Langenbeck's Archives of Surgery

, Volume 398, Issue 2, pp 211–220 | Cite as

Preoperative therapy of esophagogastric cancer: the problem of nonresponding patients

  • S. Blank
  • A. Stange
  • L. Sisic
  • W. Roth
  • L. Grenacher
  • F. Sterzing
  • M. Burian
  • D. Jäger
  • M. Büchler
  • K. Ott
Original Article



Preoperative treatment is nowadays standard for locally advanced esophagogastric cancer in Europe. Surprisingly, little attention has been paid to nonresponders so far. The aim of our retrospective exploratory study was the comparison of responder, nonresponder, and primary resected patients in respect of outcome considering the tumor entity.

Patients and methods

From 2001–2011, 607 patients with locally advanced esophagogastric carcinoma (adenocarcinoma of the esophagogastric junction (AEG), n = 293; squamous cell cancer (SCC), n = 111; gastric cancer, n = 203) after preoperative treatment (n = 281) or primary resection (n = 326) were included. Histopathological response evaluation (Becker criteria) was available for 263.


A total of 76/263 (28.9 %) were responders (<10 % residual tumor). There was an association of response with increased R0 resections (p < 0.001) but also with a higher complication rate (p = 0.008) compared to nonresponse and primary surgery. Mortality was not influenced. Increased R0 resections after response were confirmed in every tumor entity (AEG, p = 0.010; SCC, p = 0.023; gastric cancer, p = 0.006). Median survival was best for responders with 43.5 months [95 % confidence interval (CI), 27.9–59.1], followed by nonresponders with 24.3 months (95 % CI, 21.6–27.0) and primary resected patients with 20.8 months (95 % CI, 17.7–23.9; p = 0.002). AEG (p = 0.012) and gastric cancer (p = 0.017) revealed identical results, but in the subgroup of SCC, the survival of nonresponders (median, 11.6 months; 95 % CI, 6.9–16.3) was even worse than for primary resected patients (median, 23.8 months; 95 % CI, 1.7–46.0; p = 0.012).


The histopathological response rate was low. Generally, nonresponding patients with AEG or gastric cancer seem not to have a disadvantage compared to primary resected patients, but nonresponders with SCC have a worse prognosis, which strengthens the demand for a critical patient selection in surgery for this tumor entity.


Esophagogastric cancer Nonresponder Prognosis Morbidity Mortality 



Thank you very much Cathryn Bernaciak for revising the manuscript.

Conflicts of interest



  1. 1.
    Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Geneve J, Lasser P, Rougier P (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29(13):1715–1721. doi: 10.1200/JCO.2010.33.0597 PubMedCrossRefGoogle Scholar
  2. 2.
    Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, Participants MT (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20. doi: 10.1056/NEJMoa055531 PubMedCrossRefGoogle Scholar
  3. 3.
    Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12 (7):681–692. doi: 10.1016/S1470-2045(11)70142-5 Google Scholar
  4. 4.
    Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, Haag C, Mauer ME, Hasan B, Welch J, Ott K, Hoelscher A, Schneider PM, Bechstein W, Wilke H, Lutz MP, Nordlinger B, Van Cutsem E, Siewert JR, Schlag PM (2010) 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 28(35):5210–5218 doi: 10.1200/JCO.2009.26.6114 Google Scholar
  5. 5.
    Lowy AM, Mansfield PF, Leach SD, Pazdur R, Dumas P, Ajani JA (1999) Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg 229(3):303–308PubMedCrossRefGoogle Scholar
  6. 6.
    Ott K, Sendler A, Becker K, Dittler HJ, Helmberger H, Busch R, Kollmannsberger C, Siewert JR, Fink U (2003) Neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: a prospective phase II study. Gastric Cancer 6(3):159–167. doi: 10.1007/s10120-003-0245-4 PubMedCrossRefGoogle Scholar
  7. 7.
    Bader FG, Lordick F, Fink U, Becker K, Hofler H, Busch R, Siewert JR, Ott K (2008) Paclitaxel in the neoadjuvant treatment for adeno carcinoma of the distal esophagus (AEG I). A comparison of two phase II trials with long-term follow-up. Onkologie 31(7):366–372. doi: 10.1159/000135515 PubMedCrossRefGoogle Scholar
  8. 8.
    Lorenzen S, Brucher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Hofler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F (2008) Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer 99(7):1020–1026. doi: 10.1038/sj.bjc.6604659 PubMedCrossRefGoogle Scholar
  9. 9.
    Bollschweiler E, Metzger R, Drebber U, Baldus S, Vallbohmer D, Kocher M, Holscher AH (2009) Histological type of esophageal cancer might affect response to neo-adjuvant radiochemotherapy and subsequent prognosis. Ann Oncol 20(2):231–238. doi: 10.1093/annonc/mdn622 PubMedCrossRefGoogle Scholar
  10. 10.
    Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG (2007) Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 25(24):3719–3725. doi: 10.1200/JCO.2006.10.4760 PubMedCrossRefGoogle Scholar
  11. 11.
    Brucher BL, Becker K, Lordick F, Fink U, Sarbia M, Stein H, Busch R, Zimmermann F, Molls M, Hofler H, Siewert JR (2006) The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer 106(10):2119–2127. doi: 10.1002/cncr.21850 PubMedCrossRefGoogle Scholar
  12. 12.
    Ott K, Bader FG, Lordick F, Feith M, Bartels H, Siewert JR (2009) Surgical factors influence the outcome after Ivor-Lewis esophagectomy with intrathoracic anastomosis for adenocarcinoma of the esophagogastric junction: a consecutive series of 240 patients at an experienced center. Ann Surg Oncol 16(4):1017–1025. doi: 10.1245/s10434-009-0336-5 PubMedCrossRefGoogle Scholar
  13. 13.
    Blank S, Blaker H, Schaible A, Lordick F, Grenacher L, Buechler M, Ott K (2012) Impact of pretherapeutic routine clinical staging for the individualization of treatment in gastric cancer patients. Langenbecks Arch Surg 397(1):45–55. doi: 10.1007/s00423-011-0805-8 Google Scholar
  14. 14.
    Ott K, Fink U, Becker K, Stahl A, Dittler HJ, Busch R, Stein H, Lordick F, Link T, Schwaiger M, Siewert JR, Weber WA (2003) Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol 21(24):4604–4610. doi: 10.1200/JCO.2003.06.574JCO.2003.06.574 PubMedCrossRefGoogle Scholar
  15. 15.
    Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J, Friess H, Hofler H (2011) Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Ann Surg 253(5): 934–939. doi: 10.1097/SLA.0b013e318216f44900000658-201105000-00014 Google Scholar
  16. 16.
    Langer R, Ott K, Feith M, Lordick F, Siewert JR, Becker K (2009) Prognostic significance of histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. Mod Pathol 22(12):1555–1563. doi: 10.1038/modpathol.2009.123 PubMedCrossRefGoogle Scholar
  17. 17.
    Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C (2007) Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25(10):1160–1168. doi: 10.1200/JCO.2005.04.7118 PubMedCrossRefGoogle Scholar
  18. 18.
    Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H (2005) Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23(10):2310–2317. doi: 10.1200/JCO.2005.00.034 PubMedCrossRefGoogle Scholar
  19. 19.
    Bartels H, Stein HJ, Siewert JR (1998) Preoperative risk analysis and postoperative mortality of oesophagectomy for resectable oesophageal cancer. Br J Surg 85(6):840–844. doi: 10.1046/j.1365-2168.1998.00663.x PubMedCrossRefGoogle Scholar
  20. 20.
    Law S, Kwong DL, Wong KH, Kwok KF, Wong J (2006) The effects of neoadjuvant chemoradiation on pTNM staging and its prognostic significance in esophageal cancer. J Gastrointest Surg 10(9):1301–1311. doi: 10.1016/j.gassur.2006.06.009 PubMedCrossRefGoogle Scholar
  21. 21.
    Sarela AI, Tolan DJ, Harris K, Dexter SP, Sue-Ling HM (2008) Anastomotic leakage after esophagectomy for cancer: a mortality-free experience. J Am Coll Surg 206(3):516–523. doi: 10.1016/j.jamcollsurg.2007.09.016 PubMedCrossRefGoogle Scholar
  22. 22.
    Siewert JR, Ott K (2007) Are squamous and adenocarcinomas of the esophagus the same disease? Semin Radiat Oncol 17(1):38–44. doi: 10.1016/j.semradonc.2006.09.007 PubMedCrossRefGoogle Scholar
  23. 23.
    Heidecke CD, Weighardt H, Feith M, Fink U, Zimmermann F, Stein HJ, Siewert JR, Holzmann B (2002) Neoadjuvant treatment of esophageal cancer: immunosuppression following combined radiochemotherapy. Surgery 132(3):495–501PubMedCrossRefGoogle Scholar
  24. 24.
    Yamaguchi Y, Hihara J, Hironaka K, Ohshita A, Okita R, Okawaki M, Matsuura K, Nagamine I, Ikeda T, Ohara M, Hamai Y (2006) Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: possible application for compensatory anti-inflammatory response syndrome. Oncol Rep 15(4):895–901PubMedGoogle Scholar
  25. 25.
    Rizk NP, Bach PB, Schrag D, Bains MS, Turnbull AD, Karpeh M, Brennan MF, Rusch VW (2004) The impact of complications on outcomes after resection for esophageal and gastroesophageal junction carcinoma. J Am Coll Surg 198(1):42–50. doi: 10.1016/j.jamcollsurg.2003.08.007 PubMedCrossRefGoogle Scholar
  26. 26.
    Geh JI, Bond SJ, Bentzen SM, Glynne-Jones R (2006) Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response. Radiother Oncol 78(3):236–244. doi: 10.1016/j.radonc.2006.01.009 PubMedCrossRefGoogle Scholar
  27. 27.
    Reim D, Gertler R, Novotny A, Becker K, Buschenfelde CM, Ebert M, Dobritz M, Langer R, Hoefler H, Friess H, Schumacher C (2012) Adenocarcinomas of the esophagogastric junction are more likely to respond to preoperative chemotherapy than distal gastric cancer. Ann Surg Oncol 19(7):2108–2118. doi: 10.1245/s10434-011-2147-8 Google Scholar
  28. 28.
    Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, Schaefer H, Thiele J, Dienes HP, Mueller RP, Hoelscher AH (2005) Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg 242(5):684–692PubMedCrossRefGoogle Scholar
  29. 29.
    Lorenzen S, Blank S, Lordick F, Siewert JR, Ott K (2012) Prediction of response and prognosis by a score including only pretherapeutic parameters in 410 neoadjuvant treated gastric cancer patients. Ann Surg Oncol 19(7):2119–27. doi: 10.1245/s10434-012-2254-1 Google Scholar
  30. 30.
    Maschuw K, Kress R, Ramaswamy A, Braun I, Langer P, Gerdes B (2006) Short-term preoperative radiotherapy in rectal cancer patients leads to a reduction of the detectable number of lymph nodes in resection specimens. Langenbecks Arch Surg 391(4):364–368. doi: 10.1007/s00423-006-0056-2 PubMedCrossRefGoogle Scholar
  31. 31.
    Wichmann MW, Muller C, Meyer G, Strauss T, Hornung HM, Lau-Werner U, Angele MK, Schildberg FW (2002) Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer. Arch Surg 137(2):206–210PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • S. Blank
    • 1
  • A. Stange
    • 2
  • L. Sisic
    • 1
  • W. Roth
    • 3
  • L. Grenacher
    • 4
  • F. Sterzing
    • 5
  • M. Burian
    • 1
  • D. Jäger
    • 2
  • M. Büchler
    • 1
  • K. Ott
    • 1
  1. 1.Department of SurgeryUniversity Hospital of HeidelbergHeidelbergGermany
  2. 2.National Center of Tumor DiseasesUniversity of HeidelbergHeidelbergGermany
  3. 3.Institute of PathologyUniversity of HeidelbergHeidelbergGermany
  4. 4.Department of Diagnostic and Interventional RadiologyUniversity of HeidelbergHeidelbergGermany
  5. 5.Department of Radiation Oncology and Radiation TherapyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations