Advertisement

International Journal of Colorectal Disease

, Volume 30, Issue 4, pp 447–457 | Cite as

A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer

  • Fausto Petrelli
  • Andrea Coinu
  • Veronica Lonati
  • Sandro Barni
Review

Abstract

Background

Current guidelines support the use of adjuvant chemotherapy (CT) following neoadjuvant chemoradiotherapy (CTRT) and surgery to treat rectal cancer, although clinical trials have provided little evidence that it is effective. We performed a systematic review of published studies to assess whether adjuvant CT improves outcome after neoadjuvant therapy and radical surgery in cases of rectal cancer.

Materials and methods

We conducted an electronic database search for randomized and nonrandomized studies in PubMed, EMBASE, Web of Science, Scopus and the Cochrane Register of Controlled Trials. We then carried out a meta-analysis by using the fixed- or random-effects models. The primary endpoint was 5-year overall survival (OS) reported as odds ratios (ORs) and 95 % confidence intervals (CIs).

Results

Two randomized controlled trials (RCTs), one pooled analysis of five RCTs and 10 retrospective studies that included a total of 5,457 patients matched our selection criteria. Meta-analysis showed that for rectal cancer patients treated with surgery and neoadjuvant CTRT, adjuvant CT improves 5-year OS (OR, 0.64; 95 % CI, 0.46–0.88; p = 0.006) and 5-year disease-free survival (DFS) (OR, 0.71; 95 % CI, 0.6–0.83; p < 0.0001). The 5-year OS benefit was significantly larger in downstaged patients and in retrospective series. A better DFS was instead noted in all studies due to a reduced risk of local relapse.

Conclusions

Amongst rectal cancer patients treated with neoadjuvant therapy and surgery, adjuvant CT seems to improve the 5-year DFS and OS rates and may be discussed with patients. However, the benefit derives mainly from retrospective evidence.

Keywords

Rectal cancer Adjuvant chemotherapy Overall survival Neoadjuvant chemoradiotherapy Surgery 

References

  1. 1.
    Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C et al (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30(16):1926–1933CrossRefPubMedGoogle Scholar
  2. 2.
    Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S (2012) Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 3:CD004078PubMedGoogle Scholar
  3. 3.
    Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ et al (2014) Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 15(2):184–190CrossRefPubMedGoogle Scholar
  4. 4.
    Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM et al (2014) Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (Xelox) versus control. Ann Oncol 25(7):1356–1362Google Scholar
  5. 5.
    Cionini L, Sainato A, De Paoli A (2010) Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol 96(suppl 1):S113–S114Google Scholar
  6. 6.
    Breugom AJ, van den Broek CBM, van Gijn W (2013) The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemotherapy followed by TME-surgery: the PROCTOR/SCRIPT study. Eur J Cancer 49(suppl 3):S1Google Scholar
  7. 7.
  8. 8.
  9. 9.
    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:e1000097CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012CrossRefPubMedGoogle Scholar
  11. 11.
    Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605CrossRefPubMedGoogle Scholar
  12. 12.
    Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions Version 5.1.0. The Cochrane Collaboration; 2011 [updated March 2011].Google Scholar
  13. 13.
    You KY, Huang R, Ding PR, Qiu B, Zhou GQ, Chang H et al (2014) Selective use of adjuvant chemotherapy for rectal cancer patients with ypN0. Int J Color Dis 29(4):529–538CrossRefGoogle Scholar
  14. 14.
    Tiselius C, Gunnarsson U, Smedh K, Glimelius B, Påhlman L (2013) Patients with rectal cancer receiving adjuvant chemotherapy have an increased survival: a population-based longitudinal study. Ann Oncol 24(1):160–165CrossRefPubMedGoogle Scholar
  15. 15.
    Kiran RP, Kirat HT, Burgess AN, Nisar PJ, Kalady MF, Lavery IC (2012) Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol 19(4):1206–1212CrossRefPubMedGoogle Scholar
  16. 16.
    Govindarajan A, Reidy D, Weiser MR, Paty PB, Temple LK, Guillem JG et al (2011) Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. Ann Surg Oncol 18(13):3666–3672CrossRefPubMedGoogle Scholar
  17. 17.
    Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M et al (2011) Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol 29(23):3163–3172CrossRefPubMedGoogle Scholar
  18. 18.
    Du CZ, Chen YC, Cai Y, Xue WC, Gu J (2011) Oncologic outcomes of primary and post-irradiated early stage rectal cancer: a retrospective cohort study. World J Gastroenterol 17(27):3229–3234PubMedCentralPubMedGoogle Scholar
  19. 19.
    Kusters M, Valentini V, Calvo FA, Krempien R, Nieuwenhuijzen GA, Martijn H et al (2010) Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases. Ann Oncol 21(6):1279–1284CrossRefPubMedGoogle Scholar
  20. 20.
    Huh JW, Kim HR (2009) Postoperative chemotherapy after neoadjuvant chemoradiation and surgery for rectal cancer: is it essential for patients with ypT0-2N0? J Surg Oncol 100(5):387–391CrossRefPubMedGoogle Scholar
  21. 21.
    Valentini V, Coco C, Rizzo G, Manno A, Crucitti A, Mattana C et al (2009) Outcomes of clinical T4M0 extra-peritoneal rectal cancer treated with preoperative radiochemotherapy and surgery: a prospective evaluation of a single institutional experience. Surgery 145(5):486–494CrossRefPubMedGoogle Scholar
  22. 22.
    Collette L, Bosset JF, den Dulk M, Nguyen F, Mineur L, Maingon P et al (2007) Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25(28):4379–4386CrossRefPubMedGoogle Scholar
  23. 23.
    Hildebrandt B, Rau B, Löffel J, Wust P, Nicolaou A, Gellermann J et al (2006) Adjuvant chemotherapy with folinic acid and 5-fluorouracil in patients with locally advanced rectal cancer previously treated by preoperative radiochemotherapy and curative tumor resection. Int J Color Dis 21(6):582–589CrossRefGoogle Scholar
  24. 24.
    Chan AK, Wong A, Jenken D, Heine J, Buie D, Johnson D (2004) Is postoperative adjuvant chemotherapy necessary in locally advanced rectal cancers after preoperative chemoradiation. Int J Radiat Oncol Biol Phys 60(1 Suppl):S297CrossRefGoogle Scholar
  25. 25.
    De Caluwé L, Van Nieuwenhove Y, Ceelen WP (2013) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev 2:CD006041PubMedGoogle Scholar
  26. 26.
    An X, Lin X, Wang FH, Goodman K, Cai PQ, Kong LH et al (2013) Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: a meta analysis. Eur J Cancer 49(4):843–851CrossRefPubMedGoogle Scholar
  27. 27.
    Habr-Gama A, Gama-Rodrigues J, São Julião GP, Proscurshim I, Sabbagh C, Lynn PB et al (2014) Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 88(4):822–828CrossRefPubMedGoogle Scholar
  28. 28.
    Gunderson LL, Sargent DJ, Tepper JE, Wolmark N, O'Connell MJ, Begovic M et al (2004) Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22(10):1785–1796CrossRefPubMedGoogle Scholar
  29. 29.
    Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M et al (2005) Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23(34):8664–8670CrossRefPubMedGoogle Scholar
  30. 30.
    Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T et al (2014) Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J Clin Oncol 32(22):2380–2385Google Scholar
  31. 31.
    André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O et al (2007) Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 25(24):3732–3738CrossRefPubMedGoogle Scholar
  32. 32.
    Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT et al (2012) Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 13(6):579–588CrossRefPubMedGoogle Scholar
  33. 33.
    Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A et al (2010) Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol 11(3):241–248CrossRefPubMedGoogle Scholar
  34. 34.
    Petrelli F, Sgroi G, Sarti E, Barni S (2013) Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies. Ann Surg. doi: 10.1097/SLA.0000000000000368
  35. 35.
    Khrizman P, Niland JC, ter Veer A, Milne D, Bullard Dunn K, Carson WE 3rd et al (2013) Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis. J Clin Oncol 31(1):30–38CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fausto Petrelli
    • 1
  • Andrea Coinu
    • 1
  • Veronica Lonati
    • 2
  • Sandro Barni
    • 1
  1. 1.Medical Oncology Unit, Oncology DepartmentAzienda Ospedaliera TreviglioTreviglioItaly
  2. 2.Medical Oncology Unit, Clinical Trials Office, Oncology DepartmentAzienda Ospedaliera TreviglioTreviglioItaly

Personalised recommendations