和紫杉醇（60 - 100 mg/m²）。在三个较高剂量水平评估了紫杉醇和吉西他滨的血浆药代动力学。
由于累积毒性增加导致在第6和第7剂量水平（紫杉醇100 mg/m²加吉西他滨分别为1750和2000 mg/m²）进行剂量调整或治疗延迟，未确定MTD便停止了剂量递增。血液学毒性包括3%的周期出现4级中性粒细胞减少、1个周期出现3级血小板减少以及3个周期出现发热性中性粒细胞减少。最大非血液学毒性分别为8%和5%的周期出现3级血清转氨酶升高和2级神经感觉毒性。在两个较高剂量水平观察到吉西他滨的非线性药代动力学，Cmax和AUC有显著变异性。未报告药代动力学相互作用。所有剂量水平均可见客观缓解，30例可评估患者的总缓解率为43%（95%置信区间（95%CI）：25.5% - 62.6%）。
吉西他滨和紫杉醇每周给药耐受性良好，在NSCLC中显示出有前景的抗肿瘤活性。鉴于累积毒性和吉西他滨的药代动力学特征，推荐在II期研究中使用1500 mg/m²的吉西他滨和100 mg/m²的紫杉醇。
