A phase II study of gefitinib monotherapy in advanced Esophageal adenocarcinoma: Evidence of gene expression, cellular, and clinical response
A phase II study of gefitinib monotherapy in advanced Esophageal adenocarcinoma: Evidence of gene expression, cellular, and clinical response
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DOI：
10.1158/1078-0432.ccr-06-1970
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发表时间：
2007-10-01
影响因子：
11.5
通讯作者：
Jankowski, Janusz
中科院分区：
文献类型：
--
作者：
Ferry, David R.;Anderson, Mark;Jankowski, Janusz
目的：目前，大多数食管腺癌 (ACE) 病例无法手术。尽管化疗可以延长生存期，但患者最终会因难治性疾病而死亡。表皮生长因子受体 (EGFR) 在 ACE 中几乎普遍表达，是一个负面预后因素。 实验设计：这项开放标签、两中心、非比较、两部分 11 期试验评估了 EGFR 酪氨酸激酶抑制剂吉非替尼 (500 mg/d) 在晚期、无法手术的 ACE 患者中的作用。主要终点是肿瘤反应。还通过吉非替尼治疗前和治疗后 28 天进行的肿瘤活检的基因表达分析来评估 EGFR 抑制的效果。 结果：招募了 27 名患者，并可评估肿瘤反应和安全性。 3 名患者出现部分缓解，7 名患者疾病稳定，疾病控制率（部分缓解 + 疾病稳定）为 37%。药物相关不良事件一般较轻微：19 例患者出现腹泻（三例为 3 级），19 例患者出现皮疹（五例为 3 级），没有出现 4 级药物相关不良事件。肿瘤活检的微阵列实验表明，吉非替尼还下调与肿瘤进展相关的癌基因。在治疗前后进行的七次活检中，有 5 次 Ki67（肿瘤生长标志物）表达下降。 结论：吉非替尼（500 mg/d）是一种有效且总体耐受性良好的 ACE 治疗方法。内窥镜活检的研究是可行的，并表明吉非替尼在 500 mg/d 的剂量下可抑制基因表达和细胞生物学，这些可能为预测生物标志物提供替代终点。吉非替尼的进一步试验是必要的，特别是因为患者的反应似乎是持久的，并且目前的二线化疗方案尚未被证明能够延长生命。
Purpose: At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor.Experimental Design: This open-label, two-center, noncomparative, two-part phase 11 trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after.Results: Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment.Conclusion: Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.