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Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas

Ajlan Atasoy, MD
Michael K Gibson, MD, PhD, FACP
Mark F Berry, MD
Noah C Choi, MD
Section Editors
Joseph S Friedberg, MD
Kenneth K Tanabe, MD
Richard M Goldberg, MD
Deputy Editors
Diane MF Savarese, MD
Wenliang Chen, MD, PhD


Esophageal and gastric cancers are significant worldwide health problems. They are often lethal diseases, with a case-fatality ratio of 84 percent (esophageal) and 75 percent (gastric), respectively [1].

The esophagogastric junction (EGJ; also called the gastroesophageal junction or GEJ) and gastric cardia (figure 1), represent anatomical sites with a remarkably high and rapidly rising incidence of adenocarcinoma. (See "Epidemiology of gastric cancer", section on 'Change in histology pattern' and "Epidemiology, pathobiology, and clinical manifestations of esophageal cancer", section on 'Epidemiology'.)

Although surgery is the primary curative modality for EGJ cancers, long-term outcomes are not satisfactory with resection alone, even if microscopically complete (R0). This poor long-term outcome has prompted an evaluation of neoadjuvant (preoperative) and adjuvant (postoperative) combined modality therapy. The best form of multimodality therapy is not established.

This topic will cover the definition and classification of EGJ tumors and provide an overview of the clinical trials that support the multimodality management of locally advanced but potentially resectable EGJ adenocarcinomas, focusing on considerations that influence the choice of the specific multimodality approach. Principles of surgical management for gastric tumors and thoracic esophageal tumors, treatment of locally advanced, unresectable esophageal cancers, adjuvant and neoadjuvant approaches to gastric cancers, and neoadjuvant and adjuvant approaches to tumors of the thoracic esophagus are covered elsewhere, as is management of dysplasia and early superficial cancer (including adenocarcinoma) arising in Barrett's esophagus.

(See "Surgical management of invasive gastric cancer".)


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Literature review current through: Sep 2016. | This topic last updated: Sep 19, 2016.
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  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69.
  2. Mönig SP, Hölscher AH. Clinical classification systems of adenocarcinoma of the esophagogastric junction. Recent Results Cancer Res 2010; 182:19.
  3. Ectors N, Driessen A, De Hertog G, et al. Is adenocarcinoma of the esophagogastric junction or cardia different from Barrett adenocarcinoma? Arch Pathol Lab Med 2005; 129:183.
  4. Chandrasoma P, Makarewicz K, Wickramasinghe K, et al. A proposal for a new validated histological definition of the gastroesophageal junction. Hum Pathol 2006; 37:40.
  5. Misumi A, Murakami A, Harada K, et al. Definition of carcinoma of the gastric cardia. Langenbecks Arch Chir 1989; 374:221.
  6. American Joint Committee on Cancer Staging Manual, 7th, Edge S, Byrd, DR, Compton, CC, et al (Eds), Springer, New York 2010.
  7. Siewert JR, Hölscher AH, Becker K, Gössner W. [Cardia cancer: attempt at a therapeutically relevant classification]. Chirurg 1987; 58:25.
  8. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998; 85:1457.
  9. Mariette C, Piessen G, Briez N, et al. Oesophagogastric junction adenocarcinoma: which therapeutic approach? Lancet Oncol 2011; 12:296.
  10. Hasegawa S, Yoshikawa T, Aoyama T, et al. Esophagus or stomach? The seventh TNM classification for Siewert type II/III junctional adenocarcinoma. Ann Surg Oncol 2013; 20:773.
  11. Rüdiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000; 232:353.
  12. Fang WL, Wu CW, Chen JH, et al. Esophagogastric junction adenocarcinoma according to Siewert classification in Taiwan. Ann Surg Oncol 2009; 16:3237.
  13. Hasegawa S, Yoshikawa T, Cho H, et al. Is adenocarcinoma of the esophagogastric junction different between Japan and western countries? The incidence and clinicopathological features at a Japanese high-volume cancer center. World J Surg 2009; 33:95.
  14. Meier I, Merkel S, Papadopoulos T, et al. Adenocarcinoma of the esophagogastric junction: the pattern of metastatic lymph node dissemination as a rationale for elective lymphatic target volume definition. Int J Radiat Oncol Biol Phys 2008; 70:1408.
  15. Hasegawa S, Yoshikawa T. Adenocarcinoma of the esophagogastric junction: incidence, characteristics, and treatment strategies. Gastric Cancer 2010; 13:63.
  16. Hansen S, Vollset SE, Derakhshan MH, et al. Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status. Gut 2007; 56:918.
  17. McColl KE, Going JJ. Aetiology and classification of adenocarcinoma of the gastro-oesophageal junction/cardia. Gut 2010; 59:282.
  18. Derakhshan MH, Malekzadeh R, Watabe H, et al. Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer. Gut 2008; 57:298.
  19. Ren JS, Kamangar F, Qiao YL, et al. Serum pepsinogens and risk of gastric and oesophageal cancers in the General Population Nutrition Intervention Trial cohort. Gut 2009; 58:636.
  20. Hosokawa Y, Kinoshita T, Konishi M, et al. Clinicopathological features and prognostic factors of adenocarcinoma of the esophagogastric junction according to Siewert classification: experiences at a single institution in Japan. Ann Surg Oncol 2012; 19:677.
  21. Barbour AP, Rizk NP, Gerdes H, et al. Endoscopic ultrasound predicts outcomes for patients with adenocarcinoma of the gastroesophageal junction. J Am Coll Surg 2007; 205:593.
  22. Erhunmwunsee L, Englum BR, Onaitis MW, et al. Impact of pretreatment imaging on survival of esophagectomy after induction therapy for esophageal cancer: who should be given the benefit of the doubt?: esophagectomy outcomes of patients with suspicious metastatic lesions. Ann Surg Oncol 2015; 22:1020.
  23. Weinberg JS, Suki D, Hanbali F, et al. Metastasis of esophageal carcinoma to the brain. Cancer 2003; 98:1925.
  24. Gabrielsen TO, Eldevik OP, Orringer MB, Marshall BL. Esophageal carcinoma metastatic to the brain: clinical value and cost-effectiveness of routine enhanced head CT before esophagectomy. AJNR Am J Neuroradiol 1995; 16:1915.
  25. Smith RS, Miller RC. Incidence of brain metastasis in patients with esophageal carcinoma. World J Gastroenterol 2011; 17:2407.
  26. Stahl M, Oliveira J, ESMO Guidelines Working Group. Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 Suppl 4:32.
  27. Hori Y, SAGES Guidelines Committee. Diagnostic laparoscopy guidelines : This guideline was prepared by the SAGES Guidelines Committee and reviewed and approved by the Board of Governors of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), November 2007. Surg Endosc 2008; 22:1353.
  28. Cordin J, Lehmann K, Schneider PM. Clinical staging of adenocarcinoma of the esophagogastric junction. Recent Results Cancer Res 2010; 182:73.
  29. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991; 265:1287.
  30. Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83:2049.
  31. Vial M, Grande L, Pera M. Epidemiology of adenocarcinoma of the esophagus, gastric cardia, and upper gastric third. Recent Results Cancer Res 2010; 182:1.
  32. Hansen S, Wiig JN, Giercksky KE, Tretli S. Esophageal and gastric carcinoma in Norway 1958-1992: incidence time trend variability according to morphological subtypes and organ subsites. Int J Cancer 1997; 71:340.
  33. Apisarnthanarax S, Tepper JE. Crossroads in the combined-modality management of gastroesophageal junction carcinomas. Gastrointest Cancer Res 2008; 2:235.
  34. Tepper JE, O'Neil B. Transition in biology and philosophy in the treatment of gastroesophageal junction adenocarcinoma. J Clin Oncol 2009; 27:836.
  35. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355:11.
  36. 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; 345:725.
  37. Whiteman DC, Parmar P, Fahey P, et al. Association of Helicobacter pylori infection with reduced risk for esophageal cancer is independent of environmental and genetic modifiers. Gastroenterology 2010; 139:73.
  38. Leers JM, DeMeester SR, Chan N, et al. Clinical characteristics, biologic behavior, and survival after esophagectomy are similar for adenocarcinoma of the gastroesophageal junction and the distal esophagus. J Thorac Cardiovasc Surg 2009; 138:594.
  39. Whitson BA, Groth SS, Li Z, et al. Survival of patients with distal esophageal and gastric cardia tumors: a population-based analysis of gastroesophageal junction carcinomas. J Thorac Cardiovasc Surg 2010; 139:43.
  40. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.103.
  41. Stahl M, Walz MK, Stuschke M, 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.
  42. Paulson EC, Ra J, Armstrong K, et al. Underuse of esophagectomy as treatment for resectable esophageal cancer. Arch Surg 2008; 143:1198.
  43. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002; 359:1727.
  44. Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009; 27:5062.
  45. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339:1979.
  46. 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; 29:1715.
  47. 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; 28:5210.
  48. Data presented at the Annual meeting of the American Society of Clinical Oncology, Orlando, FL, May 15, 2005.
  49. Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12:681.
  50. Anderson D, Langley RE, Nankivell MG, et al. Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072) (abstract). J Clin Oncol 33, 2015 (suppl; abstr 4002). Abstract available online at http://meetinglibrary.asco.org/content/149773-156 (Accessed on August 20, 2015).
  51. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462.
  52. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012; 366:2074.
  53. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008; 26:1086.
  54. Shapiro J, van Lanschot JJ, Hulshof MC, 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.
  55. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19:305.
  56. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 2014; 32:2416.
  57. Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus. Cochrane Database Syst Rev 2013; :CD008107.
  58. Gaast AV, van Hagen P, Hulshof M, et al. Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric cancer: Results from a multinational randomized phase III study (abstract 4004). J Clin Oncol 2010; 28:302s.
  59. Huang TC, Hsu CH, Lin CC, Tu YK. Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer. Jpn J Clin Oncol 2015; 45:1023.
  60. Fields RC, Strong VE, Gönen M, et al. Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma. Br J Cancer 2011; 104:1840.
  61. Lorenzen S, Thuss-Patience P, Al-Batran SE, et al. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann Oncol 2013; 24:2068.
  62. Davies AR, Gossage JA, Zylstra J, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol 2014; 32:2983.
  63. Stahl M, Riera-Knorrenschild J, Stuschke M, et al. Preoperative chemoradiotherapy and the long-term run in curative treatment of locally advanced oesophagogastric junction adenocarcinoma: Update of the POET phase III study (abstract). J Clin Oncol 34, 2016 (suppl; abstr 4031). Abstract available online at http://meetinglibrary.asco.org/content/164151-176 (Accessed on July 18, 2016).
  64. Klevebro F, Alexandersson von Döbeln G, Wang N, 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.
  65. Burmeister BH, Thomas JM, Burmeister EA, 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.
  66. Leong T, et al. TOPGEAR: an international randomized phase III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG). J clin Oncol 30, 2012 (suppl; abstr TPS4141). Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=99024 (Accessed on June 14, 2012).
  67. Fuchs CS, Tepper JE, Niedzwiecke D, et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101 (abstract 4003). J Clin Oncol 2011; 29:256s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82318 (Accessed on June 29, 2011).
  68. 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; 30:268.
  69. Armanios M, Xu R, Forastiere AA, et al. Adjuvant chemotherapy for resected adenocarcinoma of the esophagus, gastro-esophageal junction, and cardia: phase II trial (E8296) of the Eastern Cooperative Oncology Group. J Clin Oncol 2004; 22:4495.
  70. Speicher PJ, Englum BR, Ganapathi AM, et al. Adjuvant chemotherapy is associated with improved survival after esophagectomy without induction therapy for node-positive adenocarcinoma. J Thorac Oncol 2015; 10:181.
  71. 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; 379:315.
  72. Cools-Lartigue J, Jones D, Spicer J, et al. Management of Dysphagia in Esophageal Adenocarcinoma Patients Undergoing Neoadjuvant Chemotherapy: Can Invasive Tube Feeding be Avoided? Ann Surg Oncol 2015; 22:1858.
  73. Gill PG, Denham JW, Jamieson GG, et al. Patterns of treatment failure and prognostic factors associated with the treatment of esophageal carcinoma with chemotherapy and radiotherapy either as sole treatment or followed by surgery . J Clin Oncol 1992; 10:1037.
  74. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the Society of Thoracic Surgeons database. Ann Thorac Surg 2013; 96:382.
  75. Crabtree TD, Yacoub WN, Puri V, et al. Endoscopic ultrasound for early stage esophageal adenocarcinoma: implications for staging and survival. Ann Thorac Surg 2011; 91:1509.
  76. Rice TW, Mason DP, Murthy SC, et al. T2N0M0 esophageal cancer. J Thorac Cardiovasc Surg 2007; 133:317.
  77. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011; 92:491.
  78. Zhang JQ, Hooker CM, Brock MV, et al. Neoadjuvant chemoradiation therapy is beneficial for clinical stage T2 N0 esophageal cancer patients due to inaccurate preoperative staging. Ann Thorac Surg 2012; 93:429.
  79. Speicher PJ, Ganapathi AM, Englum BR, et al. Induction therapy does not improve survival for clinical stage T2N0 esophageal cancer. J Thorac Oncol 2014; 9:1195.
  80. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003; 185:538.
  81. Kleinberg L, Knisely JP, Heitmiller R, et al. Mature survival results with preoperative cisplatin, protracted infusion 5-fluorouracil, and 44-Gy radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2003; 56:328.
  82. Bruzzi JF, Swisher SG, Truong MT, et al. Detection of interval distant metastases: clinical utility of integrated CT-PET imaging in patients with esophageal carcinoma after neoadjuvant therapy. Cancer 2007; 109:125.
  83. Lordick F, Ott K, Krause BJ, 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.
  84. Javeri H, Xiao L, Rohren E, et al. The higher the decrease in the standardized uptake value of positron emission tomography after chemoradiation, the better the survival of patients with gastroesophageal adenocarcinoma. Cancer 2009; 115:5184.
  85. Verheij M, Jansen EPM, Cats A, et al. 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 (abstract). J Clin Oncol 34, 2016 (suppl; abstr 4000). Abstract available online at http://meetinglibrary.asco.org/content/165706-176 (Accessed on September 15, 2016).
  86. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999; 281:1623.
  87. Lee S, Park SH, Kang WK, et al. Prognostic value of the metastatic lymph node (N) ratio in the adjuvant chemoradiotherapy in stomach tumors (ARTIST) phase III trial (abstract). J Clin Oncol 34.2016 (suppl; abstr 4038). Abstract available online at http://meetinglibrary.asco.org/content/165241-176 (Accessed on September 12, 2016).
  88. Eom BW, Ryu KW, Lee JH, et al. Oncologic effectiveness of regular follow-up to detect recurrence after curative resection of gastric cancer. Ann Surg Oncol 2011; 18:358.
  89. Yoon SS. How closely should we follow gastric cancer patients following surgical resection? Ann Surg Oncol 2011; 18:311.
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