Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial
Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial
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DOI：
10.1016/s1470-2045(14)70024-5
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发表时间：
2014-07-01
期刊：
影响因子：
51.1
通讯作者：
Petty, Russell D.
中科院分区：
文献类型：
--
作者：
Dutton, Susan J.;Ferry, David R.;Petty, Russell D.
背景：化疗后进展的食管癌治疗有效性的证据很少，也没有随机试验的报道。我们的目的是比较吉非替尼与安慰剂在以前治疗过的晚期食管cancer.Methods的3期，平行，随机，安慰剂对照试验，合格的患者是成年人与晚期食管癌或I/II型Siewert交界肿瘤，组织学证实的鳞状细胞癌或腺癌，化疗后进展，与WHO的性能状态0 - 2，并且在CT扫描中具有可测量或可评估的疾病。参与者从48个英国中心招募，并通过简单随机化（1：1）随机分配至吉非替尼（500 mg）或匹配的安慰剂组，无分层因素。患者、临床医生和试验办公室工作人员对治疗分配设盲。治疗持续至疾病进展、不可接受的毒性或患者选择。主要结果是总生存率，分析意向treat.This试验注册，编号ISRCTN29580179.Findings在2009年3月30日至2011年11月18日，450例患者被随机分配到治疗组（1例患者撤回同意，224例分配吉非替尼和225例分配安慰剂包括在分析中）。两组的总生存期无差异（吉非替尼组的中位生存期为3 73个月，95%CI为3 23 - 4 50，安慰剂组为3 67个月，95%CI为2.97 - 4.37;风险比[HR]为0.90，95%CI为0.74 - 1 09，p = 0.29）。在预先规定的患者报告结局中（110名吉非替尼组患者和121名安慰剂组患者完成了基线和4周问卷调查，并被纳入分析），吉非替尼组的吞咽疼痛明显好于安慰剂组。（校正的平均差异为-8.61，95%CI为-14.49至-2.73; n = 227; p = 0.004），而其他结局与安慰剂相比无显著改善：全球生活质量（2.69，95% CI-2.33至7.72，n = 231，p = 0.293），吞咽困难（-3.18，95% CI-8.36至2.00，n = 231，p = 0.228）和进食（-4.11，95% CI-9.96至1.75，n = 229，p = 0.168）。吉非替尼组的中位无进展生存期略长于安慰剂组（吉非替尼组1.57个月，95% CI 1.23 - 1.90 vs安慰剂组1.17个月，95% CI 1.07 - 1.37; HR 0.80，95% CI 0.66 - 0.96，p = 0.020）。最常见的毒性是腹泻（吉非替尼组224例患者中有36例[16%]，安慰剂组225例患者中有6例[3%]）和皮肤毒性（46例[21%]，两例[1%]），均为2级。最常见的3 - 4级毒性为疲乏（24例[11%] vs 13例[6%]患者）和腹泻（13例[6%] vs 2例[1%]）。224名接受吉非替尼治疗的患者中有109名（49%）报告了严重不良事件，225名接受安慰剂治疗的患者中有101名（45%）报告了严重不良事件。吉非替尼组中54例（24%）患者在8周时达到疾病控制，安慰剂组中35例（16%）患者也达到疾病控制（p = 0.023）。解释使用吉非替尼作为食管癌二线治疗的食管癌患者不能提高总生存率，但在这些难以治疗的患者中具有姑息性益处，预期寿命短。未来的研究应该集中在识别预测性生物标志物，以确定这一亚组的受益患者。
Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer.Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179.Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3 73 months, 95% CI 3 23-4 50, for gefitinib vs 3 67 months, 95% CI 2.97-4.37, for placebo; hazard ratio [HR] 0.90, 95% CI 0.74-1 09, p=0.29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8.61, 95% CI -14.49 to -2 73; n=227; p=0.004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2.69, 95% CI -2.33 to 7.72, n=231, p=0.293), dysphagia (-3.18, 95% CI -8.36 to 2.00, n=231, p=0.228), and eating (-4.11, 95% CI -9.96 to 1.75, n=229, p=0.168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1.57 months, 95% CI 1.23-1.90 in the gefitinib group vs 1.17 months, 95% CI 1.07-1.37 in the placebo group; HR 0.80, 95% CI 0.66-0.96, p=0.020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0.023).Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.