Department of Medical Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
World J Gastroenterol. 2013 Jul 28;19(28):4511-9. doi: 10.3748/wjg.v19.i28.4511.
To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer.
We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out.
From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS).
Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.
研究厄洛替尼联合固定剂量率吉西他滨（FDR-Gem）治疗晚期胰腺癌的疗效、毒性和预后因素。
我们设计了一项单臂前瞻性、多中心、开放标签的 II 期研究，以评估厄洛替尼（100mg/d，口服）联合每周 FDR-Gem（1000mg/m²，以 10mg/m²/分钟的速度输注）在未经治疗的局部晚期、不可切除或转移性胰腺癌患者中的疗效。主要终点为 6 个月无进展生存率（PFS-6）；次要终点为总缓解率（ORR）、缓解持续时间、耐受性、总生存期（OS）和临床获益。如果 PFS-6<20%（p0=20%），则认为治疗没有进一步的意义；如果 PFS-6>40%，则具有相当大的意义（p1=40%）；拒绝错误率为 5%（α=5%），效力为 80%，则需要入组 35 名转移性疾病完全可评估的患者才能完成研究。还进行了生存预后因素的分析。
从 2007 年 5 月至 2009 年 9 月，共纳入 46 名患者（男/女：25/21；中位年龄：64 岁；基线时肿瘤标志物 19-9（CA 19-9）的中位数：897U/mL；局部晚期/转移性疾病：5/41）。PFS-6 和中位 PFS 分别为 30.4%和 14 周（95%CI：10-19），1 年和中位 OS 分别为 20.2%和 26 周（95%CI：8-43）。5 名患者达到客观缓解（ORR：10.9%，95%CI：1.9-19.9）；疾病控制率为 56.5%（95%CI：42.2-70.8）；临床获益率为 43.5%（95%CI：29.1-57.8）。与基线相比，23 名可评估患者中有 14 名（63.6%）的 CA 19-9 血清水平下降>25%。治疗耐受性良好，皮疹是预测 PFS（P<0.0001）和 OS（P=0.01）的最有力因素（有皮疹和无皮疹患者的中位 OS 分别为 42 周和 15 周，Log-rank P=0.03）。更好的预后的其他预测因素包括：CA 19-9 下降、女性（对 PFS）和良好的体能状态（对 OS）。
主要研究终点未达到。然而，皮疹强烈预测了厄洛替尼的疗效，这表明基于药效学的患者选择策略值得进一步研究。
