Skip to main content
SpringerLink
Log in

Effect of Anastomotic Leak on Long-Term Survival After Esophagectomy: Multivariate Meta-analysis and Restricted Mean Survival Times Examination

Annals of Surgical Oncology volume 30, pages 5564–5572 (2023)Cite this article

Abstract

Background

Anastomotic leak (AL) is a serious complication after esophagectomy. It is associated with prolonged hospital stay, increased costs, and increased risk for 90-day mortality. Controversy exists concerning the impact of AL on survival. This study was designed to investigate the effect of AL on long-term survival after esophagectomy for esophageal cancer.

Methods

PubMed, MEDLINE, Scopus, and Web of Science were searched through October 30, 2022. The included studies evaluated the effect of AL on long-term survival. Primary outcome was long-term overall survival. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures.

Results

Thirteen studies (7118 patients) were included. Overall, 727 (10.2%) patients experienced AL. The RMSTD analysis shows that at 12, 24, 36, 48, and 60 months, patients not experiencing AL live an average of 0.7 (95% CI 0.2–1.2; p < 0.001), 1.9 (95% CI 1.1–2.6; p < 0.001), 2.6 (95% CI 1.6–3.7; p < 0.001), 3.4 (95% CI 1.9–4.9; p < 0.001), and 4.2 (95% CI 2.1–6.4; p < 0.001) months longer compared with those with AL, respectively. The time-dependent HRs analysis for AL versus no AL shows a higher mortality hazard in patients with AL at 3 (HR 1.94, 95% CI 1.54–2.34), 6 (HR 1.56, 95% CI 1.39–1.75), 12 (HR 1.47, 95% CI 1.24–1.54), and 24 months (HR 1.19, 95% CI 1.02–1.31).

Conclusions

This study seems to suggest a modest clinical impact of AL on long-term OS after esophagectomy. Patients who experience AL seem to have a higher mortality hazard during the first 2 years of follow-up.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

Data Availability

The data collected and analyzed during the current review are available from the corresponding author on reasonable request.

References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    PubMed  Google Scholar 

  3. Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A. 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(9):1090–8.

    PubMed  Google Scholar 

  4. Preston SR, Markar SR, Baker CR, Soon Y, Singh S, Low DE. Impact of a multidisciplinary standardized clinical pathway on perioperative outcomes in patients with oesophageal cancer. Br J Surg. 2013;100(1):105–12.

    CAS  PubMed  Google Scholar 

  5. Findlay JM, Gillies RS, Millo J, Sgromo B, Marshall RE, Maynard ND. Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines. Ann Surg. 2014;259(3):413–31.

    PubMed  Google Scholar 

  6. Schmidt HM, Gisbertz SS, Moons J, Rouvelas I, Kauppi J, Brown A, Asti E, Luyer M, Lagarde SM, Berlth F, Philippron A, Bruns C, Hölscher A, Schneider PM, Raptis DA, van Berge Henegouwen MI, Nafteux P, Nilsson M, Räsanen J, Palazzo F, Rosato E, Mercer S, Bonavina L, Nieuwenhuijzen G, Wijnhoven BPL, Schröder W, Pattyn P, Grimminger PP, Gutschow CA. Defining benchmarks for transthoracic esophagectomy: a multicenter analysis of total minimally invasive esophagectomy in low risk patients. Ann Surg. 2017;266(5):814–21.

    PubMed  Google Scholar 

  7. Biere SS, van Berge Henegouwen MI, Maas KW, Bonavina L, Rosman C, Garcia JR, Gisbertz SS, Klinkenbijl JH, Hollmann MW, de Lange ES, Bonjer HJ, van der Peet DL, Cuesta MA. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet. 2012;379(9829):1887–92.

    PubMed  Google Scholar 

  8. Straatman J, van der Wielen N, Cuesta MA, Daams F, Roig Garcia J, Bonavina L, Rosman C, van Berge Henegouwen MI, Gisbertz SS, van der Peet DL. Minimally invasive versus open esophageal resection: three-year follow-up of the previously reported randomized controlled trial: the TIME trial. Ann Surg. 2017;266(2):232–6.

    PubMed  Google Scholar 

  9. Mariette C, Markar SR, Dabakuyo-Yonli TS, Meunier B, Pezet D, Collet D, D’Journo XB, Brigand C, Perniceni T, Carrère N, Mabrut JY, Msika S, Peschaud F, Prudhomme M, Bonnetain F, Piessen G, Fédération de Recherche en Chirurgie (FRENCH) and French Eso-Gastric Tumors (FREGAT) Working Group. Hybrid minimally invasive esophagectomy for esophageal cancer. N Engl J Med. 2019;380(2):152–62.

    PubMed  Google Scholar 

  10. Low DE, Kuppusamy MK, Alderson D, Cecconello I, Chang AC, Darling G, Davies A, D’Journo XB, Gisbertz SS, Griffin SM, Hardwick R, Hoelscher A, Hofstetter W, Jobe B, Kitagawa Y, Law S, Mariette C, Maynard N, Morse CR, Nafteux P, Pera M, Pramesh CS, Puig S, Reynolds JV, Schroeder W, Smithers M, Wijnhoven BPL. Benchmarking complications associated with esophagectomy. Ann Surg. 2019;269(2):291–8.

    PubMed  Google Scholar 

  11. Low DE, Alderson D, Cecconello I, Chang AC, Darling GE, D’Journo XB, Griffin SM, Hölscher AH, Hofstetter WL, Jobe BA, Kitagawa Y, Kucharczuk JC, Law SY, Lerut TE, Maynard N, Pera M, Peters JH, Pramesh CS, Reynolds JV, Smithers BM, van Lanschot JJ. International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG). Ann Surg. 2015;262(2):286–94.

    PubMed  Google Scholar 

  12. Blencowe NS, Strong S, McNair AG, Brookes ST, Crosby T, Griffin SM, Blazeby JM. Reporting of short-term clinical outcomes after esophagectomy: a systematic review. Ann Surg. 2012;255(4):658–66.

    PubMed  Google Scholar 

  13. Fumagalli U, Baiocchi GL, Celotti A, Parise P, Cossu A, Bonavina L, Bernardi D, de Manzoni G, Weindelmayer J, Verlato G, Santi S, Pallabazzer G, Portolani N, Degiuli M, Reddavid R, de Pascale S. Incidence and treatment of mediastinal leakage after esophagectomy: insights from the multicenter study on mediastinal leaks. World J Gastroenterol. 2019;25(3):356–66.

    PubMed  PubMed Central  Google Scholar 

  14. Martin LW, Swisher SG, Hofstetter W, Correa AM, Mehran RJ, Rice DC, Vaporciyan AA, Walsh GL, Roth JA. Intrathoracic leaks following esophagectomy are no longer associated with increased mortality. Ann Surg. 2005;242(3):392–9.

    PubMed  PubMed Central  Google Scholar 

  15. Junemann-Ramirez M, Awan MY, Khan ZM, Rahamim JS. Anastomotic leakage post-esophagogastrectomy for esophageal carcinoma: retrospective analysis of predictive factors, management and influence on longterm survival in a high volume centre. Eur J Cardiothorac Surg. 2005;27(1):3–7.

    CAS  PubMed  Google Scholar 

  16. Kondra J, Ong SR, Clifton J, Evans K, Finley RJ, Yee J. A change in clinical practice: a partially stapled cervical esophagogastric anastomosis reduces morbidity and improves functional outcome after esophagectomy for cancer. Dis Esophagus. 2008;21(5):422–9.

    CAS  PubMed  Google Scholar 

  17. Escofet X, Manjunath A, Twine C, Havard TJ, Clark GW, Lewis WG. Prevalence and outcome of esophagogastric anastomotic leak after esophagectomy in a UK regional cancer network. Dis Esophagus. 2010;23(2):112–6.

    CAS  PubMed  Google Scholar 

  18. Rutegård M, Lagergren P, Rouvelas I, Mason R, Lagergren J. Surgical complications and long-term survival after esophagectomy for cancer in a nationwide Swedish cohort study. Eur J Surg Oncol. 2012;38(7):555–61.

    PubMed  Google Scholar 

  19. Markar S, Gronnier C, Duhamel A, Mabrut JY, Bail JP, Carrere N, Lefevre JH, Brigand C, Vaillant JC, Adham M, Msika S, Demartines N, Nakadi IE, Meunier B, Collet D, Mariette C, FREGAT (French Eso-Gastric Tumors) Working Group, FRENCH (Fédération de Recherche EN CHirurgie), and AFC (Association Française de Chirurgie). The impact of severe anastomotic leak on long-term survival and cancer recurrence after surgical resection for esophageal malignancy. Ann Surg. 2015;262(6):972–80.

    PubMed  Google Scholar 

  20. Booka E, Takeuchi H, Nishi T, Matsuda S, Kaburagi T, Fukuda K, Nakamura R, Takahashi T, Wada N, Kawakubo H, Omori T, Kitagawa Y. The impact of postoperative complications on survivals after esophagectomy for esophageal cancer. Medicine (Baltimore). 2015;94(33):e1369.

    PubMed  Google Scholar 

  21. Van Daele E, Van de Putte D, Ceelen W, Van Nieuwenhove Y, Pattyn P. Risk factors and consequences of anastomotic leakage after Ivor Lewis oesophagectomy. Interact Cardiovasc Thorac Surg. 2016;22(1):32–7.

    PubMed  Google Scholar 

  22. Kataoka K, Takeuchi H, Mizusawa J, Igaki H, Ozawa S, Abe T, Nakamura K, Kato K, Ando N, Kitagawa Y. Prognostic impact of postoperative morbidity after esophagectomy for esophageal cancer: exploratory analysis of JCOG9907. Ann Surg. 2017;265(6):1152–7.

    PubMed  Google Scholar 

  23. Hayami M, Watanabe M, Ishizuka N, Mine S, Imamura Y, Okamura A, Kurogochi T, Yamashita K. Prognostic impact of postoperative pulmonary complications following salvage esophagectomy after definitive chemoradiotherapy. J Surg Oncol. 2018;117(6):1251–9.

    PubMed  Google Scholar 

  24. Kamarajah SK, Navidi M, Wahed S, Immanuel A, Hayes N, Griffin SM, Phillips AW. Anastomotic leak does not impact on long-term outcomes in esophageal cancer patients. Ann Surg Oncol. 2020;27(7):2414–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Fransen LFC, Berkelmans GHK, Asti E, van Berge Henegouwen MI, Berlth F, Bonavina L, Brown A, Bruns C, van Daele E, Gisbertz SS, Grimminger PP, Gutschow CA, Hannink G, Hölscher AH, Kauppi J, Lagarde SM, Mercer S, Moons J, Nafteux P, Nilsson M, Palazzo F, Pattyn P, Raptis DA, Räsanen J, Rosato EL, Rouvelas I, Schmidt HM, Schneider PM, Schröder W, van der Sluis PC, Wijnhoven BPL, Nieuwenhuijzen GAP, Luyer MDP, EsoBenchmark Collaborative. The effect of postoperative complications after minimally invasive esophagectomy on long-term survival: an international multicenter cohort study. Ann Surg. 2021;274(6):e1129-37.

    PubMed  Google Scholar 

  26. Tverskov V, Wiesel O, Solomon D, Orgad R, Kashtan H. The impact of cervical anastomotic leak after esophagectomy on long-term survival of patients with esophageal cancer. Surgery. 2022;171(5):1257–62.

    PubMed  Google Scholar 

  27. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.

    PubMed  PubMed Central  Google Scholar 

  28. Goossen K, Tenckhoff S, Probst P, Grummich K, Mihaljevic AL, Büchler MW, Diener MK. Optimal literature search for systematic reviews in surgery. Langenbecks Arch Surg. 2018;403(1):119–29.

    PubMed  Google Scholar 

  29. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, Carpenter JR, Chan AW, Churchill R, Deeks JJ, Hróbjartsson A, Kirkham J, Jüni P, Loke YK, Pigott TD, Ramsay CR, Regidor D, Rothstein HR, Sandhu L, Santaguida PL, Schünemann HJ, Shea B, Shrier I, Tugwell P, Turner L, Valentine JC, Waddington H, Waters E, Wells GA, Whiting PF, Higgins JP. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.

    PubMed  PubMed Central  Google Scholar 

  30. Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol. 2013;13:152.

    PubMed  PubMed Central  Google Scholar 

  31. Wei Y, Royston P, Tierney JF, Parmar MKB. Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data. Stat Med. 2015;34(21):2881–98.

    PubMed  PubMed Central  Google Scholar 

  32. Jackson D, White IR, Riley RD. A matrix-based method of moments for fitting the multivariate random effects model for meta-analysis and meta-regression. Biometrical J. 2013;55(2):231–45.

    Google Scholar 

  33. Guyot P, Ades A, Ouwens MJ, et al. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9.

    PubMed  PubMed Central  Google Scholar 

  34. Bona D, Micheletto G, Bonitta G, et al. Does C-reactive protein have a predictive role in the early diagnosis of postoperative complications after bariatric surgery? Systematic review and Bayesian meta-analysis. Obes Surg. 2019;29(11):3448–56. https://doi.org/10.1007/s11695-019-04013-0.

    Article  PubMed  Google Scholar 

  35. Charvat H, Belot A. Mexhaz: an R package for fitting flexible hazard-based regression models for overall and excess mortality with a random effect. J Stat Softw. 2021;98(14):1–36. https://doi.org/10.18637/jss.v098.i14.

    Article  Google Scholar 

  36. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at http://www.R-project.org/. Accessed 30 Nov 2018.

  37. Aiolfi A, Asti E, Rausa E, et al. Use of C-reactive protein for the early prediction of anastomotic leak after esophagectomy: Systematic review and Bayesian meta-analysis. PLoS ONE. 2018;13(12):e0209272.

    PubMed  PubMed Central  Google Scholar 

  38. Okamura A, Takeuchi H, Matsuda S, Ogura M, Miyasho T, Nakamura R, Takahashi T, Wada N, Kawakubo H, Saikawa Y, Kitagawa Y. Factors affecting cytokine change after esophagectomy for esophageal cancer. Ann Surg Oncol. 2015;22(9):3130–5.

    PubMed  Google Scholar 

  39. Ogura M, Takeuchi H, Kawakubo H, Nishi T, Fukuda K, Nakamura R, Takahashi T, Wada N, Saikawa Y, Omori T, Miyasho T, Yamada S, Kitagawa Y. Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma. Surgery. 2013;154(3):512–20.

    PubMed  Google Scholar 

  40. McArdle CS, McMillan DC, Hole DJ. Impact of anastomotic leakage on long-term survival of patients undergoing curative resection for colorectal cancer. Br J Surg. 2005;92:e1150-54. https://doi.org/10.1002/bjs.5054.

    Article  Google Scholar 

  41. Gujjuri RR, Kamarajah SK, Markar SR. Effect of anastomotic leaks on long-term survival after oesophagectomy for oesophageal cancer: systematic review and meta-analysis. Dis Esophagus. 2021;34(3):doaa085.

    PubMed  Google Scholar 

  42. Barraclough H, Simms L, Govindan R. Biostatistics primer: what a clinician ought to know: hazard ratios. J Thorac Oncol. 2011;6(6):978–82.

    PubMed  Google Scholar 

  43. Oesophago-Gastric Anastomosis Study Group on behalf of the West Midlands Research Collaborative. Comparison of short-term outcomes from the International Oesophago-Gastric Anastomosis Audit (OGAA), the Esophagectomy Complications Consensus Group (ECCG), and the Dutch Upper Gastrointestinal Cancer Audit (DUCA). BJS Open. 2021;5(3):zrab010.

  44. Takahashi A, Yamamoto H, Kakeji Y, et al. Estimates of the effects of centralization policy for surgery in Japan: does centralization affect the quality of healthcare for esophagectomies? Surg Today. 2021;51(6):1010–9. https://doi.org/10.1007/s00595-021-02245-1.

    Article  PubMed  Google Scholar 

  45. Song Y, Shannon AB, Concors SJ, Roses RE, Fraker DL, DeMatteo RP, Kelz RR, Karakousis GC. Are volume pledge standards worth the travel burden for major abdominal cancer operations? Ann Surg. 2022;275(6):e743–51.

    PubMed  Google Scholar 

  46. van Workum F, Stenstra MHBC, Berkelmans GHK, et al. Learning curve and associated morbidity of minimally invasive esophagectomy: a retrospective multicenter study. Ann Surg. 2019;269:88–94.

    PubMed  Google Scholar 

  47. Markar SR, Lagergren J. Surgical and surgeon-related factors related to long-term survival in esophageal cancer: a review. Ann Surg Oncol. 2020;27(3):718–23.

    PubMed  Google Scholar 

  48. Derogar M, Sadr-Azodi O, Johar A, Lagergren P, Lagergren J. Hospital and surgeon volume in relation to survival after esophageal cancer surgery in a population-based study. J Clin Oncol. 2013;31:551–7.

    PubMed  Google Scholar 

  49. Brusselaers N, Mattsson F, Lagergren J. Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis. Gut. 2014;63:1393–400.

    PubMed  Google Scholar 

  50. Rausa E, Asti E, Aiolfi A, Bianco F, Bonitta G, Bonavina L. Comparison of endoscopic vacuum therapy versus endoscopic stenting for esophageal leaks: systematic review and meta-analysis. Dis Esophagus. 2018. https://doi.org/10.1093/dote/doy060.

    Article  PubMed  Google Scholar 

  51. Bona D, Lombardo F, Matsushima K, et al. Three-field versus two-field lymphadenectomy for esophageal squamous cell carcinoma: a long-term survival meta-analysis. Surgery. 2022;171(4):940–7.

    PubMed  Google Scholar 

  52. The Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541:169–75.

    PubMed Central  Google Scholar 

  53. Aiolfi A, Sozzi A, Bonitta G, et al. Linear- versus circular-stapled esophagogastric anastomosis during esophagectomy: systematic review and meta-analysis. Langenbecks Arch Surg. 2022;407(8):3297–309.

    PubMed  Google Scholar 

Download references

Acknowledgment

None

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. I.R.C.C.S. Ospedale Galeazzi – Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy

    Alberto Aiolfi MD, FACS, FEBS (UGI), Andrea Sozzi MD, Michele Manara MD, Gianluca Bonitta MSc, Luigi Bonavina MD, FACS & Davide Bona MD, FACS

  2. Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK

    Ewen A. Griffiths MD, FRCS

  3. Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    Ewen A. Griffiths MD, FRCS

Authors
  1. Alberto Aiolfi MD, FACS, FEBS (UGI)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ewen A. Griffiths MD, FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Sozzi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michele Manara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianluca Bonitta MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luigi Bonavina MD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Bona MD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AA: Conceptualization, Investigation, Analysis, Writing—original draft, review, and editing; EG: Conceptualization, Investigation, Writing—review and editing; AS: Investigation, review and editing; MM: Writing - review and editing; GB: Conceptualization, Analysis, Writing—review and editing; DB: Conceptualization, Investigation, Writing—original draft, review and editing, Supervision. All authors contributed to interpretation of data, critical revisions and approved the final version of the manuscript.

Corresponding author

Correspondence to Alberto Aiolfi MD, FACS, FEBS (UGI).

Ethics declarations

Disclosure

The authors have no related conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 17 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aiolfi, A., Griffiths, E.A., Sozzi, A. et al. Effect of Anastomotic Leak on Long-Term Survival After Esophagectomy: Multivariate Meta-analysis and Restricted Mean Survival Times Examination. Ann Surg Oncol 30, 5564–5572 (2023). https://doi.org/10.1245/s10434-023-13670-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-023-13670-6

Keywords

search

Navigation