【摘要】 目的确定泰索帝每周给药联合顺铂治疗晚期非小细胞肺癌的最大耐受剂量(MTD)和剂量限制毒性(DLT),观察其疗效(RR)和安全性,并进行药代动力学研究。方法泰索帝每周给药,连用3周,休息1周,顺铂每周期的第1天给药;每28d为1个治疗周期。顺铂的剂量为75mg/m2。泰索帝在Ⅰ期临床阶段共有4个剂量组:25mg/m2、30mg/m2、35mg/m2和40mg/m2,每个剂量组至少入选3例患者。在Ⅱ期临床阶段,根据Ⅰ期临床推荐剂量,泰索帝35mg/m2每周给药。药代动力学为第一周期第1天和第15天抽取血样待分析。根据Ⅰ期临床研究推荐剂量,进行Ⅱ期临床研究。结果Ⅰ期临床的15例患者中,有14例可评价疗效,其中5例部分缓解,有效率为35.7%,其中位生存时间16个月(范围5~40个月)。1、2、3年生存率分别为73.3%、26.6%和20.0%。中位疾病进展时间9个月(6~14个月)。Ⅱ期临床研究的83例初治的晚期非小细胞肺癌患者共接受了216个周期的化疗,可评价者75例。有1例患者完全缓解,22例患者部分缓解,占全部入组病例的27.7%(23/83),占可评价病例的30.7%(23/75);其中位生存时间为10.7个月(范围3~34个月),1年生存率为48.6%。主要不良反应为Ⅲ~Ⅳ度的粒细胞减少以及乏力、指甲毒性及液体潴留。结论泰索帝(35mg/m2)每周给药联合顺铂(75mg/m2)作为一线方案治疗晚期非小细胞肺癌,疗效较好,骨髓毒性较小。更多还原

【Abstract】 Objective The purpose of this phase Ⅰ/Ⅱ study is to investigate the safety/toxicity profile of weekly administration of docetaxel in combination with cisplatin for the chemo-naive patients with advanced non-small cell lung cancer (NSCLC), and to evaluate the efficacy of this regime. Methods In phase I trial, 15 patients were included. Ⅳ infusion of escalating doses of docetaxel consisting of four levels from 25 to 40 mg/m~2 (25, 30, 35, 40 mg/m~2) on D1, 8, 15 and cisplatin of 75 mg/m~2 on D1 was administered. The regime was repeated every 4 weeks. Blood samples were obtained on D1, 15 in the first cycle to measure the PK. Dose limiting toxicity(DLT) was determined in cycle 1 and defined as any grade 3 non-hematologic toxicity which could not be reverted into grade less than grade 2 within 4 days or any grade 4 hematologic toxicity. Eighty-three patients completed their phase Ⅱ study with administration of docetaxel at a dose of 35 mg/m~2 based on the data of phase Ⅰ trial.Results In the phase Ⅰ trial, grade 3/4 neutropenia was mainly observed in patients who received docetaxel of 40 mg/m~2 (level 4) with one patient suffering from an infection signifying dose limiting toxicity(DLT). Non-hematological toxicities including nausea/vomiting, alopecia, fluid retension and asthenia were tolerable. Based on these data, the maximum tolerence dose (MTD) did not reach the level of weekly giving docetaxel at a dose of 40 mg/m~2 in combination with cisplatin 75 mg/m~2 every 4 weeks. The pharmacokinetic/dynamics results There was no statistically significant difference between clearance value among the 4 dose levels of docetaxel from 25 to 40 mg/m~2 when measured by Cmax and AUC. The pharmacokinetics of docetaxel was not influenced by the presence of co-administration of cisplatin when compared D1 with D15 as based on CmaxN, AUCN and CL.In the phase Ⅱ trial, totally 83 patients received 216 cycles of chemotherapy. One CR (complete response ) and 22 PR(partial response) were achieved with an objective response rate of 27.7 % in this series and 30.7% in the evaluable patients. The 1-year survival was 48.6% with a median survival of 10.7 months (range: 3-34 months). Hematologic toxicities were the major side effects, though most were mild; grade Ⅲ/Ⅳ neutropenia developed in 15%. The common non-hematologic toxicities were nausea, vomiting and asthenia. Conclusion Weekly consecutive administration of docetaxel on D1,8,15 for 3 weeks plus cisplatin on D1 is tolerable and effective with minimal myelosuppression in chemo-naive patients with advanced NSCLC.更多还原