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通讯作者:

季加孚(1959-),男,内蒙古呼和浩特市人,博士生导师,主要从事胃癌临床与转化研究。E-mail:jijiafu@hsc.pku.edu.cn

中图分类号:R735.2

文献标识码:A

文章编号:2096-8965(2021)01-0033-06

DOI:10.12287/j.issn.2096-8965.20210105

参考文献 1
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参考文献 5
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参考文献 6
KIM W,KIM H H,HAN S U,et al.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)[J].Ann Surg,2016,263(1):28-35.
参考文献 7
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参考文献 8
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参考文献 9
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参考文献 10
HYUNG W J,YANG H K,PARK Y K,et al.Long-term outcomes of laparoscopic distal gastrectomy for locally advanced gastric cancer:the KLASS-02-RCT randomized clinical trial[J].J Clin Oncol,2020,38(28):3304-3313.
参考文献 11
AL-BATRAN S E,HOMANN N,PAULIGK C,et al.Perioperative chemotherapy with fluorouracil plus leucovorin,oxaliplatin,and docetaxel versus fl uorouracil or capecitabine plus cisplatin and epirubicin for locally advanced,resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4):a randomised,phase 2/3 trial[J].Lancet,2019,393(10184):1948-1957.
参考文献 12
AL-BATRAN S E,HOFHEINZ R D,PAULIGK C,et al.Histopathological regression after neoadjuvant docetaxel,oxaliplatin,fl uorouracil,and leucovorin versus epirubicin,cisplatin,and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4-AIO):results from the phase 2 part of a multicentre,open-label,randomised phase 2/3 trial[J].Lancet Oncol,2016,17(12):1697-1708.
参考文献 13
BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376(9742):687-697.
参考文献 14
FUCHS C S,DOI T,JANG R W,et al.Safety and effi cacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophagealjunction cancer:phase 2 clinical KEYNOTE-059 trial[J].JAMA Oncol,2018,4(5):e180013.
参考文献 15
KANG Y K,BOKU N,SATOH T,et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebocontrolled,phase 3 trial[J].Lancet,2017,390(10111):2461-2471.
参考文献 16
SHITARA K,OZGUROGLU M,BANG Y J,et al.Pembrolizumab versus paclitaxel for previously treated,advanced gastric or gastro-oesophageal junction cancer(KEYNOTE-061):a randomised,open-label,controlled,phase 3 trial[J].Lancet,2018,392(10142):123-133.
参考文献 17
SHITARA K,VAN CUTSEM E,BANG Y J,et al.Effi cacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line,advanced gastric cancer:the KEYNOTE-062 phase 3 randomized clinical trial[J].JAMA Oncol,2020,6(10):1571-1580.
参考文献 18
KANG Y K,CHIN K,CHUNG H C,et al.S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as fi rst-line therapy in patients with advanced gastric cancer(SOLAR):a randomised,open-label,phase 3 trial[J].Lancet Oncol,2020,21(8):1045-1056.
参考文献 19
SHITARA K,BANG Y J,IWASA S,et al.Trastuzumab deruxtecan in previously treated her2-positive gastric cancer[J].N Engl J Med,2020,382(25):2419-2430.
参考文献 20
KAWAZOE A,FUKUOKA S,NAKAMURA Y,et al.Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting(EPOC1706):an open-label,single-arm,phase 2 trial[J].Lancet Oncol,2020,21(8):1057-1065.
参考文献 21
ALLEMANI C,MATSUDA T,DI CARLO V,et al.Global surveillance of trends in cancer survival 2000-14(CONCORD-3):analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J].Lancet,2018,391(10125):1023-1075.
参考文献 22
BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376:687-697.
目录contents

    摘要

    胃癌是我国的高发癌种,外科治疗是胃癌治疗的基石,腔镜手术和淋巴结清扫范围仍然是外科研究的重点。同时,随着免疫及分子靶向药物的不断推陈出新,围术期治疗及晚期治疗的模式都有了长足的改变和进步,也增加了患者生存的机率。此外,随着分子生物学及二代测序的飞速发展,精准的筛选人群及基于亚人群的精准用药,都为胃癌患者打开了生存之门。

    Abstract

    Gastric cancer is a high incidence cancer in China. Surgical treatment is regarded as the cornerstone of gastric cancer treatment. Surgical research has been focusing on endoscopic surgery and lymph node dissection. At the same time, with the continuous innovation of immunotherapeutic and targeted therapeutic drugs, the mode of perioperative treatment and Ⅳ stage treatment has made great changes and progress, and the survival benefit of patients has been improved. In addition, with the rapid development of cancer biology and next-generation sequencing, accurate stratification of patients' populations and accurate drug use based on patients' subpopulation have been providing hopes for gastric cancer patients.

  • 前言

  • 据2013年国家癌症登记中心(National Central Cancer Registry,NCCR)的数据显示,我国约有76万新发胃癌患者,死亡患者人数约为54万 [1]。胃癌仍然是我国重要的致死性疾病,严重的影响着国民的身心健康,也给国家和社会带来巨大负担。外科治疗仍然为胃癌治疗的基石。近年来,随着腹腔镜和内镜下切除术的广泛应用,胃癌外科走向了更加精细化和合理化,损伤控制理念广泛传播。伴随着药物和人类基因组学的飞速发展,综合治疗的理念也已经深入人心。围术期及晚期胃癌的药物研究进展迅猛,依托二代测序发展起来的伴随诊断,将人类的胃癌治疗史带入了分子时代。同时,基于胃癌患者分子特征的精准分层,为具有极大异质性的胃癌治疗带来了新的契机。此外,循证医学(Evidence-based Medicine,EBM)的出现,为合理有效的治疗胃癌患者提供了坚实的基础和依据。循证医学始于20世纪90年代初,最初的重点是教育临床医生如何理解和使用已发表的文献来优化临床治疗。其对临床医学的贡献在于将临床实践建立在坚实的科学基础上,同时,认识到患者价值观和偏好在临床决策中的关键作用 [2]。而临床研究就是拥有高等级循证医学证据并用于指导临床实践的科学研究。本文将对近几年胃癌临床研究领域有高等级循证医学证据,且有突破性进展的研究进行简要综述。

  • 1 胃癌的手术治疗

  • 虽然近年来,学界在胃癌分子生物学、新药研发及药物治疗方面都取得了颇多进展,但外科手术及内镜下切除仍然是不可或缺的治疗手段。胃癌外科手术研究的热点集中于:讨论淋巴结切除术的最佳范围,以及基于屏幕交互技术的快速数字技术发展,这些技术引导了微创手术的出现,如早期胃癌的内镜黏膜切除术和早期及局部晚期胃癌的腹腔镜和机器人胃切除术。

  • 1.1 腹腔镜手术

  • 1.1.1 早期胃癌的腹腔镜手术

  • 自1994年日本的Kitano教授完成世界上首次报道腹腔镜胃大部切除手术(Laparoscopic Gastrectomy,LG)后[3],基于这种屏幕交互数字技术的微创手术得到快速发展,而腹腔镜手术凭借其超越人眼的精确及放大视野,为手术医生提供了更加精细化解剖的可能。胃癌手术也逐步从“开放和扩大根治手术”向“腔镜下和精准解剖手术”转变; 从“强调生存”向“生存及生活质量并重”转变。

  • 针对早期远端胃癌治疗(非EMR/ESD适应症),腹腔镜下远端胃癌根治术已经是主流手术方式,被《 日本胃癌指南 》 所采纳。日本的JCOG0912(The Japan Clinical Oncology Group) 研究 [4] 纳入了921名肿瘤位于胃下部临床Ⅰ期( T1N0, T1N1或T2N0)的胃癌患者,462名患者入组腹腔镜辅助组(Laparoscopy-assisted Distal Gastrectomy,LADG),459名患者入组开放手术组(Open Distal Gastrectomy,ODG)。研究发现, LADG组的5年无复发生存(Relapse-free Survival,RFS)率为95.1%(95%CI:92.7~96.8),而ODG组为94.0%(95%CI: 91.4~95.9),LADG组非劣于ODG组(HR=0.84,90%CI:0.56~1.27,P=0.007 5)。研究表明,对于位于胃下部的早期胃癌,腹腔镜手术无论是安全性还是在肿瘤学终点方面,都和开放手术类似。这种手术方式可以推荐在有经验的外科医生中开展,也将成为标准的手术方式。

  • 韩国的KLASS01(The Korean Aparoendoscopic Gastrointestinal Surgery Study Group)研究 [5] 纳入了1 416名肿瘤位于胃下部临床Ⅰ期的胃癌患者,其中LADG组705人,ODG组711人。相比于ODG组93.3%的5年生存率,LADG组的5年生存率为94.2%,非劣于ODG组(P=0.64)。两组的5年肿瘤特异性生存率也相似,LADG组为97.1%, ODG组为97.2%(P=0.91)。此外,在并发症方面,LADG组的总并发症发生率显著低于ODG组,分别为LADG组的13.0%对比ODG组的19.9%(P=0.001)。而LADG组伤口相关的并发症发生率明显低于ODG组(3.1%vs.7.7%,P< 0.001)[6],这同样提示了,腹腔镜手术不论是在安全性方面,还是在肿瘤学终点方面都非劣于开放手术,甚至在安全性方面优于开放手术。

  • 中国研究者针对早期胃癌全胃切除术的可行性,也进行了CLASS02(The Chinese Laparoendoscopic Gastrointestinal Surgery Study Group)研究 [7] 分析214例患者的发病率和死亡率,腹腔镜全胃切除术(Laparoscopic Total Gastrectomy, LTG) 组105例,开腹全胃切除术(Open Total Gastrectomy, OTG)组109例。两组患者的总体发病率和死亡率无显著差异(95%CI:-11.8%~9.6%)。LTG组有3名患者(2.9%)出现术中并发症, OTG组有4名患者(3.7%)出现术中并发症(95%CI:-6.5%~4.9%)。此外,LTG组和OTG组的术后总并发症发生率分别为18.1%和17.4%(RD=0.7%,95%CI:-9.6%~11.0%)。LTG组和OTG组之间的死亡率没有显著差异(95%CI:-2.5%~5.2%)。CLASS02研究结果表明,临床Ⅰ期胃癌的LTG安全性与OTG相当。

  • 1.1.2 进展期胃癌的腹腔镜手术

  • 学界对进展期胃癌患者行腹腔镜手术仍然有一定争议。部分学者认为腹腔镜手术增加患者腹腔转移风险,也有学者认为腹腔镜手术进展期胃癌患者和开放手术具有同样的肿瘤学终点。我国CLASS01研究 [8] 是进展期胃癌腹腔镜手术的Ⅲ 期随机对照临床研究(Randomized Controlled Trial, RCT),研究入组了中国14家中心的1 039名患者接受手术,其中519例患者入组腹腔镜组(Laparoscopy Distal Gastrectomy,LDG),520例入组ODG组。研究结果显示:LDG组的3年无病生存率为76.5%,而ODG组为77.8%;3年生存率LDG组为83.1%,ODG组为85.2%(HR=1.19, 90%CI: 0.87~1.64,P=0.28)。同样,3年的复发率两组分别为18.8%和16.5%(HR=1.15,90%CI:0.86~1.54,P=0.35)。此外,在安全性方面 [9],LDG组和ODG组的术后并发症相类似(15.2%vs.12.9%, P=0.285),两组间的死亡率也无统计学差异(0.4%vs.0.0%,P=0.249)。

  • 韩国KLASS02研究[10] 入组1 050名cT2-4胃癌患者,分别纳入腹腔镜手术组(n=524)或开放手术组(n=526)。腹腔镜组与开放手术组相比,不论是在早期(15.7%vs.23.4%,P=0.002 7)或晚期(4.7%vs.9.5%,P=0.003 8)并发症都显著少。腹腔镜组3年无复发生存率为80.3%(95%CI: 76.0%~85.0%),开放组为81.3%(95%CI: 77.0%~85.0%),两组间比较无统计学差异(P=0.726)。腹腔镜远端胃切除术加D2淋巴结切除术在局部晚期胃癌患者无复发生存率方面与开放手术相当。因此腔镜下远端胃切除术加D2淋巴结切除术可能是局部晚期胃癌的一种新的标准治疗方法。

  • 2 胃癌的围术期治疗

  • 围术期化疗增加了根治性切除的机会,同时消灭了潜在的微转移,为术后的药物使用提供了依据,也增加了患者围术期化疗的完成率。依据FLOT4研究 [11] 和RESOLVE研究(ESMO 2019,LBA 42) 结果,围手术期化疗已逐渐成为局部进展期胃癌东西方患者的标准治疗手段。

  • 德国的FLOT4研究入组716例cT2以上或淋巴结阳性的局部可切除的胃及胃食管结合部癌症患者,其中360例患者入组传统的ECF/ECX(表柔比星、顺铂和氟尿嘧啶/卡培他滨)方案,356例入组FLOT(氟尿嘧啶、亚叶酸钙、奥沙利铂和多西紫杉醇)方案组。研究结果提示:相比于ECX/ECF方案,FLOT方案可显著提高总生存期(Overall Survival,OS)及无病生存期(Disease Free Survival,DFS),两组的OS分别为35个月和50个月(HR=0.77,P=0.012),DFS分别为18个月和30个月(HR=0.75,P=0.004)。FLOT方案无论在OS还是DFS方面都明显优于ECF/ECX方案 [11]。此外,在前期发表的数据 [12] 也显示了FOLT方案较ECF/ECX方案有着更好的病理完全缓解(Pathology Complete Response,pCR)率, FOLT方案组为16%(20/128)(95%CI:10~23), ECF/ECX方案组为6%(8/137)(95%CI:3~11), P=0.02。但是值得注意的是,FLOT方案组的3~4级不良反应(Adverse Events,AE)率为52%(67/128),较ECF/ECX组38%(52/137)明显升高,主要的不良反应为白细胞减少症、恶心、感染、疲劳和呕吐。FLOT研究也成为美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)指南中推荐的围术期治疗方案。

  • 中国的RESLOVE研究(ESMO 2019, LBA 42)入组了1 022例患者,其中术后辅助XELOX(卡培他滨、奥沙利铂)方案化疗组345例,术后辅助SOX(替吉奥、奥沙利铂)方案化疗组340例和围术期SOX方案化疗组337例。研究结果显示:围术期SOX方案组3年的无病生存率(62.02%) 明显高于手术辅助XELOX方案组(54.78%),无病生存风险降低21%(HR=0.79,95%CI:0.62~0.99,P=0.045)。首次在亚洲人群中证明围术期化疗的有效性及安全性,SOX方案化疗更加适合亚洲人。

  • 随着靶向治疗药物的研发及应用,给围术期治疗提供了更多的可能。2020年欧洲肿瘤内科学会(European Society for Medical Oncology,ESMO) 报道了PETRARCA研究(ESMO 2020,Mino Oral1 421),研究入组40例FLOT联合曲妥珠单抗和帕妥珠单抗方案患者,41例FLOT方案患者,治疗可切除HER2阳性胃食管结合部腺癌。研究结果显示:FLOT联合Tres/Per组的pCR率35%(14/40)明显高于单纯FLOT组12%(5/41),P=0.02。 RAMSES/FLOT7研究(ESMO 2020,Mino Oral1 424)入组了90例雷莫芦单抗联合FLOT方案化疗和91例FLOT方案化疗的患者,研究结果显示,雷莫芦单抗联合FLOT方案化疗组的R0手术率为97%,而单纯FLOT方案化疗组为83%(P=0.004 9)。雷莫芦单抗组的R0切除率显著高于单纯FLOT化疗组。

  • 以上这些研究都为胃癌的围术期治疗展现出更多的可能性,但是针对何种药物的联合、用药人群的精准筛选及以何种指标来作为OS的替代性研究终点,都是十分重要的临床问题,也是未来研究的热点及方向。

  • 3 胃癌的晚期治疗

  • 晚期胃癌患者约占整个胃癌患者的20%左右(中国胃癌联盟数据),晚期胃癌的治疗多以化疗为主,且有效率在40%左右,无进展生存期(Progression Free Survival,PFS)在5-6个月左右,OS在10-12个月左右 [13]。但随着免疫检查点抑制剂(Immune Checkpoint Inhibitor,ICI)药物的快速发展,将给整个晚期胃癌治疗带来新的变革与契机。越来越多的证据表明在晚期胃癌中程序性细胞死亡受体-1(Program Death 1, PD-1)及其配体(Program Death 1Ligand,PD-L1)可以为胃癌患者带来生存获益。其中,国外的药物有纳武利尤单抗(Nivolumab,Nivo)和帕博利珠单抗(Pembrolizumab,Pembro)等,国内的药物有卡瑞利珠单抗、信迪利单抗、特瑞普利单抗和替雷利珠单抗等。2017年基于Keynote059[14] 和Attraction2研究 [15],美国FDA(Food Drug Administration) 和日本分别批准了Pembro和Nivo用于晚期胃癌的三线治疗,也正式标志着ICI治疗晚期胃癌患者获得了高等级循证医学证据。但是,在随后的Keynote061研究 [16] 向胃癌二线治疗推进,以及Keynote062研究 [17] 向胃癌一线治疗推进的过程中,ICI治疗都未达到预设的主要研究终点,一度让ICI治疗晚期胃癌的应用蒙上了一层阴影。

  • 3.1 晚期一线治疗

  • CheckMate649研究(ESMO 2020,LBA 6)纳入了789例Nivo联合化疗患者,792例单纯化疗患者,治疗晚期胃及胃食管结合部癌。研究结果显示,在PD-L1表达的CPS(Combined Positive Score)≥ 5的人群中, Nivo联合化疗组(n=473)的中位OS相比单纯化疗组(n=482)提高3.3个月,且死亡风险下降29%。这项研究具有划时代意义,也是胃癌一线治疗首次成功的免疫治疗研究,且未来终将改变晚期一线胃癌治疗模式,成为新的标准治疗。

  • SOLAR研究 [18] 入组711例未经治疗的晚期胃及胃食管结合部癌患者,其中TAS-118(S-1+ 亚叶酸钙)联合奥沙利铂组356例,S-1联合顺铂组355例。研究显示,经过中位26个月的随访,TAS118联合奥沙利铂组的OS为16个月(95%CI: 13.8~18.3),而S-1联合顺铂组为15.1个月(95%CI:13.6~16.4)(HR=0.83,95%CI:0.69~0.99, P=0.039)。TAS-118组的严重不良反应约为44%(155/352),与另一组相似46%(159/348)。该研究结果表明TAS-118联合奥沙利铂化疗优于S-1联合顺铂化疗,有望成为亚洲胃癌患者新的一线治疗。

  • 3.2 晚期后线治疗

  • 人类表皮生长因子受体(Human Epidermal Growth Factor Receptor 2,HER2)是胃癌治疗的重要靶点,HER2在胃癌患者中的表达阳性率约为15%[22]。曲妥珠单抗deruxtecan(T-DXd;DS8201) 是抗HER2抗体同可裂解的四肽连接体和细胞毒性拓扑异构酶Ⅰ抑制剂组成的抗体-药物结合物。此药物在乳腺癌的研究中大放异彩。DS8201在胃癌中的一项二期研究 [19] 针对HER2阳性的胃及胃食管结合部腺癌中至少接受过二线治疗的患者,研究入组187例,DS8201组125例,化疗组62例。研究表明DS8201组的客观缓解率(Objective Response Rate,ORR)为51%,远高于化疗组的14%(P< 0.001)。DS8201的OS更长(12.5m vs.8.4m,HR=0.59,95%CI:0.3~0.88,P=0.01), PFS也更好。3~4级不良事件有:中性粒细胞计数下降(DS8201组为51%,化疗组为24%),贫血(38%和23%)和白细胞计数减少(21%和11%); 有12名患者患有DS8201相关的间质性肺病或肺炎(9名患者为1级或2级,3名患者为3级或4级);DS8201组有1例药物相关死亡(因肺炎),化疗组无药物相关死亡。既往一线化疗的OS也只有12个月左右,而DS8201在后线的数据就已经达到了这个水平,不能不为之赞叹。因此, DS8201在胃癌治疗中,值得期待更多更好的数据,以及更多前线及围术期的证据。

  • 另外一项EPOC1706单臂二期研究 [20],研究药物乐伐替尼是血管内皮生长因子(Vascular Endothelial Growth Factor,VEGF)受体和其他受体酪氨酸激酶的多激酶抑制剂,可显著减少肿瘤相关巨噬细胞和增加CD8+T细胞的浸润,可增强PD-1抑制剂的抗肿瘤活性。研究入组29例患者,接受乐伐替尼联合Pembro的治疗,中位随访12.6个月(10.5~14.3)。ORR为69%(20/29)(95%CI: 49~85)。最常见的3级治疗相关不良事件为高血压、蛋白尿和血小板计数下降,分别为11例(38%)、 5例(17%)和2例(7%)。乐伐替尼联合Pembro的治疗体现了良好的安全性和有效性,这也为免疫联合抗血管生成药物治疗胃癌打开了广阔的前景。

  • 4 总结

  • 我国胃癌患者的5年生存率为35.9%,虽然近些年,我国胃癌诊疗水平有了长足的进步,但与韩国(68.9%)和日本(60.3%)仍存在较大差距 [21]。我国的进展期胃癌患者较多,随着药物及基因组学迅速发展,为胃癌的精准治疗提供了机遇,而基于外科手术不论是围术期联合免疫、靶向及化疗的治疗模式,还是晚期的多药联合治疗模式,都将成为胃癌患者全程化管理的重要组成部分。外科治疗需要从既往的追求生存期,转向降低并发症发生率、改善患者的生活质量。而研究方面需加强研究的规范性和统一性,提高治疗水平,建立良好的临床数据库和生物组学数据库,加强交叉学科平台建设,为精准治疗提供理论支撑;同时,也需要加强国际合作,积极参与国际性研究课题,学习国外的先进经验,提高研究质量,扩大国际学术影响力。在此,谨以此文和各位同道互相勉励,为中国胃癌诊疗水平的提高,做一份自己的努力和贡献。

  • 参考文献

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    • [2] DJULBEGOVIC B,GUYATT G H.Progress in evidencebased medicine:a quarter century on[J].Lancet,2017,390(10092):415-423.

    • [3] KITANO S,ISO Y,MORIYAMA M,et al.Laparoscopyassisted billroth I gastrectomy[J].Surg Laparosc Endosc,1994,4(2):146-148.

    • [4] KATAI H,MIZUSAWA J,KATAYAMA H,et al.Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer(JCOG0912):a multicentre,non-inferiority,phase 3 randomised controlled trial[J].Lancet Gastroenterol Hepatol,2020,5(2):142-151.

    • [5] KIM H H,HAN S U,KIM M C,et al.Effect of laparoscopic distal gastrectomy vs open distal gastrectomy on long-term survival among patients with stage I gastric cancer:the KLASS-01 randomized clinical trial[J].JAMA Oncol,2019,5(4):506-513.

    • [6] KIM W,KIM H H,HAN S U,et al.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)[J].Ann Surg,2016,263(1):28-35.

    • [7] LIU F,HUANG C,XU Z,et al.Morbidity and mortality of laparoscopic vs open total gastrectomy for clinical stage I gastric cancer:the class02 multicenter randomized clinical trial[J].JAMA Oncol,2020,6(10):1590-1597.

    • [8] YU J,HUANG C,SUN Y,et al.Eff ect of laparoscopic vs open distal gastrectomy on 3-year disease-free survival in patients with locally advanced gastric cancer:the CLASS-01 randomized clinical trial[J].JAMA,2019,321(20):1983-1992.

    • [9] HU Y,HUANG C,SUN Y,et al.Morbidity and mortality of laparoscopic versus open D2 distal gastrectomy for advanced gastric cancer:a randomized controlled trial[J].J Clin Oncol,2016,34(12):1350-1357.

    • [10] HYUNG W J,YANG H K,PARK Y K,et al.Long-term outcomes of laparoscopic distal gastrectomy for locally advanced gastric cancer:the KLASS-02-RCT randomized clinical trial[J].J Clin Oncol,2020,38(28):3304-3313.

    • [11] AL-BATRAN S E,HOMANN N,PAULIGK C,et al.Perioperative chemotherapy with fluorouracil plus leucovorin,oxaliplatin,and docetaxel versus fl uorouracil or capecitabine plus cisplatin and epirubicin for locally advanced,resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4):a randomised,phase 2/3 trial[J].Lancet,2019,393(10184):1948-1957.

    • [12] AL-BATRAN S E,HOFHEINZ R D,PAULIGK C,et al.Histopathological regression after neoadjuvant docetaxel,oxaliplatin,fl uorouracil,and leucovorin versus epirubicin,cisplatin,and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4-AIO):results from the phase 2 part of a multicentre,open-label,randomised phase 2/3 trial[J].Lancet Oncol,2016,17(12):1697-1708.

    • [13] BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376(9742):687-697.

    • [14] FUCHS C S,DOI T,JANG R W,et al.Safety and effi cacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophagealjunction cancer:phase 2 clinical KEYNOTE-059 trial[J].JAMA Oncol,2018,4(5):e180013.

    • [15] KANG Y K,BOKU N,SATOH T,et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebocontrolled,phase 3 trial[J].Lancet,2017,390(10111):2461-2471.

    • [16] SHITARA K,OZGUROGLU M,BANG Y J,et al.Pembrolizumab versus paclitaxel for previously treated,advanced gastric or gastro-oesophageal junction cancer(KEYNOTE-061):a randomised,open-label,controlled,phase 3 trial[J].Lancet,2018,392(10142):123-133.

    • [17] SHITARA K,VAN CUTSEM E,BANG Y J,et al.Effi cacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line,advanced gastric cancer:the KEYNOTE-062 phase 3 randomized clinical trial[J].JAMA Oncol,2020,6(10):1571-1580.

    • [18] KANG Y K,CHIN K,CHUNG H C,et al.S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as fi rst-line therapy in patients with advanced gastric cancer(SOLAR):a randomised,open-label,phase 3 trial[J].Lancet Oncol,2020,21(8):1045-1056.

    • [19] SHITARA K,BANG Y J,IWASA S,et al.Trastuzumab deruxtecan in previously treated her2-positive gastric cancer[J].N Engl J Med,2020,382(25):2419-2430.

    • [20] KAWAZOE A,FUKUOKA S,NAKAMURA Y,et al.Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting(EPOC1706):an open-label,single-arm,phase 2 trial[J].Lancet Oncol,2020,21(8):1057-1065.

    • [21] ALLEMANI C,MATSUDA T,DI CARLO V,et al.Global surveillance of trends in cancer survival 2000-14(CONCORD-3):analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J].Lancet,2018,391(10125):1023-1075.

    • [22] BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376:687-697.

  • 参考文献

    • [1] CHEN W,ZHENG R,ZHANG S,et al.Cancer incidence and mortality in China in 2013:an analysis based on urbanization level[J].Chin J Cancer Res,2017,29(1):1-10.

    • [2] DJULBEGOVIC B,GUYATT G H.Progress in evidencebased medicine:a quarter century on[J].Lancet,2017,390(10092):415-423.

    • [3] KITANO S,ISO Y,MORIYAMA M,et al.Laparoscopyassisted billroth I gastrectomy[J].Surg Laparosc Endosc,1994,4(2):146-148.

    • [4] KATAI H,MIZUSAWA J,KATAYAMA H,et al.Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer(JCOG0912):a multicentre,non-inferiority,phase 3 randomised controlled trial[J].Lancet Gastroenterol Hepatol,2020,5(2):142-151.

    • [5] KIM H H,HAN S U,KIM M C,et al.Effect of laparoscopic distal gastrectomy vs open distal gastrectomy on long-term survival among patients with stage I gastric cancer:the KLASS-01 randomized clinical trial[J].JAMA Oncol,2019,5(4):506-513.

    • [6] KIM W,KIM H H,HAN S U,et al.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)[J].Ann Surg,2016,263(1):28-35.

    • [7] LIU F,HUANG C,XU Z,et al.Morbidity and mortality of laparoscopic vs open total gastrectomy for clinical stage I gastric cancer:the class02 multicenter randomized clinical trial[J].JAMA Oncol,2020,6(10):1590-1597.

    • [8] YU J,HUANG C,SUN Y,et al.Eff ect of laparoscopic vs open distal gastrectomy on 3-year disease-free survival in patients with locally advanced gastric cancer:the CLASS-01 randomized clinical trial[J].JAMA,2019,321(20):1983-1992.

    • [9] HU Y,HUANG C,SUN Y,et al.Morbidity and mortality of laparoscopic versus open D2 distal gastrectomy for advanced gastric cancer:a randomized controlled trial[J].J Clin Oncol,2016,34(12):1350-1357.

    • [10] HYUNG W J,YANG H K,PARK Y K,et al.Long-term outcomes of laparoscopic distal gastrectomy for locally advanced gastric cancer:the KLASS-02-RCT randomized clinical trial[J].J Clin Oncol,2020,38(28):3304-3313.

    • [11] AL-BATRAN S E,HOMANN N,PAULIGK C,et al.Perioperative chemotherapy with fluorouracil plus leucovorin,oxaliplatin,and docetaxel versus fl uorouracil or capecitabine plus cisplatin and epirubicin for locally advanced,resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4):a randomised,phase 2/3 trial[J].Lancet,2019,393(10184):1948-1957.

    • [12] AL-BATRAN S E,HOFHEINZ R D,PAULIGK C,et al.Histopathological regression after neoadjuvant docetaxel,oxaliplatin,fl uorouracil,and leucovorin versus epirubicin,cisplatin,and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma(FLOT4-AIO):results from the phase 2 part of a multicentre,open-label,randomised phase 2/3 trial[J].Lancet Oncol,2016,17(12):1697-1708.

    • [13] BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376(9742):687-697.

    • [14] FUCHS C S,DOI T,JANG R W,et al.Safety and effi cacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophagealjunction cancer:phase 2 clinical KEYNOTE-059 trial[J].JAMA Oncol,2018,4(5):e180013.

    • [15] KANG Y K,BOKU N,SATOH T,et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebocontrolled,phase 3 trial[J].Lancet,2017,390(10111):2461-2471.

    • [16] SHITARA K,OZGUROGLU M,BANG Y J,et al.Pembrolizumab versus paclitaxel for previously treated,advanced gastric or gastro-oesophageal junction cancer(KEYNOTE-061):a randomised,open-label,controlled,phase 3 trial[J].Lancet,2018,392(10142):123-133.

    • [17] SHITARA K,VAN CUTSEM E,BANG Y J,et al.Effi cacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line,advanced gastric cancer:the KEYNOTE-062 phase 3 randomized clinical trial[J].JAMA Oncol,2020,6(10):1571-1580.

    • [18] KANG Y K,CHIN K,CHUNG H C,et al.S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as fi rst-line therapy in patients with advanced gastric cancer(SOLAR):a randomised,open-label,phase 3 trial[J].Lancet Oncol,2020,21(8):1045-1056.

    • [19] SHITARA K,BANG Y J,IWASA S,et al.Trastuzumab deruxtecan in previously treated her2-positive gastric cancer[J].N Engl J Med,2020,382(25):2419-2430.

    • [20] KAWAZOE A,FUKUOKA S,NAKAMURA Y,et al.Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting(EPOC1706):an open-label,single-arm,phase 2 trial[J].Lancet Oncol,2020,21(8):1057-1065.

    • [21] ALLEMANI C,MATSUDA T,DI CARLO V,et al.Global surveillance of trends in cancer survival 2000-14(CONCORD-3):analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J].Lancet,2018,391(10125):1023-1075.

    • [22] BANG Y J,VAN CUTSEM E,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[J].Lancet,2010,376:687-697.

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