Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
Lancet Gastroenterol Hepatol. 2017 Apr;2(4):277-287. doi: 10.1016/S2468-1253(16)30219-9. Epub 2017 Jan 19.
Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer.
We did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed.
Between March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group).
As the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer.
Taiho Pharmaceutical.
每周给予溶剂型紫杉醇是晚期胃癌的标准二线化疗方案之一。纳米白蛋白结合紫杉醇（nab-紫杉醇）的开发是为了提高紫杉醇的溶解度，不需要预先用药以避免与溶剂型紫杉醇相关的输液反应。此外，与溶剂型紫杉醇相比，nab-紫杉醇可以在更短的输注时间内给予更高的剂量，并且药物浓度更高。我们旨在研究纳武紫杉醇与先前治疗的晚期胃癌患者的溶剂型紫杉醇的疗效和安全性。
我们在日本的 72 家机构进行了一项随机、开放标签、非劣效性、3 期试验。年龄在 20 岁或以上的晚期胃腺癌患者，对含氟嘧啶的一线化疗方案耐药，疾病进展或辅助化疗最后一剂后 24 周内复发，随机（1:1:1）接受静脉内nab-紫杉醇（260mg/m）每 3 周（21 天周期的第 1 天）、每周 nab-紫杉醇（100mg/m，28 天周期的第 1、8 和 15 天）或每周溶剂型紫杉醇（80mg/m，28 天周期的第 1、8 和 15 天）。随机化采用最小化方法，分层为先前使用多西紫杉醇、腹膜转移和东部合作肿瘤学组（ECOG）表现状态。主要终点是全分析集的总生存期，包括所有接受至少一剂研究药物的随机分配患者，非劣效性边界为危险比的 1.25。这项试验在日本制药信息中心临床试验注册，编号 JapicCTI-132059，并已完成。
2013 年 3 月 13 日至 2015 年 5 月 14 日期间，741 名患者被随机分配至nab-紫杉醇每 3 周（n=247）、每周 nab-紫杉醇（n=246）或每周溶剂型紫杉醇（n=248）。总生存期的中位随访时间为 9.99 个月（IQR 6.05-15.05）。接受 nab-紫杉醇每 3 周治疗的患者中位总生存期为 10.3 个月（95%CI 8.7-11.4），每周 nab-紫杉醇组为 11.1 个月（9.9-13.0），每周溶剂型紫杉醇组为 10.9 个月（9.4-11.8）。每周 nab-紫杉醇不劣于每周溶剂型紫杉醇（危险比 0.97，97.5%CI 0.76-1.23；非劣效性单侧 p=0.0085），而 nab-紫杉醇每 3 周不劣于溶剂型紫杉醇（1.06，95%CI 0.87-1.31；非劣效性单侧 p=0.062）。主要的 3 级或更高级别的不良药物反应为中性粒细胞减少症（nab-紫杉醇每 3 周治疗组 244 例中有 158 例[65%]，每周 nab-紫杉醇组 241 例中有 99 例[41%]，每周溶剂型紫杉醇组 243 例中有 71 例[29%]）、周围感觉神经病变（nab-紫杉醇每 3 周治疗组 49 例[20%]，每周 nab-紫杉醇组 6 例[2%]，每周溶剂型紫杉醇组 6 例[2%]）和发热性中性粒细胞减少症（nab-紫杉醇每 3 周治疗组 30 例[12%]，每周 nab-紫杉醇组 7 例[3%]，每周溶剂型紫杉醇组 2 例[1%]）。nab-紫杉醇每 3 周（2 例[1%]）和每周 nab-紫杉醇（3 例[1%]）的过敏反应发生率低于每周溶剂型紫杉醇（13 例[5%]）。总体报告了 4 例与治疗相关的死亡（nab-紫杉醇每 3 周治疗组 1 例发生肺炎，每周 nab-紫杉醇组 1 例发生发热性中性粒细胞减少症/肺炎，每周溶剂型紫杉醇组 1 例发生感染性休克，每周溶剂型紫杉醇组 1 例发生呼吸疾病/间质性肺病）。
由于该试验表明每周 nab-紫杉醇在总生存期方面不劣于每周溶剂型紫杉醇，因此 nab-紫杉醇的制剂优势使其成为胃癌二线治疗的潜在方案。
大冢制药。
