Skip to main content

Advertisement

Log in

Neoadjuvant Radiotherapy for Rectal Cancer: Meta-analysis of Randomized Controlled Trials

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

Abstract

Background

Although neoadjuvant radiotherapy may improve local control of rectal cancer, its clinical value requires further evaluation as a result of potential side effects and advances in surgical technique. A meta-analysis was performed to assess effectiveness and safety of neoadjuvant radiotherapy in the management of rectal cancer.

Methods

The following databases were searched: the Cochrane Library, Biosis, Web of Science, Embase, ASCO Abstracts and WHO International Clinical Trials Registry Platform. Randomized controlled trials on the following comparisons were included: (1) neoadjuvant therapy versus surgery alone and (2) neoadjuvant chemoradiotherapy versus neoadjuvant radiotherapy.

Results

We identified 17 and 5 relevant trials that enrolled 8,568 and 2,393 patients, respectively. Neoadjuvant radiotherapy improved local control (hazard ratio 0.59; 95 % confidence interval 0.48–0.72) compared to surgery alone even after total mesorectal excision, whereas its benefit in overall survival just failed to reach statistical significance (0.93; 0.85–1.00). However, it was associated with increased perioperative mortality (1.48; 1.08–2.03), in particular if a dose of 5 Gy per fraction was administered (1.85; 1.23–2.78). Chemoradiotherapy improved local control as opposed to radiotherapy (0.53; 0.39–0.72), with no impact on perioperative outcome and long-term survival.

Conclusions

Neoadjuvant radiotherapy improves local control in patients with rectal cancer, particularly when chemoradiotherapy is administered. The question if the use of more effective chemotherapy protocols improves overall survival warrants further investigation.

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

Access this article

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. Elferink MA, Krijnen P, Wouters MW, et al. Variation in treatment and outcome of patients with rectal cancer by region, hospital type and volume in the Netherlands. Eur J Surg Oncol. 2010;36(Suppl 1):S74–82.

    Article  PubMed  Google Scholar 

  2. Schroen AT, Cress RD. Use of surgical procedures and adjuvant therapy in rectal cancer treatment: a population-based study. Ann Surg. 2001;234:641–51.

    Article  PubMed  CAS  Google Scholar 

  3. Ulrich A, Schwerdt J, Z’Graggen K, et al. Acceptance of neoadjuvant short-term radiotherapy: a survey under surgeons and radiotherapists. Langenbecks Arch Surg. 2007;392:525–33.

    Article  PubMed  Google Scholar 

  4. Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions, version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011.

  5. Armpilia CI, Dale RG, Jones B. Determination of the optimum dose per fraction in fractionated radiotherapy when there is delayed onset of tumour repopulation during treatment. Br J Radiol. 2004;77(921):765–7.

    Article  PubMed  CAS  Google Scholar 

  6. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  Google Scholar 

  7. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.

    Article  PubMed  CAS  Google Scholar 

  8. Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    Article  PubMed  Google Scholar 

  9. Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138:1714–26.

    Google Scholar 

  10. Rahbari NN, Bork U, Motschall E, et al. Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30:60–70.

    Article  PubMed  Google Scholar 

  11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  PubMed  CAS  Google Scholar 

  12. Egger M, Smith GD. Meta-analysis. Potentials and promise. BMJ. 1997;315(7119):1371–4.

    Article  PubMed  CAS  Google Scholar 

  13. Habr-Gama A, Perez RO, Kiss DR, et al. Preoperative chemoradiation therapy for low rectal cancer. Impact on downstaging and sphincter-saving operations. Hepatogastroenterology. 2004;51:1703–7.

    PubMed  Google Scholar 

  14. The evaluation of low dose pre-operative X-ray therapy in the management of operable rectal cancer; results of a randomly controlled trial. Br J Surg. 1984;71:21–5.

  15. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party. Lancet. 1996;348(9042):1605–10.

  16. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish rectal cancer trial. N Engl J Med. 1997;336:980–7.

  17. Cedermark B, Johansson H, Rutqvist LE, et al. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer. 1995;75:2269–75.

    Article  PubMed  CAS  Google Scholar 

  18. Martling A, Holm T, Johansson H, et al. The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: long-term follow-up of a population-based study. Cancer. 2001;92:896–902.

    Article  PubMed  CAS  Google Scholar 

  19. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–46.

    Article  PubMed  CAS  Google Scholar 

  20. Dahl O, Horn A, Morild I, et al. Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western Norway. Cancer. 1990;66:2286–94.

    Article  PubMed  CAS  Google Scholar 

  21. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial. Dis Colon Rectum. 1994;37:1205–14.

    Article  PubMed  CAS  Google Scholar 

  22. Reis Neto JA, Quilici FA, Reis JA Jr. A comparison of nonoperative vs preoperative radiotherapy in rectal carcinoma. A 10-year randomized trial. Dis Colon Rectum. 1989;32:702–10.

    Google Scholar 

  23. Goldberg PA, Nicholls RJ, Porter NH, et al. Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer. 1994;30A:1602–6.

    Article  PubMed  CAS  Google Scholar 

  24. Petersen S, Hellmich G, Baumann M, et al. Brief preoperative radiotherapy in surgical therapy of rectal carcinoma. Long-term results of a prospective randomized study. Chirurg. 1998;69:759–65.

    Article  PubMed  CAS  Google Scholar 

  25. Higgins GA Jr, Conn JH, Jordan PH Jr, et al. Preoperative radiotherapy for colorectal cancer. Ann Surg. 1975;181:624–31.

    Article  PubMed  Google Scholar 

  26. Higgins GA, Humphrey EW, Dwight RW, et al. Preoperative radiation and surgery for cancer of the rectum. Veterans Administration Surgical Oncology Group Trial II. Cancer. 1986;58:352–9.

    Article  PubMed  CAS  Google Scholar 

  27. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg. 1988;208:606–14.

    Article  PubMed  CAS  Google Scholar 

  28. Kligerman MM, Urdaneta N, Knowlton A, et al. Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes. Am J Roentgenol Radium Ther Nucl Med. 1972;114:498–503.

    Article  PubMed  CAS  Google Scholar 

  29. Rider WD, Palmer JA, Mahoney W, et al. Preoperative irradiation in operable cancer of the rectum: report of the Toronto trial. Can J Surg. 1977;20:335–8.

    PubMed  CAS  Google Scholar 

  30. Illenyi L, Grexa E, Gecser G, et al. Local recurrence of rectal cancer following preoperative irradiation. Acta Chir Hung. 1994;34:333–47.

    PubMed  CAS  Google Scholar 

  31. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–23.

    Article  PubMed  CAS  Google Scholar 

  32. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215–23.

    Article  PubMed  CAS  Google Scholar 

  33. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.

    Article  PubMed  Google Scholar 

  34. Boulis-Wassif S, Gerard A, Loygue J, et al. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Trial of the European Organization on Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Cancer. 1984;53:1811–8.

    Article  PubMed  CAS  Google Scholar 

  35. Latkauskas T, Pauzas H, Gineikiene I, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long-term chemoradiotherapy, both with delayed surgery. Colorectal Dis. 2012;14:294–8.

    Article  PubMed  CAS  Google Scholar 

  36. Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA. 2000;284:1008–15.

    Article  PubMed  CAS  Google Scholar 

  37. Wong RK, Tandan V, De Silva S, et al. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev. 2007;(2):CD002102.

  38. Rahbari NN, Weitz J, Hohenberger W, et al. Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer. Surgery. 2010;147:339–51.

    Article  PubMed  Google Scholar 

  39. den Dulk M, Marijnen CA, Collette L, et al. Multicentre analysis of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery. Br J Surg. 2009;96:1066–75.

    Article  Google Scholar 

  40. Smith JD, Paty PB, Guillem JG, et al. Anastomotic leak is not associated with oncologic outcome in patients undergoing low anterior resection for rectal cancer. Ann Surg. In press.

  41. Holm T, Singnomklao T, Rutqvist LE, et al. Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up of two randomized trials. Cancer. 1996;78:968–76.

    Article  PubMed  CAS  Google Scholar 

  42. Birgisson H, Pahlman L, Gunnarsson U, et al. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol. 2005;23:8697–705.

    Article  PubMed  Google Scholar 

  43. Glimelius B, Pahlman L, Cervantes A. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v82–6.

    Article  PubMed  Google Scholar 

  44. NCPGiON guidelines. Rectal cancer (version 3.2012).

  45. Marijnen CA, Kapiteijn E, van de Velde CJ, et al; Cooperative Investigators of the Dutch Colorectal Cancer Group. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol. 2002;20:817–825.

    Article  PubMed  CAS  Google Scholar 

  46. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575–82.

    Article  PubMed  Google Scholar 

  47. Marijnen CA, Nagtegaal ID, Kapiteijn E, et al. Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys. 2003;55:1311–20.

    Article  PubMed  CAS  Google Scholar 

  48. McCarthy K, Pearson K, Fulton R, et al. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;(12):CD008368.

  49. De Caluwe L, Van Nieuwenhove Y, Ceelen WP. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev. 2013;(2):CD006041.

  50. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.

    Article  PubMed  CAS  Google Scholar 

  51. Rodel C, Liersch T, Hermann RM, et al. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol. 2007;25:110–7.

    Article  PubMed  Google Scholar 

  52. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28:1638–44.

    Article  PubMed  CAS  Google Scholar 

  53. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773–80.

    Article  PubMed  CAS  Google Scholar 

  54. Rodel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13:679–87.

    Article  PubMed  Google Scholar 

Download references

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nuh N. Rahbari MD.

Additional information

Nuh N. Rahbari and Heike Elbers contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 176 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rahbari, N.N., Elbers, H., Askoxylakis, V. et al. Neoadjuvant Radiotherapy for Rectal Cancer: Meta-analysis of Randomized Controlled Trials. Ann Surg Oncol 20, 4169–4182 (2013). https://doi.org/10.1245/s10434-013-3198-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-3198-9

Keywords

Navigation