Preoperative and Postoperative Approaches to Gastroesophageal Cancer: What is All the Fuss About

Authors:
Lucy X. Ma Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Lucy X. Ma in
Current site
Google Scholar
PubMed
Close
 MD
,
Elan D. Panov Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Elan D. Panov in
Current site
Google Scholar
PubMed
Close
 MD
,
Michael J. Allen Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Michael J. Allen in
Current site
Google Scholar
PubMed
Close
 MD
,
Gail E. Darling Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital;

Search for other papers by Gail E. Darling in
Current site
Google Scholar
PubMed
Close
 MD
,
Jonathan C. Yeung Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital;

Search for other papers by Jonathan C. Yeung in
Current site
Google Scholar
PubMed
Close
 MD
,
Carol J. Swallow Department of Surgical Oncology, Princess Margaret Cancer Centre;

Search for other papers by Carol J. Swallow in
Current site
Google Scholar
PubMed
Close
 MD
,
Savtaj S. Brar Department of Surgical Oncology, Princess Margaret Cancer Centre;

Search for other papers by Savtaj S. Brar in
Current site
Google Scholar
PubMed
Close
 MD
,
Rebecca K. Wong Department of Radiation Oncology, Princess Margaret Cancer Centre; and

Search for other papers by Rebecca K. Wong in
Current site
Google Scholar
PubMed
Close
 MD
,
Patrick Veit-Haibach Joint Department Medical Imaging, and

Search for other papers by Patrick Veit-Haibach in
Current site
Google Scholar
PubMed
Close
 MD
,
Sangeetha N. Kalimuthu Department of Pathology, Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Canada.

Search for other papers by Sangeetha N. Kalimuthu in
Current site
Google Scholar
PubMed
Close
 MD
,
Eric X. Chen Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Eric X. Chen in
Current site
Google Scholar
PubMed
Close
 MD
,
Raymond W. Jang Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Raymond W. Jang in
Current site
Google Scholar
PubMed
Close
 MD
, and
Elena Elimova Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre;

Search for other papers by Elena Elimova in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Gastroesophageal cancers carry poor prognoses, and are a leading cause of cancer-related morbidity and mortality worldwide. Even in those with resectable disease, more than half of patients treated with surgery alone experience disease recurrence. Multimodality approaches using preoperative and postoperative chemotherapy and/or radiotherapy have been established, resulting in incremental improvements in outcomes. Globally, there is no standardized approach, and treatment varies with geographic location. The question remains of how to select the optimal perioperative treatment that will maximize benefit for patients while avoiding toxicities from unnecessary therapies. This article reviews currently available evidence supporting preoperative and postoperative therapy in gastroesophageal cancers, with an emphasis on recent practice-changing trials and ongoing areas of investigation, including the role of immune checkpoint inhibition and biomarker-guided treatment.

Submitted November 8, 2021; accepted for publication November 30, 2021.

Disclosures: Dr. Chen has disclosed participating in research for Zymeworks, Bristol-Myers Squibb, Merck, Novartis, Roche, and AstraZeneca; and serving as an advisory board member for Bayer and Taiho. Dr. Jang has disclosed participating in research and serving as a principal investigator for Merck; and serving as an advisory board member for Ipsen, Eisai, and Advanced Accelerator Applications/Novartis. Dr. Elimova has disclosed participating in research for Bristol-Myers Squibb and Zymeworks; serving on a data safety monitoring board for Zymeworks; serving as an advisory board member and as a consultant for Zymeworks, Bristol-Myers Squibb, Adaptimmune Therapeutics, and BeiGene; and having a spouse employed by Merck. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Elena Elimova, MD, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 7-715 700 University Avenue, Toronto, Ontario, M5G 1X6, Canada. Email: Elena.Elimova@uhn.ca

View associated content

  • Collapse
  • Expand
  • 1.

    Lagergren J, Smyth E, Cunningham D, et al. Oesophageal cancer. Lancet 2017;390:23832396.

  • 2.

    Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet 2020;396:635648.

  • 3.

    Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209249.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005;23:23102317.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25:11601168.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Cuschieri A, Weeden S, Fielding J, et al. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Br J Cancer 1999;79:15221530.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Rice TW, Rusch VW, Apperson-Hansen C, et al. Worldwide esophageal cancer collaboration. Dis Esophagus 2009;22:18.

  • 8.

    Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:18101820.

  • 9.

    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;379:315321.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:20742084.

  • 11.

    Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:19481957.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 2017;541:169175.

  • 13.

    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202209.

  • 14.

    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;29:43874393.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Noh SH, Park SR, Yang HK, 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;15:13891396.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8:111.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Landry J, Tepper JE, Wood WC, et al. Patterns of failure following curative resection of gastric carcinoma. Int J Radiat Oncol Biol Phys 1990;19:13571362.

  • 18.

    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;345: 725730.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    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;30:23272333.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Fuchs CS, Niedzwiecki D, Mamon HJ, 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;35:36713677.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Lee J, Lim DH, Kim S, et al. 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 Oncol 2012;30:268273.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Park SH, Sohn TS, Lee J, 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;33:31303136.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Park SH, Lim DH, Sohn TS, et al. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol 2021;32:368374.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:1120.

  • 25.

    Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:17151721.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Schuhmacher C, Gretschel S, Lordick 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;28:52105218.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Cats A, Jansen EPM, van Grieken NCT, 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;19:616628.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Leong T, Smithers BM, Michael M, et al. TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, Intergroup trial of the AGITG/TROG/EORTC/NCIC CTG). BMC Cancer 2015;15:532.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Slagter AE, Jansen EPM, van Laarhoven HWM, et al. CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. BMC Cancer 2018;18:877.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Stahl M, Wilke H, Lehmann N, et al. Long-term results of a phase III study investigating chemoradiation with and without surgery in locally advanced squamous cell carcinoma (LA-SCC) of the esophagus [abstract]. J Clin Oncol 2008;26(Suppl):Abstract 4530.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial. J Clin Oncol 2021;39:19952004.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Shapiro J, van Lanschot JJB, Hulshof MCCM, 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;16:10901098.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 2021;384:11911203.

  • 34.

    Cutsem EV, Singh P, Cleary JM, et al. Checkmate 577: health-related quality of life (HRQoL) in a randomized, double-blind phase III study of nivolumab (NIVO) versus placebo (PBO) as adjuvant treatment in patients (pts) with resected esophageal or gastroesophageal junction cancer (EC/GEJC) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 167.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Reynolds JV, Preston SR, O’Neill B, et al. Neo-AEGIS (neoadjuvant trial in adenocarcinoma of the esophagus and esophago-gastric junction international study): preliminary results of phase III RCT of CROSS versus perioperative chemotherapy (modified MAGIC or FLOT protocol). (NCT01726452) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 4004.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Hoeppner J, Lordick F, Brunner T, 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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Bang YJ, Van Cutsem E, Fuchs CS, et al. KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol 2019;15:943952.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Janjigian YY, Cutsem EV, Muro K, et al. MATTERHORN: efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—a randomized, double-blind, placebo-controlled, phase 3 study [abstract]. J Clin Oncol 2021;39(Suppl):Abstract TPS4151.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Al-Batran SE, Pauligk C, Hofheinz R, et al. Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK [abstract]. J Clin Oncol 2019;37(Suppl):Abstract TPS4142.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Terashima M, Kim YW, Yeh TS, et al. ATTRACTION-05 (ONO-4538-38/BMS CA209844): a randomized, multicenter, double-blind, placebo- controlled phase 3 study of nivolumab (nivo) in combination with adjuvant chemotherapy in stage III gastric and esophagogastric junction (G/EGJ) cancer. Ann Oncol 2017;28:v266267.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Eads JR, Weitz M, Gibson MK, et al. A phase II/III study of perioperative nivolumab and ipilimumab in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: a trial of the ECOG-ACRIN Cancer Research Group (EA2174) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract TPS4651.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Janjigian YY, 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). Lancet 2021;398:2740.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Pietrantonio F, Miceli R, Raimondi A, et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol 2019;37:33923400.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018;4:e180013.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy 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. JAMA Oncol 2020;6:15711580.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Bang YJ, 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). Lancet 2010;376:687697.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Rivera F, Izquierdo-Manuel M, García-Alfonso P, et al. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial. Eur J Cancer 2021;145:158167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Hofheinz RD, Hegewisch-Becker S, Kunzmann V, et al. Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma. Int J Cancer 2021;149:13221331.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Abali H, Yalcin S, Onal HC, et al. A phase II study of the combination of oxaliplatin, capecitabine, and trastuzumab and chemoradiotherapy in the adjuvant setting in operated patients with HER2-positive gastric or gastroesophageal junction cancer (TOXAG Study): a Turkish Oncology Group study. Am J Clin Oncol 2021;44:301307.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Schokker S, Molenaar RJ, Meijer SL, et al. Feasibility study of trastuzumab (T) and pertuzumab (P) added to neoadjuvant chemoradiotherapy (nCRT) in resectable HER2+ esophageal adenocarcinoma (EAC) patients (pts): the TRAP study [abstract]. J Clin Oncol 2018;36(Suppl):Abstract 4057.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Hofheinz RD, Haag GM, Ettrich TJ, et al. Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: final results of the PETRARCA multicenter randomized phase II trial of the AIO [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 4502.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Ilson D, Moughan J, Safran H, et al. O-10 trastuzumab with trimodality treatment of esophageal adenocarcinoma with HER2 overexpression: NRG Oncology/RTOG 1010 [abstract]. Ann Oncol 2020; 31:Abstract 235.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Wagner AD, Grabsch HI, Mauer M, et al. EORTC-1203-GITCG - the “INNOVATION”-trial: effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate. BMC Cancer 2019;19:494.

    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3136 819 75
PDF Downloads 1879 299 47
EPUB Downloads 0 0 0