西妥昔在头颈鳞状细胞癌治疗中的作用评价--附系统文献回顾和Meta分析

Cetuximab in head and neck squamous cell carcinoma:a systematic review and Meta-analysis

目的：客观评价西妥昔在头颈鳞状细胞癌治疗中的作用和临床价值,明确其应用的有效性和适用范围,为临床应用提供指导。方法：按照Cochrane协作组要求,检索中国内外权威数据库中的随机对照试验,按照系统评价要求进行Meta分析。主要提取指标为总体生存时间（OS）、无进展生存时间（PFS）、总体反应率（ORR）。次要提取指标为严重不良反应,包括3-4级的黏膜炎、皮肤反应、吞咽困难、中性粒细胞减少、贫血、血小板减少、低钾血症、呕吐、乏力、低镁血症、呼吸困难和脓毒症等。结果采用危险比（RR）、比值比（OR）、平均差（MD）及其95%CI。结果：最终该系统评价纳入英文文献4篇,包括局部晚期头颈鳞状细胞癌和复发转移头颈鳞状细胞癌各2篇。其中,晚期头颈鳞状细胞癌共纳入1 319例患者,2年无进展生存率和总体生存率在加用西妥昔组与未使用西妥昔组中差异无统计学意义（PFS固定效应模型：RR=1.02,95%CI为0.92-1.12;P〉0.05;OS固定效应模型：RR=1.06,95%CI为1.00-1.13,P〉0.05）;3-4级吞咽困难在2组中无明显差别;3-4级黏膜炎和皮肤反应在使用西妥昔组明显高于未使用西妥昔组。复发和转移头颈鳞状细胞癌共纳入559例患者,使用西妥昔组OS、PFS和ORR均优于未使用西妥昔组（OS固定效应模型：MD=2.41,95%CI为0.96-3.86,P〈0.01;PFS固定效应模型：MD=2.06,95%CI为1.34-2.77,P〈0.01;ORR：OR=2.38,95%CI为1.60-3.54,P〈0.01）。而1年生存率未显示明显提高（OR=1.39,95%CI为0.98-1.97,P〉0.05）。各种不良反应中,总体不良反应率使用西妥昔组较未使用西妥昔组升高;使用西妥昔组皮肤反应和厌食发生率高于未使用西妥昔组,其他不良反应发生率相近。结论：在局部晚期头颈鳞状细胞癌中,使用西妥昔不能提高2年无进展生存率和总体生存率,而皮肤反应和黏膜炎发生率高;在复发转移头颈鳞状细胞癌中,使用西妥昔可以延长OS、PFS,提高ORR,使用西妥昔增加了总体不良反应、皮肤反应和厌食的发生率。该研究结论基于有限的RCT研究文献,有关西妥昔在头颈鳞状细胞癌治疗中作用的最终结论尚有待进一步研究。

Objective： To evaluate the role and clinical value of cetuximab in the treatment of head and neck squamous cell carcinoma （HNSCC）, and figure out its effectiveness and application, so as to develop evidencebased recommendations for treatment. Method：We comprehensively searched the CBM, Pubmed, EMBASE, and the Cochrane databases to identify published studies on the effect of cetuximab in HNSCC patients. Primary outcomes included overall survival （OS）, progression-free survival（PFS） and overall response rate（ORR）. Secondary outcomes included serious adverse events, such as neutropenia, anemia, thrombocytopenia, skin reactions, hypokalemia, vomiting, asthenia, hypomagnesemia, dyspnea and sepsis. Results were dispalyed as risk ratio （RR）, odds ratio （OR）, mean difference （MD） and 95% CI. Result：A Meta-analysis was conducted on 4 randomized controlled trials, including 2 trials comprising 1,319 patients with locally advanced HNSCC and 2 trails comprising 559 patients with recurrent or metastatic HNSCC. For locally advanced HNSCC, the 2 year PFS and OS showed no significant differences in patients received cetuximab or not （PFS fixed effect： RR= 1.02, 95 MCI O. 92-1.12, P〈0.05, OS fixed effect： RR=1.06, 95%CI 1.00-1.13, P〉0.05, respectively）. Grade 3-4 dysphagia was also similar in patients treated with cetuximab or no cetuximab （dysphagia： fixed effeet RR = 0.92% 95%CI 0. 84-1. 02, P〈0.05）. Only grade 3--4 mucositis and skin reaction showed statistical significance between patients treated with cetuximab and patients with no cetuximab （mucositis： fixed effect RR= 1.21- 95%CI 1.07-- 1.36, P〈0.05） skin reaction： fixed effect： RR=1.99% 95%CI1.39--2.85, P〈0.05, respectively）. For recur rent or metastatic HNSCC, the OS overall mean difference was 2.41 （95% CI 0. 96-3.86,P〈0.05）, the PFS overall mean difference was 2.06 （95% CI 1.34- 2.77, P〈0. 05）, and the ORR overall Odds ratio was 2.38 （955 CI 1.60--3.54,P〈0.05）, suggesting significant effect of cetuximab in improving the prognosis of R/M HNSCC. Owing to small number of trials it was not possible to assess the presence of publication bias. Of note, the 1 year survival overall Odds ratio was 1.39 （95% CI 0. 98-1.97,P〈0.05）. The grade 3 or 4 adverse effects were described in 83.4% of patients in cetuximab group and 75.5% of patients in no cetuximab group. The overall side effects risk ratio suggested statistically significant difference between patients treated with cetuximab and patients with no cetuximab （RR=1.11, 95% CI 1.01--1.20, P〈0.05, 12=47%）. Conclusion：The 2 year pro gression-free survival and overall survival were similar between cetuximab group and no eetuximab group in patients with locally advanced head and neck squamous cell cancer. Data are limited and the benefits of cetuximab on this outcome remain uncertain. Impact of grade 3--4 dysphagia was similar in both groups, however, the incidence of grade 3--4 mucositis and skin reaction were lower in patients treated with cetuximab. Existing randomized controlled trials provided a scientific evidence for the use of cetuximab in R/M HNSCC. The conclusion of the study is based on limited number of RCT, so further investigation is still needed before firm recommendations of cetuximab can be made in the treatment of HNSCC.