Skip to main content
SpringerLink
Log in

Anastomotic leak risk in complete responders to neoadjuvant therapy for rectal cancer: a systematic review

  • Review
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

The oncological benefits of achieving a complete pathological response following neoadjuvant chemoradiotherapy for rectal cancer are well defined. How a pathological response affects anastomotic healing or leak rates is not clear. The aim of this systematic review was to compare anastomotic leak rates among patients who did and did not achieve a complete pathological response.

Methods

Three major databases (PubMed, Embase, and Scopus) were searched. Predetermined inclusion criteria included prospective and retrospective articles published in English reporting complete pathological response and anastomotic leak rates following total mesorectal excision in ≥ 30 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and total mesorectal excision. The primary outcomes measured included complete pathological response and 30-day postoperative morbidity.

Results

From a total of 8919 patients with rectal cancer in 7 studies, 4165 fulfilled the criteria for inclusion. The majority (> 80%) of patients had clinical stage II or III disease. A defunctioning loop ileostomy was formed in 76.5%. A total of 589 (14.1%) patients achieved a pCR of whom 63 (10.7%) developed an anastomotic leak compared to 272/3576 (7.6%) patients without a pCR (p = 0.02).

Conclusion

Patients with complete pathological response following neoadjuvant chemoradiotherapy and total mesorectal excision may be at higher risk of anastomotic leak than incomplete responders. This may need to be taken into account when counseling patients about the relative risks of organ preservation versus anterior resection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The data that support the findings of this study are available in PubMed, Embase, and Scopus databases.

References

  1. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355(11):1114–1123

    Article  CAS  Google Scholar 

  2. Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde C, Dutch Colorectal Cancer Group (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246(5):693–701

    Article  Google Scholar 

  3. Martin ST, Heneghan HM, Winter DC (2012) Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 99(7):918–928

    Article  CAS  Google Scholar 

  4. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, Calvo FA, García-Aguilar J, Glynne-Jones R, Haustermans K, Mohiuddin M, Pucciarelli S, Small W Jr, Suárez J, Theodoropoulos G, Biondo S, Beets-Tan RGH, Beets GL (2010) Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 11(9):835–844

    Article  Google Scholar 

  5. Kang CY, Halabi WJ, Chaudhry OO, Nguyen V, Pigazzi A, Carmichael JC, Mills S, Stamos MJ (2013) Risk factors for anastomotic leakage after anterior resection for rectal cancer. JAMA Surg 148(1):65–71

    Article  Google Scholar 

  6. Boström P, Haapamäki MM, Rutegård J, Matthiessen P, Rutegård M (2019) Population-based cohort study of the impact on postoperative mortality of anastomotic leakage after anterior resection for rectal cancer. BJS Open 3(1):106–111

    Article  Google Scholar 

  7. Wang S, Liu J, Wang S, Zhao H, Ge S, Wang W (2017) Adverse effects of anastomotic leakage on local recurrence and survival after curative anterior resection for rectal cancer: a systematic review and meta-analysis. World J Surg 41(1):277–284

    Article  Google Scholar 

  8. Mirnezami A, Mirnezami R, Chandrakumaran K, Sasapu K, Sagar P, Finan P (2011) Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann Surg 253(5):890–899

    Article  Google Scholar 

  9. Lu ZR, Rajendran N, Lynch AC, Heriot AG, Warrier SK (2016) Anastomotic leaks after restorative resections for rectal cancer compromise cancer outcomes and survival. Dis Colon Rectum 59(3):236–244

    Article  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  Google Scholar 

  11. Wells G et al (2000) The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis. [cited March 2020]; Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 01/03/2020

  12. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Geisler D, Dietz DW, Lavery IC, Fazio VW, Kalady MF (2011) Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol 18(6):1590–1598

    Article  Google Scholar 

  13. Duldulao MP, Lee W, le M, Wiatrek R, Nelson RA, Chen Z, Li W, Kim J, Garcia-Aguilar J (2011) Surgical complications and pathologic complete response after neoadjuvant chemoradiation in locally advanced rectal cancer. Am Surg 77(10):1281–1285

    Article  Google Scholar 

  14. Iskander O et al (2019) Complete pathological response following radiochemotherapy for locally advanced rectal cancer: short and long-term outcome. Anticancer Res 39(9):5105–5113

    Article  CAS  Google Scholar 

  15. Landi F, Espín E, Rodrigues V, Vallribera F, Martinez A, Charpy C, Brunetti F, Azoulay D, de’Angelis N (2017) Pathologic response grade after long-course neoadjuvant chemoradiation does not influence morbidity in locally advanced mid-low rectal cancer resected by laparoscopy. Int J Color Dis 32(2):255–264

    Article  Google Scholar 

  16. Lyall A, Mc Adam TK, Townend J, Loudon MA (2007) Factors affecting anastomotic complications following anterior resection in rectal cancer. Color Dis 9(9):801–807

    Article  CAS  Google Scholar 

  17. Maggiori L, Bretagnol F, Aslam MI, Guedj N, Zappa M, Ferron M, Panis Y (2014) Does pathologic response of rectal cancer influence postoperative morbidity after neoadjuvant radiochemotherapy and total mesorectal excision? Surgery 155(3):468–475

    Article  Google Scholar 

  18. van der Sluis FJ et al (2020) Population-based study of morbidity risk associated with pathological complete response after chemoradiotherapy for rectal cancer. Br J Surg 107(1):131–139

    Article  Google Scholar 

  19. McDermott FD, Heeney A, Kelly ME, Steele RJ, Carlson GL, Winter DC (2015) Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks. Br J Surg 102(5):462–479

    Article  CAS  Google Scholar 

  20. Chioreso C, del Vecchio N, Schweizer ML, Schlichting J, Gribovskaja-Rupp I, Charlton ME (2018) Association between hospital and surgeon volume and rectal cancer surgery outcomes in patients with rectal cancer treated since 2000: systematic literature review and meta-analysis. Dis Colon Rectum 61(11):1320–1332

    Article  Google Scholar 

  21. Jacobson RA, Wienholts K, Williamson AJ, Gaines S, Hyoju S, van Goor H, Zaborin A, Shogan BD, Zaborina O, Alverdy JC (2020) Exploits the human fibrinolytic system to drive excess collagenolysis: implications in gut healing and identification of druggable targets. Am J Physiol Gastrointest Liver Physiol 318(1):G1–G9

    Article  CAS  Google Scholar 

  22. Wiegerinck M, Hyoju SK, Mao J, Zaborin A, Adriaansens C, Salzman E, Hyman NH, Zaborina O, van Goor H, Alverdy JC (2018) Novel de novo synthesized phosphate carrier compound ABA-PEG20k-Pi20 suppresses collagenase production in Enterococcus faecalis and prevents colonic anastomotic leak in an experimental model. Br J Surg 105(10):1368–1376

    Article  CAS  Google Scholar 

  23. Jacobson RA, Williamson AJ, Wienholts K, Gaines S, Hyoju S, van Goor H, Zaborin A, Shogan BD, Zaborina O, Alverdy JC (2019) Prevention of anastomotic leak via local application of tranexamic acid to target bacterial-mediated plasminogen activation: a practical solution to a complex problem. Ann Surg. https://doi.org/10.1097/SLA.0000000000003733

  24. Hyoju SK, Adriaansens C, Wienholts K et al (2019) Low-fat/high-fibre diet prehabilitation improves anastomotic healing via the microbiome: an experimental model. Br J Surg. https://doi.org/10.1002/bjs.11388

  25. Chajon E, Castelli J, Marsiglia H, de Crevoisier R (2017) The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol 111:124–132

    Article  Google Scholar 

  26. Langley RE, Bump EA, Quartuccio SG, Medeiros D, Braunhut SJ (1997) Radiation-induced apoptosis in microvascular endothelial cells. Br J Cancer 75(5):666–672

    Article  CAS  Google Scholar 

  27. van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL, Figueiredo NL, Habr-Gama A, Perez RO, Renehan AG, van de Velde CJH, Ahlberg M, Appelt A, Asoglu O, Bär MT, Barroca R, Beets-Tan RGH, Belgers EHJ, Bosker RJI, Breukink SO, Bujko K, Carvalho C, Cunningham C, Creavin B, D'Hoore A, Gérard JP, Gollins S, Hoff C, Holman FA, Hupkens BJP, Iseas S, Jakobsen A, Keshvari A, Koopal SA, Kusters M, Langheinrich M, Leijtens JWA, Maas M, Malcomson L, Mamedli ZZ, Martling A, Matzel KE, Melenhorst J, Morici ML, Murad-Regadas SM, O'Dwyer ST, Peeters KCMJ, Rosa I, Rossi G, Rutten HJT, Sanchez Loria F, van der Sande ME, São Julião GP, Saunders M, Sun Myint A, van der Sluis H, Schiappa R, Scott N, Stoot JHMB, Talsma AK, Terrasson I, Tokmak H, Vaccaro CA, Vahrmeijer AL, Wasowicz DK, Westreenen HL, Winter DC, Wolthuis AM, Zimmerman DDE (2018) Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 391(10139):2537–2545

    Article  Google Scholar 

  28. Habr-Gama A, São Julião GP, Fernandez LM, Vailati BB, Andrade A, Araújo SEA, Gama-Rodrigues J, Perez RO (2019) Achieving a complete clinical response after neoadjuvant chemoradiation that does not require surgical resection: it may take longer than you think! Dis Colon Rectum 62(7):802–808

    Article  Google Scholar 

  29. Espín E, Ciga MA, Pera M, Ortiz H, the Spanish Rectal Cancer Project (2015) Oncological outcome following anastomotic leak in rectal surgery. Br J Surg 102(4):416–422

    Article  Google Scholar 

  30. Smith JD, Paty PB, Guillem JG, Temple LK, Weiser MR, Nash GM (2012) Anastomotic leak is not associated with oncologic outcome in patients undergoing low anterior resection for rectal cancer. Ann Surg 256(6):1034–1038

    Article  Google Scholar 

  31. Sammour T, Hayes IP, Jones IT, Steel MC, Faragher I, Gibbs P (2018) Impact of anastomotic leak on recurrence and survival after colorectal cancer surgery: a BioGrid Australia analysis. ANZ J Surg 88(1–2):E6–E10

    Article  Google Scholar 

  32. Fermor B, Umpleby HC, Lever JV, Symes MO, Williamson RC (1986) Proliferative and metastatic potential of exfoliated colorectal cancer cells. J Natl Cancer Inst 76(2):347–349

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Colorectal Disease, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland

    Alexandra M. Zaborowski, Aine Stakelum & Des C. Winter

Authors
  1. Alexandra M. Zaborowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aine Stakelum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Des C. Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the literature search and data analysis, drafted the manuscript, and approved the final manuscript.

Corresponding author

Correspondence to Alexandra M. Zaborowski.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

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

Supplementary Information

ESM 1

(DOCX 20 kb).

ESM 2

(DOC 62 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zaborowski, A.M., Stakelum, A. & Winter, D.C. Anastomotic leak risk in complete responders to neoadjuvant therapy for rectal cancer: a systematic review. Int J Colorectal Dis 36, 671–676 (2021). https://doi.org/10.1007/s00384-021-03833-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-021-03833-w

Keywords

Search

Navigation