Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
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DOI：
10.1056/nejmoa1304369
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发表时间：
2013-10-31
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影响因子：
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通讯作者：
Renschler MF
中科院分区：
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作者：
Von Hoff DD;Ervin T;Arena FP;Chiorean EG;Infante J;Moore M;Seay T;Tjulandin SA;Ma WW;Saleh MN;Harris M;Reni M;Dowden S;Laheru D;Bahary N;Ramanathan RK;Tabernero J;Hidalgo M;Goldstein D;Van Cutsem E;Wei X;Iglesias J;Renschler MF
在白蛋白结合紫杉醇（nab-紫杉醇）加吉西他滨的1-2期试验中，在晚期胰腺癌患者中观察到了大量的临床活性。我们进行了一项3期研究，在转移性胰腺癌患者中比较联合用药与吉西他滨单药治疗的疗效和安全性。我们将Karnofsky体能状态评分为70分或以上的患者随机分组（在0至100的量表上，分数越高表示性能状态越好）（125 mg/m2体表面积），然后是吉西他滨（1000 mg/m2），第1、8和15天，每4周一次或吉西他滨单药治疗（1000 mg/m2），每周一次，持续7/8周（第1周期），然后每4周在第1、8和15天（第2周期和后续周期）给药。患者接受研究治疗直至疾病进展。主要终点为总生存期，次要终点为无进展生存期和总缓解率。共有861例患者被随机分配到白蛋白结合型紫杉醇+吉西他滨（431例）或吉西他滨（430例）。白蛋白结合型紫杉醇-吉西他滨组的中位总生存期为8.5个月，而吉西他滨组为6.7个月（死亡风险比为0.72; 95%可信区间[CI]为0.62 - 0.83; P<0.001）。白蛋白结合型紫杉醇-吉西他滨组1年生存率为35%，吉西他滨组为22%，2年生存率为9%，吉西他滨组为4%。nab-紫杉醇-吉西他滨组的中位无进展生存期为5.5个月，而吉西他滨组为3.7个月（疾病进展或死亡的风险比为0.69; 95%CI为0.58 - 0.82; P<0.001）;根据独立审查，两组的缓解率分别为23%和7%（P<0.001）。最常见的3级或以上不良事件是中性粒细胞减少（白蛋白结合型紫杉醇-吉西他滨组为38%，吉西他滨组为27%）、疲劳（17% vs. 7%）和神经病变（17% vs. 1%）。两组中发热性中性粒细胞减少发生率分别为3%和1%。在nab-紫杉醇-吉西他滨组中，3级或更高级别的神经病变在中位数29天内改善至1级或更低。在转移性胰腺癌患者中，白蛋白结合型紫杉醇联合吉西他滨显著改善了总生存期、无进展生存期和缓解率，但周围神经病变和骨髓抑制的发生率增加。（由Celgene资助; ClinicalTrials.gov编号，NCT 00844649。
In a phase 1–2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel–gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel–gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel–gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.)