Current trends in gastric cancer treatment in Europe

Abstract

Gastric cancer is one of the major causes of cancer-related deaths, despite the gradual decrease of its incidence in the West. Minimally invasive procedures, such as endoscopic resection and laparoscopic gastrectomy, have been successfully introduced in European high-volume centres, in the treatment of early gastric cancer. Regarding advanced, localized gastric cancer a number of prospective trials have been completed in search of better therapeutic options, aiming to optimize the efficacy vs. adverse effect ratio. From the results of these prospective randomized trials, the therapeutic strategy has in the last decades shifted emphasis from adjuvant therapy to neoadjuvant or perioperative chemotherapy, in curatively intended treatment. Moreover, recent studies have shown promising results in the use of molecular targeted agents, both in perioperative and palliative settings. The introduction of molecularly targeted therapy will enable a personalized approach based on each patient’s and tumor’s characteristics, maximizing the benefits from chemotherapy. The present review article focuses on recent therapeutic trends, as well as future perspectives, of surgical and oncological gastric cancer treatment in the Western setting, mainly based on landmark clinical trials.


Keywords

Gastric cancer / surgery / neoadjuvant / adjuvant / perioperative / chemotherapy / Western

References

[1] Tada M,Matsuo N,Yamaguchi K.Mucosectomy for gastric cancer: current status in Japan.J Gastroenterol Hepatol2000;15 Suppl:D98-102

[2] Gotoda T,Kusano C,Oda I.Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria.Br J Surg2010;97:868-71

[3] Memon MA,Yunus RM,Memon B.Meta-analysis of laparoscopic and open distal gastrectomy for gastric carcinoma.Surg Endosc2008;22:1781-9

[4] Haverkamp L,van der Sluis PC,Ruurda JP.Laparoscopic total gastrectomy versus open total gastrectomy for cancer: a systematic review and meta-analysis.Surg Endosc2013;27:1509-20

[5] Dikken JL,Allum WH,Jensen LS,Coupland VH,Lemmens VE,van der Geest LG,Cats A.Differences in outcomes of oesophageal and gastric cancer surgery across Europe.Br J Surg2013;100:83-94

[6] Choi AH,Chao J.Perioperative chemotherapy for resectable gastric cancer: MAGIC and beyond.World J Gastroenterol2015;21:7343-8 PMCID:PMC4481429

[7] Marano L,Patriti A,Falco G,De Luca R,Martinotti M,Marrelli D,Roviello F.Surgical management of advanced gastric cancer: an evolving issue.Eur J Surg Oncol2016;42:18-27

[8] Merrett ND.Multimodality treatment of potentially curative gastric cancer: geographical variations and future prospects.World J Gastroenterol2014;20:12892-9 PMCID:PMC4177471

[9] Samalin E.Neoadjuvant therapy for gastroesophageal adenocarcinoma.World J Clin Oncol2016;7:284-92 PMCID:PMC4896896

[10] Foo M.Adjuvant therapy for gastric cancer: current and future directions.World J Gastroenterol2014;20:13718-27 PMCID:PMC4194555

[11] Bang YJ,Feyereislova A,Shen L,Lordick F,Omuro Y,Aprile G,Hill J,Rüschoff J.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, randomized controlled trial.Lancet2010;376:687-97

[12] Ferlay J,Lortet-Tieulent J,Coebergh JW,Forman D.Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer2013;49:1374-403

[13] Japanese Gastric Cancer Association.Japanese gastric cancer treatment guidelines 2014 (ver.4)..Gastric Cancer2017;20:1-19 PMCID:PMC5215069

[14] Japanese Gastric Cancer Association.Japanese classification of gastric carcinoma: 3rd English edition.Gastric Cancer2011;14:101-12

[15] Waddell T,Allum W,Cervantes A.Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up.Eur J Surg Oncol2014;40:584-91

[16] World Health Organization. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide 2012

[17] Karimi P,Anandasabapathy S,Kamangar F.Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomark Prev2014;23:700-13 PMCID:PMC4019373

[18] Pimentel-Nunes P,Ponchon T,Vieth M,Amato A,Bhandari P,Conio M,Langner C,Messmann H,Neuhaus H,Rugge M,Robaszkiewicz M,Kashin S,Hassan C.Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.Endoscopy2015;47:829-54

[19] Ono H,Fujishiro M,Nimura S,Iishi H,Ajioka Y,Matsui T.Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer.Dig Endosc2016;28:3-15

[20] Probst A,Schaller T,Ebigbo A.Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?.Endoscopy2017;49:855-65

[21] Ahn JY,Choi KD,Kim MY,Choi KS,Song HJ,Kim JH.Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications.Gastrointest Endosc2011;74:485-93

[22] Park CH,Park JC,Lee SK,Lee H.Long-term outcome of early gastric cancer after endoscopic submucosal dissection: expanded indication is comparable to absolute indication.Dig Liver Dis2013;45:651-6

[23] Hotta K,Akamatsu T,Hasebe O,Kojima E,Miyabayashi H.A comparison of outcomes of endoscopic submucosal dissection (ESD) for early gastric neoplasms between high-volume and low-volume centers: multi-center retrospective questionnaire study conducted by the Nagano ESD Study Group.Intern Med2010;49:253-9

[24] Oda I,Tada M,Tanabe S,Doi T,Fujisaki J,Hamada T,Gotoda T.A multicenter retrospective study of endoscopic resection for early gastric cancer.Gastric Cancer2006;9:262-70

[25] van der Wielen N,Cuesta MA,van der Peet DL.Short-term outcomes in minimally invasive versus open gastrectomy: the differences between East and West.A systematic review of the literature. Gastric Cancer2018;21:19-30 PMCID:PMC5741797

[26] Park S,Lee SS,Yu W.Serial comparisons of quality of life after distal subtotal or total gastrectomy: what are the rational approaches for quality of life management?.J Gastric Cancer2014;14:32-8 PMCID:PMC3996247

[27] Davies J,Sue-Ling H,May J,Miller G.Total or subtotal gastrectomy for gastric carcinoma? A study of quality of life.World J Surg1998;22:1048-55

[28] Hiki N,Kubota T.Function-preserving gastrectomy for early gastric cancer.Ann Surg Oncol2013;20:2683-92

[29] Kosuga T,Nunobe S,Honda M,Sano T.Feasibility and nutritional impact of laparoscopy-assisted subtotal gastrectomy for early gastric cancer in the upper stomach.Ann Surg Oncol2014;21:2028-35

[30] Jiang X,Nunobe S,Kumagai K,Yamaguchi T.Laparoscopy-assisted subtotal gastrectomy with very small remnant stomach: a novel surgical procedure for selected early gastric cancer in the upper stomach.Gastric Cancer2011;14:194-9

[31] Postlewait LM,Kooby DA,Weber SM,Fields RC,Votanopoulos KI,Ejaz A,Worhunsky DJ,Swords D,Cho CS,Cardona K,Maithel SK.The importance of the proximal resection margin distance for proximal gastric adenocarcinoma: a multi-institutional study of the US Gastric Cancer Collaborative.J Surg Oncol2015;112:203-7

[32] Numata N,Tanaka S,Sanomura Y,Arihiro K,Chayama K.Risk factors and management of positive horizontal margin in early gastric cancer resected by en bloc endoscopic submucosal dissection.Gastric Cancer2015;18:332-8

[33] Hartgrink HH,Putter H,Klein Kranenbarg E,Welvaart K,Meijer S,van Elk PJ,Gouma DJ,Taat CW,von Meyenfeldt MF,Sasako M.Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial.J Clin Oncol2004;22:2069-77

[34] Songun I,Kranenbarg EM,van de Velde CJ.Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial.Lancet Oncol2010;11:439-49

[35] Kung CH,Nilsson M,Kumagai K,Tsai JA.Postoperative pancreatic fistula formation according to ISGPF criteria after D2 gastrectomy in Western patients.Gastric Cancer2014;17:571-7

[36] Uyama I,Matsui H,Komori Y.Laparoscopic D2 lymph node dissection for advanced gastric cancer located in the middle or lower third portion of the stomach.Gastric Cancer2000;3:50-5

[37] Kitano S,Fujii K,Inomata M.A randomized controlled trial comparing open vs laparoscopy-assisted distal gastrectomy for the treatment of early gastric cancer: an interim report.Surgery2002;131:S306-11

[38] Lee JH,Lee JH.A prospective randomized study comparing open vs laparoscopy-assisted distal gastrectomy in early gastric cancer: early results.Surg Endosc2005;19:168-73

[39] Kim HH,Cho GS,Han SU,Ryu SW,Song KY.Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report--a phase III multicenter, prospective, randomized trial (KLASS Trial).Ann Surg2010;251:417-20

[40] Zou ZH,Mou TY,Yu J,Chen H,An SL.Laparoscopic vs open D2 gastrec- tomy for locally advanced gastric cancer: a meta-analysis.World J Gastroenterol2014;20:16750-64 PMCID:PMC4248223

[41] Macdonald JS,Benedetti J,Estes NC,Haller DG,Gunderson LL,Martenson JA.Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.N Engl J Med2001;345:725-30

[42] Cunningham D,Stenning SP,Van de Velde CJ,Scarffe JH,Falk SJ,Smith DB,Verma M,Chua YJ.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med2006;355:11-20

[43] Al-Batran SE,Pauligk C,Haag GM,Meiler J,Lorenzen S,Probst S,Egger M,Caca K,Martens UM,Fischbach W,Clemens M,Zirlik K,Schmiegel W,Heike M,Schuler M,Königsrainer A,Schirmacher P,Reichart A,Sievert M,Mönig S.Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, 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.Lancet Oncol2016;17:1697-708

[44] Sakuramoto S,Yamaguchi T,Fujii M,Furukawa H,Ohashi Y,Higashino M,Kurita A.Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.N Engl J Med2007;357:1810-20

[45] Bang YJ,Yang HK,Park YK,Lee KW,Noh SI,Mok YJ,Ji J,Button P,Noh SH.Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.Lancet2012;379:315-21

[46] Lee J,Kim S,Park JO,Lim HY,Sohn TS,Bae JM,Sohn I,Park CK,Kang WK.Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial.J Clin Oncol2012;30:268-73

[47] Dikken JL,Maurits Swellengrebel HA,Putter H,Boot H,van de Velde CJ,Cats A.Neoadjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS).BMC Cancer2011;11:329 PMCID:PMC3175221

[48] Verheij M,Cats A,Aaronson NK.A multicenter randomized phase III trial of neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy in resectable gastric cancer: First results from the CRITICS study.J Clin Oncol2016;34 suppl 15:abstr4000

[49] Phase III Randomized Trial of Adjuvant Chemotherapy With S-1 vs S-1/Oxaliplatin ± Radiotherapy for Completely Resected Gastric Adenocarcinoma: The ARTIST II Trial (ARTIST-II). ClinicalTrials.gov Identifier: NCT01761461

[50] Kumagai K,Tsai JA,Klevebro F,Ye W,Nilsson M.Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers.Br J Surg2014;101:321-38

[51] Cunningham D,Rao S,Nicolson M,Middleton G,Oates J.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med2008;358:36-46

[52] Ryu MH.ML17032 trial: capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in advanced gastric cancer.Expert Rev Anticancer Ther2009;9:1745-51

[53] Okines AF,McCloud P,Cunningham D.Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer.Ann Oncol2009;20:1529-34

[54] Al-Batran SE,Schmalenberg H,Haag GM,Schmiegel WH,Probst S,Thuss-Patience P,Trojan J,Pauligk C,Jaeger E,Schuler M.Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial.J Clin Oncol2017;35 suppl:abstr 4004

[55] Stahl M,Stuschke M,Meyer HJ,Langer P,Bitzer M,Budach W.Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction.J Clin Oncol2009;27:851-6

[56] Chirieac LR,Ajani JA,Correa AM,Roth JA,Hamilton SR.Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation.Cancer2005;103:1347-55

[57] Leong T,Haustermans K,Gebski V,Zalcberg J,Findlay M,Verghis J,Kron T,Murray WK,Swallow C,Simes J.TOPGEAR: a randomized, phase III trial of perioperative ECF chemotherapy with or without preoperative chemoradiation for resectable gastric cancer: interim results from an international, intergroup trial of the AGITG, TROG, EORTC and CCTG.Ann Surg Oncol2017;24:2252-8

[58] European Organisation for Research and Treatment of Cancer - EORTC.Integration of trastuzumab, with or without pertuzumab, into perioperative chemotherapy of HER2- positive stomach cancer: the INNOVATION trial (EORTC-1203-GITCG).Oncol Res Treat2016;39:153-4; discussion 155

[59] Cunningham D. A randomised phase II/III trial of peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma and a feasibility study evaluating lapatinib in HER-2 positive oesophagogastric adenocarcinomas and (in selected centres) MRI and PET/CT sub-studies. Available from: http://ichgcp.net/clinical-trials-registry/NCT00450203. [Last accessed on 6 Jul 2018]

[60] Wagner AD,Haerting J,Grothey A.Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data.J Clin Oncol2006;24:2903-9

[61] Dank M,Barone C,Yalcin S,Wenczl M,Cisar L,Bugat R.Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.Ann Oncol2008;19:1450-7

[62] Moehler M,Geissler M,Ebert MP,Flieger D,Galle PR.A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction.Ann Oncol2010;21:71-7

[63] Kang YK,Shin DB,Xiong J,Lichinitser M,Khasanov R,Philco-Salas M,Santamaria J,McCloud PI.Capecitabine/ cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.Ann Oncol2009;20:666-73

[64] Wagner AD,Grothe W,Grothey A,Fleig WE.Chemotherapy for advanced gastric cancer.Cochrane Database Syst Rev2010;(3):CD004064

[65] Van Cutsem E,Tjulandin S,Constenla M,Rodrigues A,Chao Y,Risse ML.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 Oncol2006;24:4991-7

[66] Lorenzen S,Homann N,Jäger E.Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with (FLOT) or without (FLO) docetaxel in elderly patients with locally advanced esophagogastric cancer.Br J Cancer2013;108:519-26 PMCID:PMC3593547

[67] Kang JH,Lim do H,Oh SY,Hwang IG,Nam E,Lee J,Park YS,Kang WK.Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.J Clin Oncol2012;30:1513-8

[68] Hironaka S,Yasui H,Tsuda M,Sugimoto N,Tokunaga S,Esaki T,Fujitani K,Ura T,Morita S,Boku N.Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial.J Clin Oncol2013;31:4438-44

[69] Thuss-Patience PC,Bichev D,Hinke A,Dogan Y,Schumacher G.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 Cancer2011;47:2306-14

[70] Ford HE,Bridgewater JA,Coxon FY,Mansoor W,Madhusudan S,Swinson D,Chau I,Kareclas P,Blazeby JM.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial.Lancet Oncol2014;15:78-86

[71] Tey J,Shakespeare TP,Lu JJ,Wong LC,Zhu M.The role of palliative radiation therapy in symptomatic locally advanced gastric cancer.Int J Radiat Oncol Biol Phys2007;67:385-8

[72] Tey J,Koh WY,Choo BA,Vellayappan B,Tham IW.Palliative radiotherapy for gastric cancer: a systematic review and meta-analysis.Oncotarget2017;8:25797-805 PMCID:PMC5421969

[73] Wilke H,Van Cutsem E,Bodoky G,Hironaka S,Lipatov O,Cunningham D,Komatsu Y,Emig M,Ferry D,Schwartz JD.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 Oncol2014;15:1224-35

[74] Fuchs CS,Yong CJ,Passalacqua R,Safran H,Aprile G,Melichar B,Topuzov E,Chau I,Sivanandan C,Koshiji M,Liepa AM,Schwartz JD.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet2014;383:31-9

[75] Kang YK,Satoh T,Chao Y,Chung HC,Muro K,Yeh KH,Oh SC,Tamura T,Hamamoto Y,Chin K,Minashi K,Tsuda M.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, placebo-controlled, phase 3 trial.Lancet2017;390:2461-71

[76] Kang YK,Tassone P,Yu R,Garg A.A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer.Br J Cancer2014;111:660-6 PMCID:PMC4134501

[77] Ohtsu A,Van Cutsem E,Sawaki A,Lim HY,Wu J,Starnawski M.Bevacizumab in combination with chemotherapy as first- line therapy in advanced gastric cancer: a randomized, double- blind, placebo-controlled phase III study.J Clin Oncol2011;29:3968-76

[78] Lordick F,Chung HC,Oh SC,Kurteva G,Moiseyenko VM,Park JO,Celik I,Melezínková H.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol2013;14:490-9

[79] Waddell T,Cunningham D,Okines AF,Wotherspoon A,Middleton G,Ferry D,Crosby T,Smith D,Iveson T,Slater S,Barbachano Y.Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.Lancet Oncol2013;14:481-9

[80] Thuss-Patience PC,Ohtsu A,Ajani JA,Mansoor W,Bodoky G,Phillips GDL,Harle-Yge ML,Kang YK.Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.Lancet Oncol2017;18:640-53

[81] The Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014;513:202-9 PMCID:PMC4170219

[82] Kakiuchi M,Ueda H,Tanaka A,Yamamoto S,Katoh H,Ichimura T,Funahashi S,Wada I,Nomura S,Seto Y,Aburatani H.Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.Nat Genet2014;46:583-7

[83] Ushiku T,Kakiuchi M,Katoh H,Lauwers GY.RHOA mutation in diffuse-type gastric cancer: a comparative clinicopathology analysis of 87 cases.Gastric Cancer2016;19:403-11 PMCID:PMC4824805

[84] Hansford S,Li-Chang H,Senz J,Schrader KA,Shumansky K,Santos TA,Carvalho J,Padilla S,Talhouk A,Richardson S,Lindor NM,MacMillan A,Keller G,Shah SP,Gallinger S,Roviello F,Oliveira C,Huntsman DG.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol2015;1:23-32