University of Wisconsin, Madison, WI 53792, USA.
J Clin Oncol. 2010 Jul 20;28(21):3491-7. doi: 10.1200/JCO.2010.28.4075. Epub 2010 Jun 7.
Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras.
Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction.
Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes.
Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.
胆管癌过度表达表皮生长因子受体（EGFR），并且血管生成与不良预后相关。表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼和血管内皮生长因子（VEGF）抑制剂贝伐单抗已被证明在胆管癌中具有活性。本研究的主要目的是通过实体瘤反应评价标准（RECIST）评估缓解率。次要终点包括总生存期（OS）、无进展生存期（TTP）、VEGF 水平以及 EGFR 和 k-ras 的分子研究。
符合条件的患者患有晚期胆管癌或胆囊癌。患者接受贝伐单抗 5mg/kg 静脉注射，第 1 天和第 15 天，厄洛替尼 150mg 口服，第 1 天至第 28 天。通过 RECIST 评估反应。收集 VEGF 水平，并通过聚合酶链反应分析 EGFR 突变。
在 8 个地点招募了 53 名符合条件的患者。在 49 名可评估患者中，6 名（12%；95%CI，6%至 27%）有确认的部分缓解。另外 25 名患者（51%）有稳定的疾病。皮疹是最常见的 3 级毒性。4 名患者出现 4 级毒性。中位 OS 为 9.9 个月，TTP 为 4.4 个月。EGFR 内含子 1 多态性低重复（<16）和 k-ras Q38 基因型（野生型）G>G 与改善结果相关。
贝伐单抗和厄洛替尼联合化疗在晚期胆管癌患者中显示出临床活性，不良反应发生率低（3 级和 4 级）。基于初步的分子分析，k-ras 突变的存在可能改变厄洛替尼的疗效。贝伐单抗和厄洛替尼的联合可能是晚期胆管癌患者的一种治疗选择。
