Wagner Anna Dorothea, Syn Nicholas Lx, Moehler Markus, Grothe Wilfried, Yong Wei Peng, Tai Bee-Choo, Ho Jingshan, Unverzagt Susanne
Department of Oncology, Lausanne University Hospitals and Clinics, Rue du Bugnon 46, Lausanne, Switzerland, 1011.
Cochrane Database Syst Rev. 2017 Aug 29;8(8):CD004064. doi: 10.1002/14651858.CD004064.pub4.
Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen.
To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs).
We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer.
Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information.
We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three-drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high-quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU-containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain.
AUTHORS' CONCLUSIONS: Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or two-drug (platinum/5-FUcombination) show significant survival benefits in the comparisons studied above. Furthermore, docetaxel-containing three-drug regimens have increased response rates, but the advantages of the docetaxel-containing three-drug combinations (DCF, FLO-T) are counterbalanced by increased toxicity. Additionally, oxaliplatin-containing regimens demonstrated a benefit in OS as compared to the same regimen containing cisplatin, and there is a modest survival improvement of S-1 compared to 5-FU-containing regimens.Whether the survival benefit for three-drug combinations including cisplatin, 5-FU, and epirubicin as compared to the same regimen without epirubicin is still valid when second-line therapy is routinely administered and when cisplatin is replaced by oxaliplatin and 5-FU by capecitabine is questionable. Furthermore, the magnitude of the observed survival benefits for the three-drug regimens is not large enough to be clinically meaningful as defined recently by the American Society for Clinical Oncology (Ellis 2014). In contrast to the comparisons in which a survival benefit was observed by adding a third drug to a two-drug regimen at the cost of increased toxicity, the comparison of regimens in which another chemotherapy was replaced by irinotecan was associated with a survival benefit (of borderline statistical significance), but without increased toxicity. For this reason irinotecan/5-FU-containing combinations are an attractive option for first-line treatment. Although they need to be interpreted with caution, subgroup analyses of one study suggest that elderly people have a greater benefit form oxaliplatin, as compared to cisplatin-based regimens, and that people with locally advanced disease or younger than 65 years might benefit more from a three-drug regimen including 5-FU, docetaxel, and oxaliplatin as compared to a two-drug combination of 5-FU and oxaliplatin, a hypothesis that needs further confirmation. For people with good performance status, the benefit of second-line chemotherapy has been established in several RCTs.
胃癌是全球第五大常见癌症。在“西方”国家，大多数患者要么在疾病晚期才被诊断出来，要么在接受根治性手术后复发。对于晚期患者，目前靶向治疗的显著益处仅限于一线使用曲妥珠单抗联合化疗治疗的HER-2阳性疾病。在二线治疗中，雷莫西尤单抗单药或联合紫杉醇显示出显著的生存获益。因此，全身化疗仍然是晚期胃癌治疗的主要手段。关于治疗方案的选择仍存在不确定性。
评估化疗与最佳支持治疗（BSC）、联合化疗与单药化疗以及不同化疗方案在晚期胃癌中的疗效。
我们检索了截至2016年6月的Cochrane对照试验中心注册库、MEDLINE和Embase，研究的参考文献列表，并联系了制药公司和专家以识别随机对照试验（RCT）。
我们仅纳入了关于晚期胃癌全身、静脉或口服化疗与BSC、联合化疗与单药化疗以及不同化疗方案的RCT。
两位综述作者独立识别研究并提取数据。如有分歧，会咨询第三位研究者。我们联系研究作者以获取缺失信息。
我们纳入了64项RCT，其中60项RCT（11698名参与者）为总生存的荟萃分析提供了数据。我们发现化疗比BSC使总生存（OS）延长约6.7个月（风险比（HR）0.3，95%置信区间（CI）0.24至0.55，184名参与者，三项研究，中等质量证据）。联合化疗比单药化疗使OS略有延长（额外延长1个月）（HR 0.84，95%CI 0.79至0.89，4447名参与者，23项研究，中等质量证据），这部分被增加的毒性所抵消。表柔比星在三药联合方案（顺铂被奥沙利铂替代且5-氟尿嘧啶被卡培他滨替代）中的益处尚不清楚。伊立替康比不含伊立替康的方案使OS略有延长（额外延长1.6个月）（HR 0.87，95%CI 0.80至0.95，2135名参与者，10项研究，高质量证据）。多西他赛比不含多西他赛的方案使OS略有延长（略超过1个月）（HR 0.86，95%CI 0.78至0.95，2001名参与者，八项研究，高质量证据）。然而，由于亚组分析，我们不确定含多西他赛的联合方案（多西他赛添加到单药或两药联合方案中）是否能延长OS，因为证据质量中等（HR 0.80，95%CI 0.71至0.91，1466名参与者，四项研究，中等质量证据）。当另一种化疗药物被多西他赛替代时，OS可能几乎没有差异（HR 1.05；0.87至1.27，479名参与者，三项研究，中等质量证据）。我们发现卡培他滨与含5-氟尿嘧啶的方案相比，OS可能几乎没有差异（HR 0.94，95%CI 0.79至1.11，732名参与者，五项研究，中等质量证据）。奥沙利铂与含顺铂的方案相比，可能使OS延长（不到1个月）（HR 0.81，95%CI 0.67至0.98，1105名参与者，五项研究，低质量证据）。由于证据质量极低，我们不确定含（与不含）氟嘧啶的紫杉烷-铂联合方案是否能延长OS（HR 0.86，95%CI 0.71至1.06，482名参与者，三项研究，极低质量证据）。S-1方案比含5-氟尿嘧啶的方案使OS略有改善（不到额外1个月）（HR 0.91，95%CI 0.83至1.00，1793名参与者，四项研究，高质量证据），然而由于亚洲和非亚洲人群使用S-1的剂量和疗程不同，这一发现对个体人群的适用性尚不确定。
与BSC相比，化疗可提高生存率（额外延长6.7个月），与单药5-氟尿嘧啶相比，联合化疗可提高生存率（额外延长1个月）。对所有患者进行HER-2状态检测可能有助于识别HER-2阳性肿瘤患者，对于这些患者，在无禁忌证的情况下，曲妥珠单抗联合卡培他滨或5-氟尿嘧啶联合顺铂已被证明是有益的。对于HER-2阴性患者，所有不同的两药和三药联合方案，包括伊立替康、多西他赛、奥沙利铂或口服5-氟尿嘧啶前体药物，都是晚期胃癌的有效治疗选择，在治疗决策中考虑每种方案的副作用至关重要。含伊立替康的联合方案和含多西他赛的联合方案（多西他赛添加到单药或两药（铂/5-氟尿嘧啶联合）方案中）在上述研究比较中显示出显著的生存获益。此外，含多西他赛的三药方案反应率有所提高，但含多西他赛的三药联合方案（DCF、FLO-T）的优势被增加的毒性所抵消。此外，含奥沙利铂的方案与含顺铂的相同方案相比，在OS方面显示出益处，与含5-氟尿嘧啶的方案相比，S-1有适度的生存改善。当常规给予二线治疗且顺铂被奥沙利铂替代、5-氟尿嘧啶被卡培他滨替代时，含顺铂、5-氟尿嘧啶和表柔比星的三药联合方案与不含表柔比星的相同方案相比的生存获益是否仍然有效尚不确定。此外，观察到的三药方案的生存获益幅度不足以达到美国临床肿瘤学会最近定义的临床意义（Ellis 2014）。与以增加毒性为代价在两药方案中添加第三种药物的比较不同，用伊立替康替代另一种化疗药物的方案比较与生存获益相关（具有临界统计学意义），但没有增加毒性。因此，含伊立替康/5-氟尿嘧啶的联合方案是一线治疗的有吸引力的选择。尽管需要谨慎解释，但一项研究的亚组分析表明，与基于顺铂的方案相比，老年人从奥沙利铂中获益更大，与5-氟尿嘧啶和奥沙利铂的两药联合方案相比，局部晚期疾病患者或年龄小于65岁的患者可能从含5-氟尿嘧啶、多西他赛和奥沙利铂的三药联合方案中获益更多，这一假设需要进一步证实。对于身体状况良好的患者，二线化疗的益处已在多项RCT中得到证实。
