Skip to main content
SpringerLink
Log in

Defining Non-inferiority Margins for Quality of Surgical Resection for Rectal Cancer: A Delphi Consensus Study

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

Abstract

Introduction

Quality of surgical resection metrics (QSRMs) have been used as surrogates for long-term oncologic outcomes in non-inferiority randomized clinical trials (RCTs) comparing laparoscopic and open surgery for rectal cancer. However, non-inferiority margins (ΔNI) for QSRMs have not been previously defined.

Methods

A two-round, web-based Delphi was used to define ΔNI for four QSRMs: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes. Overall, 130 international experts in rectal cancer (68 surgeons, 20 medical oncologists, 16 radiation oncologists, and 26 pathologists) were invited to participate. Experts were presented with evidence syntheses summarizing the association between QSRMs and long-term outcomes, and pooled quality of surgical resection outcomes for open surgery, and were asked to provide ΔNI for all outcomes balancing the risks and benefits of minimally invasive surgery.

Results

Seventy-two experts participated: 57 completed the initial questionnaire and 58 completed the revised questionnaire, with 43 participating in both rounds. Consensus was reached for all individual QSRM ΔNI but not for the composite. The mean (standard deviation) ΔNI was an absolute difference of 2.33% (1.59%) for the proportion of positive CRMs when comparing surgical interventions for the treatment of rectal cancer: 2.85% (1.83%) for incomplete PME; 1.28% (1.13%) for positive DRMs; and 2.71% (2.28%) for the composite. However, opinions varied widely for the composite outcome.

Conclusions

Web-based Delphi processes are a feasible approach to generate ΔNI to evaluate novel surgical interventions. The generated ΔNI for QSRMs for rectal cancer can be used for future RCTs and non-inferiority meta-analyses.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schwenk W, Haase O, Neudecker J, Muller JM. Short term benefits for laparoscopic colorectal resection. Cochrane Database Syst Rev. 2005;3:CD003145.

  2. Mulla SM, Scott IA, Jackevicius CA, You JJ, Guyatt GH. How to use a noninferiority trial: users’ guides to the medical literature. JAMA. 2012;308(24):2605–11.

    Article  CAS  Google Scholar 

  3. Baber N. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). Br J Clin Pharmacol. 1994;37(5):401–4.

    Article  CAS  Google Scholar 

  4. Committee for Medicinal Products for Human Use (CHMP) guideline on the choice of the non-inferiority margin. Stat Med. 2006;25(10):1628.

  5. Rothmann M, Li N, Chen G, Chi GY, Temple R, Tsou HH. Design and analysis of non-inferiority mortality trials in oncology. Stat Med. 2003;22(2):239–64.

    Article  Google Scholar 

  6. Rothmann MD, Tsou HH. On non-inferiority analysis based on delta-method confidence intervals. J Biopharm Stat. 2003;13(3):565–83.

    Article  Google Scholar 

  7. Wyrwich KW, Spertus JA, Kroenke K, et al. Clinically important differences in health status for patients with heart disease: an expert consensus panel report. Am Heart J. 2004;147(4):615–22.

    Article  Google Scholar 

  8. Bellamy N, Carette S, Ford P, et al. Osteoarthritis antirheumatic drug trials. III. Setting the delta for clinical trials—results of a consensus development (Delphi) exercise. J Rheumatol. 1992;19(3):451–7.

    CAS  PubMed  Google Scholar 

  9. McGlothlin AE, Lewis RJ. Minimal clinically important difference: defining what really matters to patients. JAMA. 2014;312(13):1342–3.

    Article  CAS  Google Scholar 

  10. Wells G, Beaton D, Shea B, et al. Minimal clinically important differences: review of methods. J Rheumatol. 2001;28(2):406–12.

    CAS  PubMed  Google Scholar 

  11. Treadwell JR, Uhl S, Tipton K, et al. Assessing equivalence and noninferiority. J Clin Epidemiol. 2012;65(11):1144–9.

    Article  Google Scholar 

  12. Stevenson AR, Solomon MJ, Lumley JW, et al. Effect of laparoscopic-assisted resection vs open resection on pathological outcomes in rectal cancer: the ALaCaRT randomized clinical trial. JAMA. 2015;314(13):1356–63.

    Article  CAS  Google Scholar 

  13. Fleshman J, Branda M, Sargent DJ, et al. Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: the ACOSOG Z6051 randomized clinical trial. JAMA. 2015;314(13):1346–55.

    Article  CAS  Google Scholar 

  14. Kennedy RH, Francis EA, Wharton R, et al. Multicenter randomized controlled trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme: EnROL. J Clin Oncol. 2014;32(17):1804–11.

    Article  Google Scholar 

  15. van der Pas MH, Haglind E, Cuesta MA, et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol. 2013;14(3):210–8.

    Article  Google Scholar 

  16. Gong J, Shi D-B, Li X-X, Cai S-J, Guan Z-Q, Xu Y. Short-term outcomes of laparoscopic total mesorectal excision compared to open surgery. World J Gastroenterol. 2012;18(48):7308.

    Article  Google Scholar 

  17. Liang XB, Hou SH, Li GD, et al. Randomized controlled trial of rectal laparoscopic surgery compared to open surgery 3-year efficacy summary. European Surgery—Acta Chirurgica Austriaca. 2015. In: Conference: 8th annual meeting of the chinese college of surgeons and 19th annual meeting of the European Society of Surgery. Beijing. Conference Publication: (var.pagings), vol. 47, p. S79.

  18. Kang SB, Park JW, Jeong SY, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial. Lancet Oncol. 2010;11(7):637–45.

    Article  Google Scholar 

  19. Lujan J, Valero G, Hernandez Q, Sanchez A, Frutos M, Parrilla P. Randomized clinical trial comparing laparoscopic and open surgery in patients with rectal cancer. Br J Surg. 2009;96(9):982–9.

    Article  CAS  Google Scholar 

  20. Pechlivanides G, Gouvas N, Tsiaoussis J, et al. Lymph node clearance after total mesorectal excision for rectal cancer: laparoscopic versus open approach. Dig Dis. 2007;25(1):94–9.

    Article  Google Scholar 

  21. Braga M, Frasson M, Vignali A, Zuliani W, Capretti G, Di Carlo V. Laparoscopic resection in rectal cancer patients: outcome and cost-benefit analysis. Dis Colon Rectum. 2007;50(4):464–471.

    Article  Google Scholar 

  22. Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet. 2005;365(9472):1718–26.

    Article  Google Scholar 

  23. Ng SS, Leung KL, Lee JF, et al. Laparoscopic-assisted versus open abdominoperineal resection for low rectal cancer: a prospective randomized trial. Ann Surg Oncol. 2008;15(9):2418–25.

    Article  Google Scholar 

  24. Ng SS, Leung KL, Lee JF, Yiu RY, Li JC, Hon SS. Long-term morbidity and oncologic outcomes of laparoscopic-assisted anterior resection for upper rectal cancer: ten-year results of a prospective, randomized trial. Dis Colon Rectum. 2009;52(4):558–66.

    Article  Google Scholar 

  25. Ng SS, Lee JF, Yiu RY, et al. Laparoscopic-assisted versus open total mesorectal excision with anal sphincter preservation for mid and low rectal cancer: a prospective, randomized trial. Surg Endosc. 2014;28(1):297–306.

    Article  Google Scholar 

  26. Zhou X, Liu F, Lin C, et al. Hand-assisted laparoscopic surgery compared with open resection for mid and low rectal cancer: a case-matched study with long-term follow-up. World J Surg Oncol. 13(1) (no pagination), 2015. 2015;Article Number:199. Date of Publication: June 110.

  27. Araujo SEA, Sousa Jr AHdS, Campos FGCMd, et al. Conventional approach × laparoscopic abdominoperineal resection for rectal cancer treatment after neoadjuvant chemoradiation: results of a prospective randomized trial. Revista do Hospital das Clínicas. 2003;58(3):133–40.

    Article  Google Scholar 

  28. Hsu C-C, Sandford BA. The Delphi technique: making sense of consensus. Pract Assess Res Eval. 2007;12(10):1–8.

    Google Scholar 

  29. Lee AC, Cousens S, Darmstadt GL, et al. Care during labor and birth for the prevention of intrapartum-related neonatal deaths: a systematic review and Delphi estimation of mortality effect. BMC Public Health. 2011;11(Suppl 3):S10.

    Article  Google Scholar 

  30. Roxburgh CS, Guillem JG. Outcomes of open vs laparoscopic rectal cancer resection. JAMA Oncol. 2017;3(1):115–6.

    Article  Google Scholar 

  31. Rehal S, Morris TP, Fielding K, Carpenter JR, Phillips PPJ. Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals. BMJ Open. 2016;6(10):e012594.

    Article  Google Scholar 

  32. Gayet-Ageron A, Agoritsas T, Rudaz S, Courvoisier D, Perneger T. The choice of the noninferiority margin in clinical trials was driven by baseline risk, type of primary outcome, and benefits of new treatment. J Clin Epidemiol. 2015;68(10):1144–51.

    Article  Google Scholar 

Download references

Funding

This study was funded by a Canadian Institutes of Health Research (CIHR) Operating Grant (Funding Reference No. 115164) and CIHR Foundation Grant (Funding Reference No. 148470). The funding sources had no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; or preparation, review or approval of the manuscript.

Author information

Authors and Affiliations

  1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada

    Sergio A. Acuna MD, PhD & Nancy N. Baxter MD, PhD

  2. Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

    Sergio A. Acuna MD, PhD, Sonali T. Amarasekera BSc & Nancy N. Baxter MD, PhD

  3. Department of Surgery, St. Michael’s Hospital, Toronto, ON, Canada

    Sergio A. Acuna MD, PhD & Nancy N. Baxter MD, PhD

  4. Division of General Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada

    Sergio A. Acuna MD, PhD, Tyler R. Chesney MD, MSc & Nancy N. Baxter MD, PhD

  5. Faculty of Science, McGill University, Montreal, QC, Canada

    Sonali T. Amarasekera BSc

  6. Division of General Surgery, St. Michael’s Hospital, Toronto, ON, Canada

    Nancy N. Baxter MD, PhD

Authors
  1. Sergio A. Acuna MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tyler R. Chesney MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonali T. Amarasekera BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nancy N. Baxter MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy N. Baxter MD, PhD.

Ethics declarations

Disclosure

Sergio A. Acuna, Tyler R. Chesney, Sonali T. Amarasekera, and Nancy N. Baxter have no conflicts of interest to disclose.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 919 kb)

Supplementary material 2 (PDF 290 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Acuna, S.A., Chesney, T.R., Amarasekera, S.T. et al. Defining Non-inferiority Margins for Quality of Surgical Resection for Rectal Cancer: A Delphi Consensus Study. Ann Surg Oncol 25, 3171–3178 (2018). https://doi.org/10.1245/s10434-018-6639-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-018-6639-7

Keywords

Search

Navigation