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Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Diffuse type adenocarcinoma and, more specifically, signet ring cell carcinoma (SRCC) of the stomach and gastroesophageal junction (GEJ) have a poor prognosis and the value of neoadjuvant chemo(radio)therapy (nCRT) is unclear.

Methods

All patients who underwent surgery for diffuse type gastric and GEJ carcinoma between 2004 and 2015 were retrospectively included from the Netherlands Cancer Registry. The primary outcome was overall survival after surgery. Kaplan–Meier curves were plotted. Furthermore, multivariable Poisson and Cox regressions were performed, correcting for confounders. To comply with the Cox regression proportional hazard assumption, gastric cancer survival was split into two groups, i.e. <90 days and >90 days, postoperatively by adding an interaction variable.

Results

Analyses included 2046 patients with diffuse type cancer: 1728 gastric cancers (50% SRCC) and 318 GEJ cancers (39% SRCC). In the gastric cancer group, 49% received neoadjuvant chemotherapy (nCT) and 51% received primary surgery (PS). All-cause mortality within 90 days postoperatively was lower after nCT (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.20–0.44; p < 0.001). Also after 90 days, mortality was lower in the nCT group (HR for the interaction variable 2.84, 95% CI 1.87–4.30, p < 0.001; total HR 0.29*2.84 = 0.84). In the GEJ group, 38% received nCT, 22% received nCRT, and 39% received PS. All-cause mortality was lower after nCT (HR 0.63, 95% CI 0.43–0.93; p = 0.020) compared with PS. The nCRT group was removed from the Cox regression analysis since the Kaplan–Meier curves of nCRT and PS intersected. The results for gastric and GEJ carcinomas were similar between the SRCC and non-SRCC subgroups.

Conclusion

For gastric and GEJ diffuse type cancer, including SRCC, nCT was associated with increased survival.

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References

  1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histoclinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49. https://doi.org/10.1111/apm.1965.64.1.31.

    Article  CAS  PubMed  Google Scholar 

  2. Jass JR, Sobin LH, Watanabe H. The World Health Organization’s histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer. 1990;66:2162–7. https://doi.org/10.1002/1097-0142(19901115)66:10%3c2162::aid-cncr2820661020%3e3.0.co;2-n.

    Article  CAS  PubMed  Google Scholar 

  3. Dassen AE, Dikken JL, Bosscha K, Wouters MWJM, Cats A, Van De Velde CJH, et al. Gastric cancer: decreasing incidence but stable survival in the Netherlands. Acta Oncol (Madr). 2014;53:138–42. https://doi.org/10.3109/0284186X.2013.789139.

    Article  Google Scholar 

  4. Dikken JL, Lemmens VE, Wouters MWJM, Wijnhoven BP, Siersema PD, Nieuwenhuijzen GA, et al. Increased incidence and survival for oesophageal cancer but not for gastric cardia cancer in the Netherlands. Eur J Cancer. 2012;48:1624–32. https://doi.org/10.1016/j.ejca.2012.01.009.

    Article  PubMed  Google Scholar 

  5. Cunningham D, Allum WWH, Stenning SSP, Thompson JNJ, Van de Velde CJH, Nicolson M, Scarffe J, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. https://doi.org/10.1056/NEJMoa055531.

    Article  CAS  PubMed  Google Scholar 

  6. Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg. 2009;250:878–87. https://doi.org/10.1097/SLA.0b013e3181b21c7b.

    Article  PubMed  Google Scholar 

  7. Kim JP, Kim SC, Yang HK. Prognostic significance of signet ring cell carcinoma of the stomach. Surg Oncol. 1994;3:221–7.

    Article  CAS  PubMed  Google Scholar 

  8. Li C, Kim S, Lai JF, Hyung WJ, Choi WH, Choi SH, et al. Advanced gastric carcinoma with signet ring cell histology. Oncology. 2007;72:64–8. https://doi.org/10.1159/000111096.

    Article  PubMed  Google Scholar 

  9. Yokota T, Kunii Y, Teshima S, Yamada Y, Saito T, Kikuchi S, et al. Signet ring cell carcinoma of the stomach: a clinicopathological comparison with the other histological types. Tohoku J Exp Med. 1998;186:121–30. https://doi.org/10.1620/tjem.186.121.

    Article  CAS  PubMed  Google Scholar 

  10. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, 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;393:1948–57. https://doi.org/10.1016/S0140-6736(18)32557-1.

    Article  PubMed  Google Scholar 

  11. Nafteux PR, Lerut TE, Villeneuve PJ, Dhaenens JM, De Hertogh G, Moons J, et al. Signet ring cells in esophageal and gastroesophageal junction carcinomas have a more aggressive biological behavior. Ann Surg. 2014;260:1023–9. https://doi.org/10.1097/SLA.0000000000000689.

    Article  PubMed  Google Scholar 

  12. van der Kaaij RT, Koemans WJ, van Putten M, Snaebjornsson P, Luijten JC, van Dieren JM, et al. A population-based study on intestinal and diffuse type adenocarcinoma of the oesophagus and stomach in The Netherlands between 1989 and 2015. Eur J Cancer. 2020;130:23–31. https://doi.org/10.1016/j.ejca.2020.02.017.

    Article  PubMed  Google Scholar 

  13. Messager M, Lefevre JH, Pichot-Delahaye V, Souadka A, Piessen G, Mariette C. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg. 2011;254:684–93. https://doi.org/10.1097/SLA.0b013e3182352647.

    Article  PubMed  Google Scholar 

  14. Ugo D, Agnes A, Grieco M, Biondi A, Persiani R. Global updates in the treatment of gastric cancer: a systematic review. Part 2: perioperative management, multimodal therapies, new technologies, standardization of the surgical treatment and educational aspects. Updates Surg. 2020;72:12–8.

    Google Scholar 

  15. Moehler M, Baltin CTH, Ebert M, Fischbach W, Gockel I, Grenacher L, et al. International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus. Gastric Cancer. 2015;18:550–63. https://doi.org/10.1007/s10120-014-0403-x.

    Article  PubMed  Google Scholar 

  16. Hamilton SR, Aaltonen LA. World health organization classification of tumours pathology and genetics of tumours of the digestive system. Lyon: International Agency Res for Research on Cancer (IARC Press); 2000.

    Google Scholar 

  17. Stichting PALGA. Landelijke PALGA Protocol: Oesofagus-Maagcarcinoom 2019:versie 45.

  18. Mariette C, Carneiro F, Grabsch HI, van der Post RS, Allum W, de Manzoni G, et al. Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma. Gastric Cancer. 2019;22(1):1–9. https://doi.org/10.1007/s10120-018-0868-0.

    Article  CAS  PubMed  Google Scholar 

  19. Verhage RJJ, Zandvoort HJA, Ten Kate FJW, Van Hillegersberg R. How to define a positive circumferential resection margin in T3 adenocarcinoma of the esophagus. Am J Surg Pathol. 2011;35:919–26. https://doi.org/10.1097/PAS.0b013e31821a5692.

    Article  PubMed  Google Scholar 

  20. Washington K. 7th edition of the AJCC cancer staging manual: Stomach. Ann Surg Oncol. 2010;17:3077–9. https://doi.org/10.1245/s10434-010-1362-z.

    Article  PubMed  Google Scholar 

  21. Integraal Kankercentrum Nederland. Richtlijn Diagnostiek, behandeling en follow-up van het maagcarcinoom 2009.

  22. Integraal Kankercentrum Nederland. Diagnostiek, behandeling en follow-up van het maagcarcinoom 2016:1–7. http://www.oncoline.nl/uploaded/docs/Maagcarcinoom/Richtlijnmaagcarcinoom.pdf.

  23. van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EWW, van Berge Henegouwen MI, Wijnhoven BPLP, et al. Preoperative chemoradiotherapy for Esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84. https://doi.org/10.1056/NEJMoa1112088.

    Article  PubMed  Google Scholar 

  24. Van Der Kruijssen DEW, Brouwer NPM, Van Der Kuil AJS, Verhoeven RHA, Elias SG, Vink GR, et al. Interaction between primary tumor resection, primary tumor location, and survival in synchronous metastatic colorectal cancer: a population-based study. Am J Clin Oncol Cancer Clin Trials. 2021;44:315–24. https://doi.org/10.1097/COC.0000000000000823.

    Article  CAS  Google Scholar 

  25. Modest DP, Ricard I, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, et al. Evaluation of survival across several treatment lines in metastatic colorectal cancer: analysis of the FIRE-3 trial (AIO KRK0306). Eur J Cancer. 2017;84:262–9.

    Article  CAS  PubMed  Google Scholar 

  26. Walters DM, McMurry TL, Isbell JM, Stukenborg GJ, Kozower BD. Understanding mortality as a quality indicator after esophagectomy. Ann Thorac Surg. 2014;98:506–12. https://doi.org/10.1016/j.athoracsur.2014.03.041.

    Article  PubMed  Google Scholar 

  27. Low DE, Alderson D, Cecconello I, Chang AC, Darling GE, D’Journo XB, et al. International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG). Ann Surg. 2015;262:286–94. https://doi.org/10.1097/SLA.0000000000001098.

    Article  PubMed  Google Scholar 

  28. Baiocchi GL, Giacopuzzi S, Marrelli D, Reim D, Piessen G, Matos da Costa P, et al. International consensus on a complications list after gastrectomy for cancer. Gastric Cancer. 2019;22:172–89. https://doi.org/10.1007/s10120-018-0839-5.

    Article  PubMed  Google Scholar 

  29. Knol MJ, Le Cessie S, Algra A, Vandenbroucke JP, Groenwold RHH. Overestimation of risk ratios by odds ratios in trials and cohort studies: Alternatives to logistic regression. CMAJ. 2012;184:895–9. https://doi.org/10.1503/cmaj.101715.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol. 1983;1:710–9. https://doi.org/10.1200/JCO.1983.1.11.710.

    Article  CAS  PubMed  Google Scholar 

  31. Concato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis I. Background, goals, and general strategy. J Clin Epidemiol. 1995;48:1495–501. https://doi.org/10.1016/0895-4356(95)00510-2.

    Article  CAS  PubMed  Google Scholar 

  32. Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis II. J Clin Epidemiol. 1995;48:1503–10.

    Article  CAS  PubMed  Google Scholar 

  33. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:702–6. https://doi.org/10.1093/aje/kwh090.

    Article  PubMed  Google Scholar 

  34. Cats A, Jansen EPM, van Grieken NCT, 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(5):616–628. https://doi.org/10.1016/S1470-2045(18)30132-3.

    Article  CAS  PubMed  Google Scholar 

  35. Piessen G, Messager M, Le Malicot K, Robb WB, Di Fiore F, Guilbert M, et al. Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas—PRODIGE 19—FFCD1103—ADCI002. BMC Cancer. 2013. https://doi.org/10.1186/1471-2407-13-281.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Heger U, Sisic L, Nienhüser H, Blank S, Hinz U, Haag GM, et al. Neoadjuvant therapy improves outcomes in locally advanced signet-ring-cell containing esophagogastric adenocarcinomas. Ann Surg Oncol. 2018;25:2418–27. https://doi.org/10.1245/s10434-018-6541-3.

    Article  PubMed  Google Scholar 

  37. Li Y, Ma FH, Xue LY, Tian YT. Neoadjuvant chemotherapy vs upfront surgery for gastric signet ring cell carcinoma: a retrospective, propensity score-matched study. World J Gastroenterol. 2020;26:818–27. https://doi.org/10.3748/wjg.v26.i8.818.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Reynolds JV, Preston SR, O’Neill B, Baeksgaard L, Griffin SM, Mariette C, et al. ICORG 10–14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS). BMC Cancer. 2017;17:1–10. https://doi.org/10.1186/s12885-017-3386-2.

    Article  CAS  Google Scholar 

  39. 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;16:1–10. https://doi.org/10.1186/s12885-016-2564-y.

    Article  CAS  Google Scholar 

  40. van Putten M, Nelen SD, Lemmens VEPP, Stoot JHMB, Hartgrink HH, Gisbertz SS, et al. Overall survival before and after centralization of gastric cancer surgery in the Netherlands. Br J Surg. 2018;105:1807–15. https://doi.org/10.1002/bjs.10931.

    Article  PubMed  Google Scholar 

  41. Jensen LS, Nielsen H, Mortensen PB, Pilegaard HK, Johnsen SP. Enforcing centralization for gastric cancer in Denmark. Eur J Surg Oncol. 2010;36:S50–4. https://doi.org/10.1016/j.ejso.2010.06.025.

    Article  PubMed  Google Scholar 

  42. Nelen SD, Heuthorst L, Verhoeven RHA, Polat F, Kruyt PM, Reijnders K, et al. Impact of centralizing gastric cancer surgery on treatment, morbidity, and mortality. J Gastrointest Surg. 2017;21:2000–8. https://doi.org/10.1007/s11605-017-3531-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee JH, Chang KK, Yoon C, Tang LH, Strong VE, Yoon SS. Lauren histologic type is the most important factor associated with pattern of recurrence following resection of gastric adenocarcinoma. Ann Surg. 2018;267:105–13. https://doi.org/10.1097/SLA.0000000000002040.

    Article  PubMed  Google Scholar 

  44. Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v38–49. https://doi.org/10.1093/annonc/mdw350.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

The authors would like to thank all participating hospitals in The Netherlands for collecting the data, and the NCR and PALGA for supplying the data for this study.

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Author notes

  1. Emma C. Gertsen and Arjen van der Veen contributed equally to this work.

Authors and Affiliations

  1. Division Cancer Center, Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Emma C. Gertsen MD, PhD, Arjen van der Veen MD, PhD, Hylke J. F. Brenkman MD, PhD, Richard van Hillegersberg MD, PhD & Jelle P. Ruurda MD, PhD

  2. Department of Surgery, Meander Medical Center, Amersfoort, The Netherlands

    Hylke J. F. Brenkman MD, PhD

  3. Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Lodewijk A. A. Brosens MD, PhD

  4. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

    Rachel S. van der Post MD, PhD

  5. Department of Research and Development, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands

    Rob H. A. Verhoeven PhD, Josianne C. H. B. M. Luijten MD & Pauline A. J. Vissers PhD

  6. Department of Medical Oncology, Amsterdam UMC, Amsterdam, The Netherlands

    Rob H. A. Verhoeven PhD

  7. Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

    Erik Vegt MD, PhD

  8. Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands

    Peter D. Siersema MD, PhD

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  1. Emma C. Gertsen MD, PhD
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Correspondence to Emma C. Gertsen MD, PhD.

Ethics declarations

Human Rights Statement and Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This study was performed with nationwide, anonymous data; thus, informed consent or its substitute was waived by the Ethical Review Board of the NCR.

Disclosures

Relevant financial activities outside the submitted work. Peter D. Siersema is receiving research support from Pentax (Japan), The eNose Company, MicroTech (China) and Motus GI (USA). Rob H.A. Verhoeven has received research grants from Bristol-Myer Squibb and Roche. Emma C. Gertsen, Arjen van der Veen, Hylke J.F. Brenkman, Lodewijk A.A. Brosens, Rachel S. van der Post, Josianne C.H.B.M. Luijten, Pauline A.J. Vissers, Erik Vegt, Richard van Hillegersberg, and Jelle P. Ruurda have no disclosures to declare.

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Gertsen, E.C., van der Veen, A., Brenkman, H.J.F. et al. Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study. Ann Surg Oncol 31, 1760–1772 (2024). https://doi.org/10.1245/s10434-023-14690-y

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