胃癌

对于早期局限性疾病，如果医疗上合适，手术切除应作为主要的治疗方式。对于所有 T2 或更高分期以及任意 N 期的所有患者，应当考虑围手术期治疗。多项随机研究正在比较治疗胃癌的腹腔镜胃切除术与开腹胃切除术。[33]Ohtani H, Tamamori Y, Noguchi K, et al. A meta-analysis of randomized controlled trials that compared laparoscopy-assisted and open distal gastrectomy for early gastric cancer. J Gastrointest Surg. 2010 Jun;14(6):958-64.http://www.ncbi.nlm.nih.gov/pubmed/20354807?tool=bestpractice.com[34]Kim W, Kim HH, Han SU, et al; Korean Laparo-endoscopic Gastrointestinal Surgery Study (KLASS) Group. Decreased morbidity of laparoscopic distal gastrectomy compared with open distal gastrectomy for stage I gastric cancer: short-term outcomes from a multicenter randomized controlled trial (KLASS-01). Ann Surg. 2016 Jan;263(1):28-35.http://www.ncbi.nlm.nih.gov/pubmed/26352529?tool=bestpractice.com [ ]How does laparoscopic compare with open gastrectomy at improving outcomes in people with gastric cancer?https://cochranelibrary.com/cca/doi/10.1002/cca.1485/full显示答案

手术切除范围取决于肿瘤的位置。 对于胃近端肿瘤，通常建议行全胃切除术。 远端胃癌患者行全胃切除术与胃次全切除术相比，并无生存获益。[37]Bozzetti F, Marubini E, Bonfanti G, et al. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg. 1999 Aug;230(2):170-8.http://www.ncbi.nlm.nih.gov/pubmed/10450730?tool=bestpractice.com[38]Gouzi JL, Huguier M, Fagniez PL, et al. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg. 1989 Feb;209(2):162-6.http://www.ncbi.nlm.nih.gov/pubmed/2644898?tool=bestpractice.com

表浅的早期胃癌（T1a）患者可以采用内镜下黏膜切除 (endoscopic mucosal resection, EMR) 进行治疗。 EMR的适应证是：腺瘤局限在黏膜层、直径小于2cm、中或低度分化、无溃疡证据且无血管淋巴受累。[42]Bennett C, Wang Y, Pan T. Endoscopic mucosal resection for early gastric cancer. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD004276.http://www.ncbi.nlm.nih.gov/pubmed/19821324?tool=bestpractice.com[43]Takekoshi T, Baba Y, Ota H, et al. Endoscopic resection of early gastric carcinoma; results of a retrospective analysis of 308 cases. Endoscopy. 1994 May;26(4):352-8.http://www.ncbi.nlm.nih.gov/pubmed/8076567?tool=bestpractice.com[44]Soetikno R, Kaltenbach T, Yeh R, et al. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol. 2005 Jul 10;23(20):4490-8.http://www.ncbi.nlm.nih.gov/pubmed/16002839?tool=bestpractice.com

淋巴结清扫术的范围目前仍有争议。 相关研究未能表明 D2 淋巴结清扫术（切除胃周围淋巴结及沿着胃左动脉、肝动脉、腹腔及脾动脉的淋巴结）与 D1 淋巴结清扫术（切除胃周围淋巴结）有生存获益方面的差异。 D2淋巴结清扫术可能会降低肿瘤的局部复发率及胃癌相关死亡率，但是也可能增加手术的并发症发病率及死亡率。 在很多医学中心采用改良的D2（保留脾）淋巴结清扫术。 此外，D2淋巴结清扫术外加腹主动脉旁淋巴结切除并不能改善生存情况。[39]Cushieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group. Lancet. 1996 Apr 13;347(9007):995-9.http://www.ncbi.nlm.nih.gov/pubmed/8606613?tool=bestpractice.com[40]Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010 May;11(5):439-49.http://www.ncbi.nlm.nih.gov/pubmed/20409751?tool=bestpractice.com[41]Sasako M, Sano T, Yamamoto S, et al; Japan Clinical Oncology Group. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. 2008 Jul 31;359(5):453-62.https://www.nejm.org/doi/full/10.1056/NEJMoa0707035http://www.ncbi.nlm.nih.gov/pubmed/18669424?tool=bestpractice.com [ ]In people with adenocarcinoma of the stomach, how do different types of lymph node dissection affect outcomes?https://cochranelibrary.com/cca/doi/10.1002/cca.954/full显示答案

针对经选择患者组全部患者的治疗推荐

病理分期为 II-IIIC 期、有任何 T、N+ 疾病或者 R1 切除的患者都应接受术后放疗及辅助氟尿嘧啶化疗，经证实，该方案可以延长患者的总生存期。[45]Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30.https://www.nejm.org/doi/10.1056/NEJMoa010187http://www.ncbi.nlm.nih.gov/pubmed/11547741?tool=bestpractice.com[46]Smalley SR, Benedetti JK, Haller DG,et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012 Jul 1;30(19):2327-33.http://www.ncbi.nlm.nih.gov/pubmed/22585691?tool=bestpractice.com 术后放化疗包括放疗前1个周期及放疗后2个周期的氟尿嘧啶（联合或不联合亚叶酸钙）化疗。在放疗的最初4天及最后3天给予氟尿嘧啶。放疗的副作用包括恶心、呕吐（放疗前患者可能需要服用止吐药）、消瘦及腹泻。一些较少见的副作用包括小肠梗阻、肝肾损伤等。[47]Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6.http://ascopubs.org/doi/full/10.1200/jco.2008.17.0506http://www.ncbi.nlm.nih.gov/pubmed/19139439?tool=bestpractice.com

另一种治疗方案是辅助化疗，可以提高根治性切除患者的生存率。[51]Sun P, Xiang JB, Chen ZY. Meta-analysis of adjuvant chemotherapy after radical surgery for advanced gastric cancer. Br J Surg. 2009 Jan;96(1):26-33.http://www.ncbi.nlm.nih.gov/pubmed/19016271?tool=bestpractice.com[71]Sakuramoto S, Sasako M, Yamaguchi T, et al; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007 Nov 1;357(18):1810-20.https://www.nejm.org/doi/10.1056/NEJMoa072252http://www.ncbi.nlm.nih.gov/pubmed/17978289?tool=bestpractice.com[72]Paoletti X, Oba K, Burzykowski T, et al; GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International, Collaboration) Group. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA. 2010 May 5;303(17):1729-37.http://www.ncbi.nlm.nih.gov/pubmed/20442389?tool=bestpractice.com [ ]In people with resectable gastric cancer, what are the benefits and harms of post-surgical chemotherapy?https://cochranelibrary.com/cca/doi/10.1002/cca.1087/full显示答案

使用 ECF（表柔比星、顺铂和氟尿嘧啶）进行围手术期化疗已被证明可延长Ⅱ期或更高分期的胃癌患者的总生存期。[50]Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.https://www.nejm.org/doi/full/10.1056/NEJMoa055531http://www.ncbi.nlm.nih.gov/pubmed/16822992?tool=bestpractice.com[51]Sun P, Xiang JB, Chen ZY. Meta-analysis of adjuvant chemotherapy after radical surgery for advanced gastric cancer. Br J Surg. 2009 Jan;96(1):26-33.http://www.ncbi.nlm.nih.gov/pubmed/19016271?tool=bestpractice.com然而研究显示，在治疗手术可切除的胃癌和胃食管交界癌方面，与围手术期 ECF（表柔比星、顺铂和氟尿嘧啶）/ECX（表柔比星、顺铂和卡培他滨）相比，FLOT4（多西他赛、奥沙利铂、氟尿嘧啶和亚叶酸钙）的治疗结局更佳。[52]ClinicalTrials.gov. 5-FU, leucovorin, oxaliplatin and docetaxel (FLOT) versus epirubicin, cisplatin and 5-FU (ECF) in patients with locally advanced, resectable gastric cancer. ClinicalTrials.gov Identifier: NCT01216644. Mar 2019 [internet publication].https://clinicaltrials.gov/ct2/show/NCT01216644

在美国，辅助化疗试验未能证明任何获益；但是，日本和韩国的试验支持 D2 淋巴结清扫术后进行辅助化疗。[53]Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011 Nov 20;29(33):4387-93.http://www.ncbi.nlm.nih.gov/pubmed/22010012?tool=bestpractice.com[54]Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012 Jan 28;379(9813):315-21.http://www.ncbi.nlm.nih.gov/pubmed/22226517?tool=bestpractice.com

有关剂量指南，请参阅当地专家的用药方案。

对于不适合手术的局限性疾病患者，应该给予放化疗，包括应用放疗和氟尿嘧啶（或氟尿嘧啶加一种紫杉烷类药物，如紫杉醇）。 亚叶酸钙可以加强氟尿嘧啶的疗效，因此两药通常联合应用。

放疗的副作用包括恶心、呕吐（放疗前患者可能需要服用止吐药）、消瘦及腹泻。 一些较少见的副作用包括小肠梗阻、肝肾损伤等。

有关剂量指南，请参阅当地专家的用药方案。

对于转移性胃癌患者，化疗与最佳支持治疗相比，可以改善患者的生活质量及生存情况。[56]Glimelius B, Ekström K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997 Feb;8(2):163-8.http://www.ncbi.nlm.nih.gov/pubmed/9093725?tool=bestpractice.com[57]Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017 Aug 29;(8):CD004064.https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004064.pub4/fullhttp://www.ncbi.nlm.nih.gov/pubmed/28850174?tool=bestpractice.com[58]Pyrhönen S, Kuitunen T. Nyandoto P, et al. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer. 1995 Mar;71(3):587-91.http://www.ncbi.nlm.nih.gov/pubmed/7533517?tool=bestpractice.com [ ]Does randomized controlled trial evidence support the use of chemotherapy in people with advanced gastric cancer?https://cochranelibrary.com/cca/doi/10.1002/cca.1917/full显示答案 转移性胃癌的一线治疗方案包括铂类化合物和氟尿嘧啶的联合使用。此外，通常还会联合使用第三种药物，但不同国家/地区选用的药物不同，例如在欧洲较常用蒽环类药物（例如表柔比星）（ECF=表柔比星、顺铂和氟尿嘧啶）；在美国较常用紫杉醇类药物（例如多西他赛）（DCF=多西他赛、顺铂和氟尿嘧啶）。[59]Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006 Nov 1;24(31):4991-7.http://www.ncbi.nlm.nih.gov/pubmed/17075117?tool=bestpractice.com[60]Waters JS, Norman A, Cunningham D, et al. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72.http://www.ncbi.nlm.nih.gov/pubmed/10390007?tool=bestpractice.com[61]Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007 Aug 1;25(22):3205-9.http://ascopubs.org/doi/full/10.1200/jco.2006.10.4968http://www.ncbi.nlm.nih.gov/pubmed/17664467?tool=bestpractice.com 一些研究显示卡培他滨及奥沙利铂可以取代氟尿嘧啶和顺铂。[62]Cunningham D, Rao S, Starling T, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. J Clin Oncol. 2006 Jun 20;24(18 Suppl):LBA4017.http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.lba4017[63]Al-Batran S, Hartmann JT, Probst S, et al. A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP). J Clin Oncol. 2006 Jun 20;24(18 Suppl):LBA4016.http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.lba4016 奥沙利铂取代顺铂后其毒副作用将更小。[62]Cunningham D, Rao S, Starling T, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. J Clin Oncol. 2006 Jun 20;24(18 Suppl):LBA4017.http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.lba4017[64]Montagnani F, Turrisi G, Marinozzi C, et al. Effectiveness and safety of oxaliplatin compared to cisplatin for advanced, unresectable gastric cancer: a systematic review and meta-analysis. Gastric Cancer. 2011 Mar;14(1):50-5.http://www.ncbi.nlm.nih.gov/pubmed/21340667?tool=bestpractice.com

目前EOX（表柔比星、奥沙利铂和氟尿嘧啶）方案和FLO（氟尿嘧啶、亚叶酸钙和奥沙利铂）方案正在试验中。[62]Cunningham D, Rao S, Starling T, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. J Clin Oncol. 2006 Jun 20;24(18 Suppl):LBA4017.http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.lba4017[63]Al-Batran S, Hartmann JT, Probst S, et al. A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP). J Clin Oncol. 2006 Jun 20;24(18 Suppl):LBA4016.http://ascopubs.org/doi/abs/10.1200/jco.2006.24.18_suppl.lba4016

对于局部晚期胃癌患者，接受放化疗联合治疗的患者总生存率较单纯接受放疗的患者更高。[48]Moertel CG, Childs DS, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy for locally advanced and metastatic gastric carcinoma. Lancet. 1969 Oct 25;2(7626):865-7.http://www.ncbi.nlm.nih.gov/pubmed/4186452?tool=bestpractice.com[49]Le Chevalier T, Smith FP, Harter WK, et al. Chemotherapy and combined modality therapy for locally advanced and metastatic gastric carcinoma. Semin Oncol. 1985 Mar;12(1):46-53.http://www.ncbi.nlm.nih.gov/pubmed/3883501?tool=bestpractice.com 放疗的副作用包括恶心、呕吐（放疗前患者可能需要服用止吐药）、消瘦及腹泻。 一些较少见的副作用包括小肠梗阻、肝肾损伤等。

对于HER2/neu过表达的转移性胃癌患者（免疫组化3+，或免疫组化2+同时FISH阳性），细胞毒性化疗方案中应加入曲妥珠单抗（作用于HER2/neu受体的人源性单克隆抗体）。 联合应用曲妥珠单抗会显著延长患者的总生存期。[65]Bang YJ, Van CE, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97.http://www.ncbi.nlm.nih.gov/pubmed/20728210?tool=bestpractice.com

对于经历疾病进展但具有良好表现状态的患者，应考虑替代药物。与最佳支持性治疗相比，紫杉烷类药物（例如多西他赛）或伊立替康单药或联合应用可以在一定程度上延长患者的总生存期。[66]Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer - a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 Oct;47(15):2306-14.http://www.ncbi.nlm.nih.gov/pubmed/21742485?tool=bestpractice.com[67]Kang JH, Lee SI, Lim do H, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012 May 1;30(13):1513-8.http://www.ncbi.nlm.nih.gov/pubmed/22412140?tool=bestpractice.com 同样，雷莫芦单抗（ramucirumab）（一种血管内皮生长因子抑制剂）单药治疗已被证明可改善一线铂类或含氟尿嘧啶类化疗后疾病进展的晚期胃癌或食管胃交界部腺癌患者的中位总生存期。[68]Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9.http://www.ncbi.nlm.nih.gov/pubmed/24094768?tool=bestpractice.com

有关剂量指南，请参阅当地专家的用药方案。

可能改善出血及梗阻等症状。

针对经选择患者组全部患者的治疗推荐

在一项针对转移性胃腺癌患者的临床试验（RAINBOW 试验）中，将雷莫芦单抗添加至每周一次紫杉醇作为二线治疗。 与单用紫杉醇相比，联合用药可显著延长无进展生存期和总生存期。[69]Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35.http://www.ncbi.nlm.nih.gov/pubmed/25240821?tool=bestpractice.com 

有关剂量指南，请参阅当地专家的用药方案。

可能改善出血及梗阻等症状。

针对经选择患者组全部患者的治疗推荐

帕博利珠单抗一种抗PD1抗体检查点抑制剂，被认为三线治疗。美国和其他一些国家已批准其用于治疗肿瘤表达 PDL-1（综合阳性评分 [CPS]>1）的局部晚期或转移性胃癌患者，以及先前接受二线或多线治疗后（包括含铂类方案和含氟尿嘧啶方案，以及如若适用的 HER2/neu 靶向治疗）疾病发生了进展的患者。该批准基于 KEYNOTE-059 研究结果，在该研究中发现，与预治疗的晚期胃癌患者相比，帕博利珠单抗（pembrolizumab）与安慰剂相比，提高了反应率。[70]Fuchs CS, Doi T, Jang RW, et al. KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer [abstract]. J Clin Oncol. 2017 May 20;35(15 Suppl):4003.http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4003

Trifluridine/tipiracil 同样被认为三线治疗。它被美国食品和药物管理局批准用于已经接受了至少两种先前化疗方案，并且经历了放射影像学疾病进展，不可切除的转移性胃腺癌患者。该批准基于双盲、安慰剂对照的3期试验（TAGS试验）的结果，该试验报告显示被随机分配到 trifluridine/tipiracil治疗组，不可切除的转移性胃腺癌患者中位总生存期得到显著改善（安慰剂组为5.7 vs 3.6个月；风险比：0.69，95％可信区间：0.56-0.85）。[32]Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Oct 21;19(11):1437-48.http://www.ncbi.nlm.nih.gov/pubmed/30355453?tool=bestpractice.com Trifluridine/tipiracil 同时与无进展生存期的延长呈现相关性。Trifluridine/tipiracil 组中最常报道的3级（严重但不危及生命），或更严重的不良事件是中性粒细胞减少（114 [34％]）、贫血（64 [19％]），和白细胞减少（31 [9％]）。

有关剂量指南，请参阅当地专家的用药方案。

可能改善出血及梗阻等症状。