晚期胃癌转化治疗的发展现状与研究前景

doi:10.16139/j.1007-9610.2023.01.03

摘要/Abstract

摘要：

晚期胃癌的治疗一直是胃癌治疗中的难点。Ⅳ期胃癌由于存在转移灶，往往难以达到根治性切除。转化治疗是指通过化疗、靶向治疗、免疫治疗等非外科手段，使肿瘤退缩甚至部分局部病灶消失，从而使得初始难以行根治性手术的病人获得R0切除机会。目前晚期胃癌的治疗仍以姑息手术和对症治疗为主，晚期胃癌的转化治疗尚未形成共识。评价胃癌转化治疗效果的主要指标是转化治疗后R0切除率、疾病控制率以及客观缓解率等实体瘤的疗效评价标准(response evaluation criteria in solid tumor, RECIST)。不同治疗手段和方案的疗效各异。转化治疗的最终目的是争取R0手术机会，故转化治疗后手术的合理实施也是关键问题。Yoshida提出的四分类法是目前最为普遍接受的手术决策依据。目前晚期胃癌的转化治疗仍困难重重，缺乏高质量研究。深入研究肿瘤微环境和开发新的治疗方法或许是今后研究的大方向。

关键词: 晚期胃癌, 转化治疗, 肿瘤微环境

Abstract:

The treatment of far-advanced gastric cancers has always been challenging. Due to the presence of metastases, stage Ⅳ gastric cancers are often difficult to achieve radical resection. Conversion therapy refers to non-surgical me-thods such as chemotherapy, targeted therapy, and immunotherapy to make the tumor shrink or even disappear in some areas, so that the patients who are unresectable originally can obtain the opportunity of R0 resection. At present, palliative surgery and symptomatic treatment are still the paramount methods for far-advanced gastric cancers, and no consensus has been reached on conversion therapy for gastric cancer. The main indicators for evaluating the effectiveness of conversion therapy for gastric cancer include R0 resection rate after conversion therapy, disease control rate and objective response rate of the response evaluation criteria in solid tumor (RECIST). The different treatment and schemes have different effects. The ultimate goal of conversion therapy is to strive for opportunity of R0 resection, so the rational implementation of surgery after conversion therapy is also a key issue. The four classifications proposed by Yoshida are the most commonly accepted basis for surgical decision. At present, the conversion therapy for far-advanced gastric cancer is still challenging with the lack of high-quality research. In-depth study of the tumor microenvironment and the development of new therapeutic approaches may be the major research direction in future.

Key words: Far-advanced gastric cancer, Conversion therapy, Tumor microenvironment

中图分类号:

R735.2

卢一鸣, 熊建平, 田艳涛. 晚期胃癌转化治疗的发展现状与研究前景[J]. 外科理论与实践, 2023, 28(01): 17-23.

LU Yiming, XIONG Jianping, TIAN Yantao. Current status and prospect of conversion therapy for far-advanced gastric cancer[J]. Journal of Surgery Concepts & Practice, 2023, 28(01): 17-23.

参考文献 50

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.v71.3 URL
[2]	MARX V. Tracking metastasis and tricking cancer[J]. Nature, 2013, 494(7435):133-136. doi: 10.1038/494131a
[3]	QIU M, ZHOU Y, ZHANG X, et al. Lauren classification combined with HER2 status is a better prognostic factor in Chinese gastric cancer patients[J]. BMC Cancer, 2014, 14:823. doi: 10.1186/1471-2407-14-823 pmid: 25380654
[4]	Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition)[J]. Gastric Cancer, 2023, 26(1):1-25. doi: 10.1007/s10120-022-01331-8
[5]	FUJITANI K, YANG H K, MIZUSAWA J, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial[J]. Lancet Oncol, 2016, 17(3):309-318. doi: 10.1016/S1470-2045(15)00553-7 URL
[6]	RUDLOFF U, LANGAN R C, MULLINAX J E, et al. Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial[J]. J Surg Oncol, 2014, 110(3):275-284. doi: 10.1002/jso.23633 pmid: 25042700
[7]	NAKAJIMA T, OTA K, ISHIHARA S, et al. Combined intensive chemotherapy and radical surgery for incurable gastric cancer[J]. Ann Surg Oncol, 1997, 4(3):203-208. pmid: 9142380
[8]	CASCINU S, SCARTOZZI M, LABIANCA R, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)[J]. Br J Cancer, 2004, 90(8):1521-1525. doi: 10.1038/sj.bjc.6601752
[9]	OKANO K, MAEBA T, ISHIMURA K, et al. Hepatic resection for metastatic tumors from gastric cancer[J]. Ann Surg, 2002, 235(1):86-91. doi: 10.1097/00000658-200201000-00011 pmid: 11753046
[10]	AL-BATRAN S E, HOMANN N, PAULIGK C, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial[J]. JAMA Oncol, 2017, 3(9):1237-1244. doi: 10.1001/jamaoncol.2017.0515 URL
[11]	SATO Y, OHNUMA H, NOBUOKA T, et al. Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: a multi-institutional retrospective study[J]. Gastric Cancer, 2017, 20(3):517-526. doi: 10.1007/s10120-016-0633-1 pmid: 27553665
[12]	YAMAGUCHI K, YOSHIDA K, TANAHASHI T, et al. The long-term survival of stage Ⅳ gastric cancer patients with conversion therapy[J]. Gastric Cancer, 2018, 21(2):315-323. doi: 10.1007/s10120-017-0738-1
[13]	SYM S J, CHANG H M, RYU M H, et al. Neoadjuvant docetaxel, capecitabine and cisplatin (DXP) in patients with unresectable locally advanced or metastatic gastric cancer[J]. Ann Surg Oncol, 2010, 17(4):1024-1032. doi: 10.1245/s10434-009-0838-1 pmid: 19941081
[14]	张维汉, 胡建昆. 胃癌腹膜转移诊治现状[J]. 中华胃肠外科杂志, 2021, 24(3):204-207.
	ZHANG W H, HU J K. Current status of diagnosis and treatment of gastric cancer peritoneal metastasis[J]. Chin J Gastrointest Surg, 2021, 24(3):204-207.
[15]	SUZUKI T, TANABE K, TAOMOTO J, et al. Preliminary trial of adjuvant surgery for advanced gastric cancer[J]. Oncol Lett, 2010, 1(4):743-747. pmid: 22966373
[16]	ISHIGAMI H, YAMAGUCHI H, YAMASHITA H, et al. Surgery after intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology findings[J]. Gastric Cancer, 20(Suppl 1):128-134. doi: 10.1007/s10120-016-0684-3
[17]	ISHIGAMI H, FUJIWARA Y, FUKUSHIMA R, et al. Phase Ⅲ trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial[J]. J Clin Oncol, 2018, 36(19):1922-1929. doi: 10.1200/JCO.2018.77.8613 URL
[18]	Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma[J]. Nature, 2014, 513(7517):202-209. doi: 10.1038/nature13480
[19]	VAN CUTSEM E, BANG Y J, FENG-YI F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer[J]. Gastric Cancer, 2015, 18(3):476-484. doi: 10.1007/s10120-014-0402-y pmid: 25038874
[20]	Cancer Genome Atlas Research Network, et al. Analysis Wor-king Group: Asan University, BC Cancer Agency, Integrated genomic characterization of oesophageal carcinoma[J]. Nature, 2017, 541(7636):169-175. doi: 10.1038/nature20805
[21]	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. doi: 10.1016/S0140-6736(10)61121-X URL
[22]	CATENACCI D V T, KANG Y K, PARK H, et al. Margetuximab plus pembrolizumab in patients with pre-viously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial[J]. Lancet Oncol, 2020, 21(8):1066-1076. doi: 10.1016/S1470-2045(20)30326-0 URL
[23]	PENG Z, LIU T, WEI J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase Ⅱ study[J]. Cancer Commun (Lond), 2021, 41(11):1173-1182.
[24]	CHENG X D, XU Z Y, DU Y, et al. Phase Ⅱ study of conversion therapy using S1/paclitaxel chemotherapy plus apatinib in unresectable gastric cancer(Ahead-G325 trial)[J]. J Clin Oncol, 2017, 35(4_suppl):53-53.
[25]	YE Z, ZENG Y, WEI S, et al. Short-term survival and safety of apatinib combined with oxaliplatin and S-1 in the conversion therapy of unresectable gastric cancer[J]. BMC Cancer, 2021, 21(1):702. doi: 10.1186/s12885-021-08459-3 pmid: 34126957
[26]	JANJIGIAN Y Y, MARON S B, CHATILA W K, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial[J]. Lancet Oncol, 2020; 21(6):821-831. doi: S1470-2045(20)30169-8 pmid: 32437664
[27]	JANJIGIAN Y Y, KAWAZOE A, YAÑEZ P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer[J]. Nature, 2021, 600(7890):727-730. doi: 10.1038/s41586-021-04161-3
[28]	APETOH L, GHIRINGHELLI F, TESNIERE A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy[J]. Nat Med, 2007, 13(9):1050-1059. doi: 10.1038/nm1622 pmid: 17704786
[29]	CHAGANTY B K R, QIU S, GEST A, et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion[J]. Cancer Lett, 2018, 430:47-56. doi: S0304-3835(18)30328-8 pmid: 29746929
[30]	VARADAN V, GILMORE H, MISKIMEN K L, et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperativetrastuzumab and chemotherapy in HER2-positive early breast cancer[J]. Clin Cancer Res, 2016, 22(13):3249-3259. doi: 10.1158/1078-0432.CCR-15-2021 pmid: 26842237
[31]	TRIULZI T, REGONDI V, DE CECCO L, et al. Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit[J]. Br J Cancer, 2018, 119(12):1487-1494. doi: 10.1038/s41416-018-0318-0
[32]	STAGG J, LOI S, DIVISEKERA U, et al. Anti-ErbB-2 mAb therapy requires type Ⅰ and Ⅱ interferons and sy-nergizes with anti-PD-1 or anti-CD137 mAb therapy[J]. Proc Natl Acad Sci U S A, 2011, 108(17):7142-7147. doi: 10.1073/pnas.1016569108 URL
[33]	CHEN L T, SATOH T, RYU M H, et al. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data[J]. Gastric Cancer, 2020, 23(3):510-519. doi: 10.1007/s10120-019-01034-7
[34]	KANG Y K, CHEN L T, RYU M H, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2022, 23(2):234-247. doi: 10.1016/S1470-2045(21)00692-6 URL
[35]	JANJIGIAN Y Y, SHITARA K, MOEHLER M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial[J]. Lancet, 2021, 398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2 URL
[36]	STEIN A, PASCHOLD L, TINTELNOT J, et al. Efficacy of ipilimumab vs. FOLFOX in combination with ni-volumab and trastuzumab in patients with previously untreated ERBB2-positive esophagogastric adenocarcinoma: the aio intega randomized clinical trial[J]. JAMA Oncol, 2022, 8(8):1150-1158.
[37]	SU Z R, KANG M, SHU K S, et al. S-1 combined with apatinib and trans-arterial chemotherapy and embolization for conversion therapy of unresectable locally advanced gastric cancer[J]. J Surg Res, 2022, 270:162-168. doi: 10.1016/j.jss.2021.09.012 URL
[38]	LIU S F, LU C R, CHENG H D, et al. Comparison of therapeutic efficacy between gastrectomy with transarterial chemoembolization plus systemic chemotherapy and systemic chemotherapy alone in gastric cancer with synchronous liver metastasis[J]. Chin Med J (Engl), 2015, 128(16):2194-2201.
[39]	YOSHIDA K, YAMAGUCHI K, OKUMURA N, et al. Is conversion therapy possible in stage Ⅳ gastric cancer: the proposal of new biological categories of classification[J]. Gastric Cancer, 2016, 19(2):329-338. doi: 10.1007/s10120-015-0575-z URL
[40]	HAN D S, SUH Y S, KONG S H, et al. Outcomes of surgery aiming at curative resection in good responder to induction chemotherapy for gastric cancer with distant metastases[J]. J Surg Oncol, 2013, 107(5):511-516. doi: 10.1002/jso.23284 URL
[41]	YAMAGUCHI K, YOSHIDA K, TANAKA Y, et al. Conversion therapy for stage Ⅳ gastric cancer—the present and future[J]. Transl Gastroenterol Hepatol, 2016, 1:50. doi: 10.21037/tgh URL
[42]	KERÄNEN I, KYLÄNPÄÄ L, UDD M, et al. Gastric outlet obstruction in gastric cancer: a comparison of three palliative methods[J]. J Surg Oncol, 2013, 108(8):537-541. doi: 10.1002/jso.23442 pmid: 24590674
[43]	JEURNINK S M, STEYERBERG E W, VAN HOOFT J E, et al. Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction (SUSTENT study): a multicenter randomized trial[J]. Gastrointest Endosc, 2010, 71(3):490-499. doi: 10.1016/j.gie.2009.09.042 pmid: 20003966
[44]	PAVLIDIS T E, PAVLIDIS E T. Role of stenting in the palliation of gastroesophageal junction cancer: a brief review[J]. World J Gastrointest Surg, 2014, 6(3):38-41. doi: 10.4240/wjgs.v6.i3.38 pmid: 24672648
[45]	刘昊, 徐泉, 马福海, 等. 全腹腔镜胃部分离断后胃肠吻合术治疗胃癌合并幽门梗阻的临床效果[J]. 中华肿瘤杂志, 2020, 42(6):445-448.
	LIU H, XU Q, MA F, et al. The clinical value of totally laparoscopic stomach-partitioning gastrojejunostomy for malignant gastric outlet obstruction[J]. Chin J Oncol, 2020, 42(06):445-448.
[46]	SPANO D, ZOLLO M. Tumor microenvironment: a main actor in the metastasis process[J]. Clin Exp Metastasis, 2012, 29(4):381-395. doi: 10.1007/s10585-012-9457-5 URL
[47]	SUN K, XU R, MA F, et al. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory[J]. Nat Commun, 2022, 13(1):4943. doi: 10.1038/s41467-022-32627-z pmid: 35999201
[48]	CHEN D, LIU Z, LIU W, et al. Predicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram[J]. Nat Commun, 2021, 12(1):179. doi: 10.1038/s41467-020-20429-0 pmid: 33420057
[49]	ZHU D, ZHANG T, LI Y, et al. Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-Ⅰ photodynamic therapy[J]. Biomaterials, 2022, 283:121462. doi: 10.1016/j.biomaterials.2022.121462 URL
[50]	ZHANG B, WU Q, LI B, et al. m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer[J]. Mol Cancer, 2020, 19(1):53. doi: 10.1186/s12943-020-01170-0