Locally advanced gastro-oesophageal cancer: Recent therapeutic advances and research directions

      Highlights

      • Outcome of resectable gastro-oesophageal adenocarcinoma remains poor.
      • Literature supports perioperative chemotherapy in locally advanced disease.
      • FLOT regimen has been recently established as the new standard in fit patients.
      • Adjuvant chemoradiotherapy is a choice after suboptimal or incomplete surgery.
      • Preoperative chemoradiotherapy is an alternative in junctional tumours.

      Abstract

      Gastric (GC) and gastro-oesophageal (GOJC) adenocarcinomas are often considered as a single entity, even though differences exist in epidemiology, clinical presentation, molecular biology and treatment options. Locally advanced, resectable disease represents a particularly challenging scenario, as many critical issues need to be addressed. In both GC and GOJC among Western countries, systemic chemotherapy demonstrated the greatest benefit when administered before and after surgery and perioperative chemotherapy has been set as a standard in this setting. Nonetheless, multiple chemotherapy regimens have been tested and direct comparisons have been only recently presented. Adjuvant chemoradiotherapy is an option as well, but several trials have questioned its role when more effective combination regimens are used. With regards to GOJC, preoperative chemoradiotherapy is an alternative to perioperative chemotherapy, as it is associated with higher pathologic responses and a different toxicity profile: however, a definitive comparison with chemotherapy is ongoing. Herein, we review the current options for the treatment of resectable GC and GOJC and the main open questions in the management of these patients, trying to depict an update of the available algorithms for everyday practice. Moreover, we summarize the design and preliminary results of the randomized trials in progress that will hopefully give definitive answers to the most debated issues in the field.

      Keywords

      To read this article in full you will need to make a payment

      References

        • Anderson W.F.
        • Camargo M.C.
        • Fraumeni Jr., J.F.
        • Correa P.
        • Rosenberg P.S.
        • Rabkin C.S.
        Age-specific trends in incidence of noncardia gastric cancer in US adults.
        JAMA. 2010; 303: 1723-1728
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2018.
        CA Cancer J Clin. 2018; 68: 7-30
        • Nitti D.
        • Wils J.
        • Dos Santos J.G.
        • Fountzilas G.
        • Conte P.F.
        • Sava C.
        • et al.
        Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG.
        Ann Oncol. 2006; 17: 262-269
        • De Vita F.
        • Giuliani F.
        • Orditura M.
        • Maiello E.
        • Galizia G.
        • Di Martino N.
        • et al.
        Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study).
        Ann Oncol. 2007; 18: 1354-1358
        • Cascinu S.
        • Labianca R.
        • Barone C.
        • Santoro A.
        • Carnaghi C.
        • Cassano A.
        • et al.
        Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial.
        J Natl Cancer Inst. 2007; 99: 601-607
        • Di Costanzo F.
        • Gasperoni S.
        • Manzione L.
        • Bisagni G.
        • Labianca R.
        • Bravi S.
        • et al.
        Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.
        J Natl Cancer Inst. 2008; 100: 388-398
        • Paoletti X.
        • Oba K.
        • Burzykowski T.
        • Michiels S.
        • Ohashi Y.
        • Pignon J.P.
        • et al.
        Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis.
        JAMA. 2010; 303 ([GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group]): 1729-1737
        • Diaz-Nieto R.
        • Orti-Rodríguez R.
        • Winslet M.
        Post-surgical chemotherapy versus surgery alone for resectable gastric cancer.
        Cochrane Database Syst Rev. 2013; 9: CD008415
        • Sasako M.
        • Sakuramoto S.
        • Katai H.
        • Kinoshita T.
        • Furukawa H.
        • Yamaguchi T.
        • 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; 29: 4387-4393
        • Noh S.H.
        • Park S.R.
        • Yang H.K.
        • Chung H.C.
        • Chung I.J.
        • Kim S.W.
        • et al.
        Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.
        Lancet Oncol. 2014; 15: 1389-1396
        • Bajetta E.
        • Floriani I.
        • Di Bartolomeo M.
        • Labianca R.
        • Falcone A.
        • Di Costanzo F.
        • et al.
        Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.
        Ann Oncol. 2014; 25: 1373-1378
        • Yamada T.
        • Yoshikawa T.
        • Taguri M.
        • Hayashi T.
        • Aoyama T.
        • Sue-Ling H.M.
        • et al.
        The survival difference between gastric cancer patients from the UK and Japan remains after weighted propensity score analysis considering all background factors.
        Gastric Cancer. 2016; 19: 479-489
        • Fuchs C.S.
        • Niedzwiecki D.
        • Mamon H.J.
        • Tepper J.E.
        • Ye X.
        • Swanson R.S.
        • et al.
        Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance).
        J Clin Oncol. 2017; 35: 3671-3677
        • Macdonald J.S.
        • Smalley S.R.
        • Benedetti J.
        • Hundahl S.A.
        • Estes N.C.
        • Stemmermann G.N.
        • et al.
        Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.
        N Engl J Med. 2001; 345: 725-730
        • Smalley S.R.
        • Benedetti J.K.
        • Haller D.G.
        • Hundahl S.A.
        • Estes N.C.
        • Ajani J.A.
        • 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; 30: 2327-2333
        • Cohen D.J.
        • Leichman L.
        Controversies in the treatment of local and locally advanced gastric and esophageal cancers.
        J Clin Oncol. 2015; 33: 1754-1759
        • Scartozzi M.
        • Galizia E.
        • Graziano F.
        • Catalano V.
        • Berardi R.
        • Baldelli A.M.
        • et al.
        Over-D1 dissection may question the value of radiotherapy as a part of an adjuvant programme in high-risk radically resected gastric cancer patients.
        Br J Cancer. 2005; 92: 1051-1054
        • Park S.H.
        • Sohn T.S.
        • Lee J.
        • Lim D.H.
        • Hong M.E.
        • Kim K.M.
        • et al.
        Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses.
        J Clin Oncol. 2015; 33: 3130-3136
        • Cats A.
        • Jansen E.P.M.
        • van Grieken N.C.T.
        • Sikorska K.
        • Lind P.
        • Nordsmark M.
        • et al.
        Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial.
        Lancet Oncol. 2018; 19: 616-628
        • Min C.
        • Bangalore S.
        • Jhawar S.
        • Guo Y.
        • Nicholson J.
        • Formenti S.C.
        • et al.
        Chemoradiation therapy versus chemotherapy alone for gastric cancer after R0 surgical resection: a meta-analysis of randomized trials.
        Oncology. 2014; 86: 79-85
        • Huang Y.Y.
        • Yang Q.
        • Zhou S.W.
        • Wei Y.
        • Chen Y.X.
        • Xie D.R.
        • et al.
        Postoperative chemoradiotherapy versus postoperative chemotherapy for completely resected gastric cancer with D2 lymphadenectomy: a meta-analysis.
        PLoS One. 2013; 8: e68939
        • Cunningham D.
        • Allum W.H.
        • Stenning S.P.
        • Thompson J.N.
        • Van de Velde C.J.
        • Nicolson M.
        • et al.
        Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.
        N Engl J Med. 2006; 355: 11-20
        • Ychou M.
        • Boige V.
        • Pignon J.P.
        • Conroy T.
        • Bouché O.
        • Lebreton G.
        • et al.
        Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: An FNCLCC and FFCD multicenter phase III trial.
        J Clin Oncol. 2011; 29: 1715-1721
        • Fazio N.
        • Biffi R.
        • Maibach R.
        • Hayoz S.
        • Thierstein S.
        • Brauchli P.
        • et al.
        Preoperative versus postoperative docetaxel–cisplatin–fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.
        Ann Oncol. 2016; 27: 668-673
        • Al-Batran S.E.
        • Hofheinz R.D.
        • Pauligk C.
        • Kopp H.G.
        • Haag G.M.
        • Luley K.B.
        • et al.
        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 Oncol. 2016; 17: 1697-1708
        • Al-Batran S.E.
        • Homann N.
        • Schmalenberg H.
        • Kopp H.G.
        • Haag G.M.
        • Luley K.B.
        • et al.
        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 Oncol. 2017; 35 ([suppl; abstr 4004])
        • Al-Batran S.E.
        • Pauligk C.
        • Homann N.
        • Schmalenberg H.
        • Kopp H.
        • Haag G.M.
        • et al.
        Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO).
        Ann Oncol. 2017; 28 ([suppl; abstr LBA27])
        • Cassidy J.
        • Saltz L.
        • Twelves C.
        • Van Cutsem E.
        • Hoff P.
        • Kang Y.
        • et al.
        Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients.
        Ann Oncol. 2011; 22: 2604-2609
        • Al-Batran S.E.
        • Hartmann J.T.
        • Probst S.
        • Schmalenberg H.
        • Hollerbach S.
        • Hofheinz R.
        • et al.
        Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie.
        J Clin Oncol. 2008; 26: 1435-1442
        • Ter Veer E.
        • Haj Mohammad N.
        • van Valkenhoef G.
        • Ngai L.L.
        • Mali R.M.A.
        • Anderegg M.C.
        • et al.
        The efficacy and safety of first-line chemotherapy in advanced esophagogastric cancer: a network meta-analysis.
        J Natl Cancer Inst. 2016; 108https://doi.org/10.1093/jnci/djw166
        • Smyth E.C.
        • Verheij M.
        • Allum W.
        • Cunningham D.
        • Cervantes A.
        • Arnold D.
        • ESMO Guidelines Committee
        Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27: v38-v49
        • Al-Batran S.E.
        • Homann N.
        • Pauligk C.
        • Illerhaus G.
        • Martens U.M.
        • Stoehlmacher J.
        • 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.
        JAMA Oncol. 2017; 3: 1237-1244
        • Coburn N.
        • Cosby R.
        • Klein L.
        • Knight G.
        • Malthaner R.
        • Mamazza J.
        • et al.
        Staging and surgical approaches in gastric cancer: a systematic review.
        Cancer Treat Rev. 2018; 63: 104-115
        • Smyth E.C.
        • Fassan M.
        • Cunningham D.
        • Allum W.H.
        • Okines A.F.
        • Lampis A.
        • et al.
        Effect of pathologic tumor response and nodal status on survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial.
        J Clin Oncol. 2002; 34: 2721-2727
        • Loupakis F.
        • Masi G.
        • Fornaro L.
        • Vasile E.
        • Allegrini G.
        • Fontana E.
        • et al.
        Phase II study of sequential cisplatin plus 5-fluorouracil/leucovorin (5-FU/LV) followed by irinotecan plus 5-FU/LV followed by docetaxel plus 5-FU/LV in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma.
        Cancer Chemother Pharmacol. 2010; 66: 559-566
      1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, accessible on: <https://www.nccn.org/professionals/physician_gls/default.aspx#site> [Gastric Cancer (Version 1.2018 - March 16, 2018) and Esophageal and Esophagogastric Junction Cancers (Version 1.2018 - March 16, 2018)] (last accessed: March 22, 2018).

        • Dikken J.L.
        • Jansen E.P.
        • Cats A.
        • Bakker B.
        • Hartgrink H.H.
        • Kranenbarg E.M.
        • et al.
        Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer.
        J Clin Oncol. 2010; 28: 2430-2436
        • Rhome R.M.
        • Moshier E.
        • Sarpel U.
        • Ohri N.
        • Mazumdar M.
        • Buckstein M.H.
        Predictors of positive margin after definitive resection for gastric adenocarcinoma and impact of adjuvant therapies.
        Int J Radiat Oncol Biol Phys. 2017; 98: 1106-1115
        • Lordick F.
        • Mariette C.
        • Haustermans K.
        • Obermannová R.
        • Arnold D.
        • ESMO Guidelines Committee
        Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27: v50-v57
        • Allum W.H.
        • Stenning S.P.
        • Bancewicz J.
        • Clark P.I.
        • Langley R.E.
        Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer.
        J Clin Oncol. 2009; 27: 5062-5067
        • Schuhmacher C.
        • Gretschel S.
        • Lordick F.
        • Reichardt P.
        • Hohenberger W.
        • Eisenberger C.F.
        • et al.
        Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954.
        J Clin Oncol. 2010; 28: 5210-5218
        • Kelsen D.P.
        • Ginsberg R.
        • Pajak T.F.
        • Sheahan D.G.
        • Gunderson L.
        • Mortimer J.
        • et al.
        Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.
        N Engl J Med. 1998; 339: 1979-1984
        • van Hagen P.
        • Hulshof M.C.
        • van Lanschot J.J.
        • Steyerberg E.W.
        • van Berge Henegouwen M.I.
        • Wijnhoven B.P.
        • et al.
        Preoperative chemoradiotherapy for esophageal or junctional cancer.
        N Engl J Med. 2012; 366: 2074-2084
        • Shapiro J.
        • van Lanschot J.J.B.
        • Hulshof M.C.C.M.
        • van Hagen P.
        • van Berge Henegouwen M.I.
        • Wijnhoven B.P.L.
        • et al.
        Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.
        Lancet Oncol. 2015; 16: 1090-1098
        • Ashraf N.
        • Hoffe S.
        • Kim R.
        Locally advanced gastroesophageal junction tumor: a treatment dilemma.
        Oncologist. 2015; 20: 134-142
        • Sjoquist K.M.
        • Burmeister B.H.
        • Smithers B.M.
        • Zalcberg J.R.
        • Simes R.J.
        • Barbour A.
        • et al.
        Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis.
        Lancet Oncol. 2011; 12 ([Australasian Gastro-Intestinal Trials Group]): 681-692
        • Stahl M.
        • Walz M.K.
        • Stuschke M.
        • Lehmann N.
        • Meyer H.J.
        • Riera-Knorrenschild J.
        • 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; 27: 851-856
        • Burmeister B.H.
        • Thomas J.M.
        • Burmeister E.A.
        • Walpole E.T.
        • Harvey J.A.
        • Thomson D.B.
        • et al.
        Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial.
        Eur J Cancer. 2011; 47: 354-360
        • Klevebro F.
        • Alexandersson von Döbeln G.
        • Wang N.
        • Johnsen G.
        • Jacobsen A.B.
        • Friesland S.
        • et al.
        A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction.
        Ann Oncol. 2016; 27: 660-667
        • Lordick F.
        • Ott K.
        • Krause B.J.
        • Weber W.A.
        • Becker K.
        • Stein H.J.
        • et al.
        PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial.
        Lancet Oncol. 2007; 8: 797-805
        • Weber W.A.
        • Ott K.
        • Becker K.
        • Dittler H.J.
        • Helmberger H.
        • Avril N.E.
        • et al.
        Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.
        J Clin Oncol. 2001; 19: 3058-3065
        • Schollaert P.
        • Crott R.
        • Bertrand C.
        • D'Hondt L.
        • Borght T.V.
        • Krug B.
        A systematic review of the predictive value of (18)FDG-PET in esophageal and esophagogastric junction cancer after neoadjuvant chemoradiation on the survival outcome stratification.
        J Gastrointest Surg. 2014; 18: 894-905
        • zum Büschenfelde C.M.
        • Herrmann K.
        • Schuster T.
        • Geinitz H.
        • Langer R.
        • Becker K.
        • et al.
        J Nucl Med. 2011; 52: 1189-1196
        • Barbour A.
        • Walpole E.
        • Mai G.T.
        • Chan H.
        • Barnes E.
        • Watson D.
        • et al.
        An AGITG trial - a randomised phase II study of pre-operative cisplatin, fluorouracil and DOCetaxel +/− radioTherapy based on poOR early response to cisplatin and fluorouracil for resectable esophageal adenocarcinoma.
        Ann Oncol. 2017; 27 ([abstract 610O]): vi207-vi242
        • Goodman K.A.
        • Hall N.
        • Bekaii-Saab T.S.
        • Ou F.S.
        • Twohy E.
        • Meyers M.O.
        • et al.
        Survival outcomes from CALGB 80803 (Alliance): a randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer.
        J Clin Oncol. 2018; 36 ([abstract 4012])
        • Oppedijk V.
        • van der Gaast A.
        • van Lanschot J.J.
        • van Hagen P.
        • van Os R.
        • van Rij C.M.
        • et al.
        Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials.
        J Clin Oncol. 2014; 32: 385-391
        • Alderson D.
        • Cunningham D.
        • Nankivell M.
        • Blazeby J.M.
        • Griffin S.M.
        • Crellin A.
        • et al.
        Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.
        Lancet Oncol. 2017; 18: 1249-1260
        • Cunningham D.
        • Stenning S.P.
        • Smyth E.C.
        • Okines A.F.
        • Allum W.H.
        • Rowley S.
        • et al.
        Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial.
        Lancet Oncol. 2017; 18: 357-370
        • Schmidt T.
        • Lordick F.
        • Herrmann K.
        • Ott K.
        Value of functional imaging by PET in esophageal cancer.
        J Natl Compr Canc Netw. 2015; 13: 239-247
        • Park S.H.
        • Lee S.J.
        • Kim S.T.
        • Lee J.
        • Park J.O.
        • Park Y.S.
        • et al.
        Multicenter phase III trial of adjuvant chemoradiotherapy in stomach tumors 2 (ARTIST 2).
        J Clin Oncol. 2015; 33 ([suppl. 3; abstr TPS228])
        • Leong T.
        • Smithers B.M.
        • Haustermans K.
        • Michael M.
        • Gebski V.
        • Miller D.
        • et al.
        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 Oncol. 2017; 24: 2252-2258
        • Hoeppner J.
        • Lordick F.
        • Brunner T.
        • Glatz T.
        • Bronsert P.
        • Röthling N.
        • et al.
        ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286).
        BMC Cancer. 2016; 16: 503
        • Reynolds J.V.
        • Preston S.R.
        • O'Neill B.
        • Baeksgaard L.
        • Griffin S.M.
        • Mariette C.
        • et al.
        ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastricjunction International Study (Neo-AEGIS).
        BMC Cancer. 2017; 17: 401
        • Choi Y.Y.
        • Kim H.
        • Yang H.K.
        • Kim W.H.
        • Kim Y.W.
        • Kook M.C.
        • et al.
        Clinical impact of microsatellite instability in patients with stage II and III gastric cancer: results from the CLASSIC trial.
        J Clin Oncol. 2017; 35 ([suppl; abstr 4022])
        • Smyth E.C.
        • Wotherspoon A.
        • Peckitt C.
        • Gonzalez D.
        • Hulkki-Wilson S.
        • Eltahir Z.
        • et al.
        Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.
        JAMA Oncol. 2017; 3: 1197-1203
        • Maleki S.S.
        • Röcken C.
        Chromosomal instability in gastric cancer biology.
        Neoplasia. 2017; 19: 412-420