Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery?

  • Carlos Fernandez-Martos
  • Xabier Garcia de Albeniz


Distant relapse has become the biggest problem in locally advanced cancer of the rectum and is the most frequent reason for the mortality of these patients. As compared with radiation alone, preoperative combined modality treatment with 5FU and radiation increase the pathological complete response (pCR) rate over radiotherapy alone, and improve locoregional control but to date have not demonstrated an improvement in disease-free survival (DFS) or overall survival (OS). Applying chemotherapy after preoperative chemoradiation (CRT) and surgery is problematic and often not feasible, as has been shown in several phase III and phase II trials. One strategy to address this issue is to deliver upfront chemotherapy prior to preoperative CRT. Compared with postoperative chemotherapy, the upfront strategy did not appear to improve pCR; it did achieve a better toxicity profile, improved compliance with treatment and greater exposure to systemic treatment. This can be important for patients at higher risk of distant relapse. Introducing systemic active combination chemotherapy prior to chemoradiation and surgery with an adequate selection of the high-risk population may well be the next step in phase III testing in order to improve DFS.


Overall Survival Rectal Cancer Adjuvant Chemotherapy National Comprehensive Cancer Network Pathological Complete Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    André T, Boni C, Navarro M (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27(19):3109–3116PubMedCrossRefGoogle Scholar
  2. 2.
    André T, Boni C, Mounedji-Boudiaf L et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351PubMedCrossRefGoogle Scholar
  3. 3.
    Assed D, Coelho S, de Freitas D et al (2010) Combination therapy in high-risk stage II or stage III colon cancer: current practice and future prospects. Ther Adv Med Oncol 2(4):261–272Google Scholar
  4. 4.
    Beets G, Maas M, Nelemans P et al (2011) Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: a pooled analysis of 2,724 individual patients. J Clin Oncol 29(suppl 4; abstract 361)Google Scholar
  5. 5.
    Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123PubMedCrossRefGoogle Scholar
  6. 6.
    Bosset JF, Calais J, Mineur L et al (2005) Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results – EORTC 22921. J Clin Oncol 23:5620–5627PubMedCrossRefGoogle Scholar
  7. 7.
    Brown G, Radcliffe AG, Newcombe RG et al (2003) Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 90:355–364PubMedCrossRefGoogle Scholar
  8. 8.
    Bujko K, Glynne-Jones R, Bujko M (2010) Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomized trials. Ann Oncol 21(9):1743–1750PubMedCrossRefGoogle Scholar
  9. 9.
    Calvo FA, Serrano FJ, Diaz-Gonzalez JA et al (2006) Improved incidence of pTO downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 17:1103–1110PubMedCrossRefGoogle Scholar
  10. 10.
    Casado E, Moreno V, Sanchez JJ et al (2011) A combined strategy of SAGE and quantitative PCR provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res 17:4145–4154PubMedCrossRefGoogle Scholar
  11. 11.
    Chau I, Brown G, Cunningham D et al (2006) Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 24:668–674PubMedCrossRefGoogle Scholar
  12. 12.
    Chau I, Allen M, Cunningham D et al (2003) Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer 88:1017–1024PubMedCrossRefGoogle Scholar
  13. 13.
    Chua YJ, Barbachano Y, Cunningham D 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 11:241–248PubMedCrossRefGoogle Scholar
  14. 14.
    Collette L, Bosset JF, den Dulk M 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 organization for research and treatment of cancer radiation oncology group. J Clin Oncol 25:4379–4386PubMedCrossRefGoogle Scholar
  15. 15.
    Cook T, DeMets DL (2010) Review of draft FDA adaptive design guidance. J Biopharm Stat 20:1132–1142PubMedCrossRefGoogle Scholar
  16. 16.
    Fernandez-Martos C, Pericay C, Salud A et al (2011) Three-year outcome of GCR-3: a phase II randomized trial comparing conventional preoperative chemoradiation (CRT) followed by surgery and postoperative adjuvant chemotherapy (CT) with induction CT followed by CRT and surgery in locally advanced rectal cancer. J Clin Oncol 29(suppl; abstract 3552)Google Scholar
  17. 17.
    Fernandez-Martos C, Pericay C, Aparicio J et al (2010) Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol 28:859–865PubMedCrossRefGoogle Scholar
  18. 18.
    Fernandez-Martos C, Aparicio J, Bosch C et al (2004) Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years’ follow-up. J Clin Oncol 22:3016–3022PubMedCrossRefGoogle Scholar
  19. 19.
    Fransen K, Klintenas M, Osterstrom A et al (2004) Mutation analysis of the BRAF, ARAF, and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 25:527–533PubMedCrossRefGoogle Scholar
  20. 20.
    Gerard JP, Conroy T, Bonnetain F et al (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers. Results of FFCD 9203. J Clin Oncol 24:4620–4625PubMedCrossRefGoogle Scholar
  21. 21.
    Gill S, Loprinzi C, Sargent D et al (2004) Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22(10):1797–1806PubMedCrossRefGoogle Scholar
  22. 22.
    Glimelius B, Pahlman L, Cervantes A (2010) Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v82–v86PubMedCrossRefGoogle Scholar
  23. 23.
    Glynne-Jones R, Grainger J, Harrison J et al (2006) Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious? Br J Cancer 94:363–371PubMedCrossRefGoogle Scholar
  24. 24.
    Gray R, Barnwell J, McConkey C et al (2007) Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:2020–2029PubMedCrossRefGoogle Scholar
  25. 25.
    Gunnlaugsson A, Anderson H, Fernebro E et al (2009) Multicentre phase II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable colorectal cancer: the CORGI-L study. Eur J Cancer 45:807–813PubMedCrossRefGoogle Scholar
  26. 26.
    Hermanek P, Merkel S, Fietkau R et al (2010) Regional lymph node metastasis and locoregional recurrence of rectal carcinoma in the era of TNM surgery. Implications for treatment decisions. Int J Colorectal Dis 25:359–368PubMedCrossRefGoogle Scholar
  27. 27.
    Horn A, Dahl O, Morild I (1991) Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis Colon Rectum 34:798–804PubMedCrossRefGoogle Scholar
  28. 28.
    Kalady MF, Sanchez JA, Manilich E et al (2009) Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas. Dis Colon Rectum 52:1039–1045PubMedCrossRefGoogle Scholar
  29. 29.
    Kapiteijn E, Marijnen CA, Nagtegaal ID et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646PubMedCrossRefGoogle Scholar
  30. 30.
    Khrizman P, Niland JC, Veer A et al (2011) Postoperative adjuvant chemotherapy (CTX) use in patients (Pts) with stage II/III rectal cancer treated with neoadjuvant therapy: a National Comprehensive Cancer Network (NCCN) analysis. J Clin Oncol 29(suppl; abstract 3515)Google Scholar
  31. 31.
    Koeberle D, Burkhard R, von Moos R et al (2008) Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer 98:1204–1209PubMedCrossRefGoogle Scholar
  32. 32.
    Lahaye MJ, Engelen SME, Nelemans PJ et al (2005) Imaging for predicting the risk factors – the circumferential resection margin and nodal disease – of local recurrence in rectal cancer: a meta-analysis. Semin Ultrasound CT MRI 26:259–268CrossRefGoogle Scholar
  33. 33.
    Merkel S, Mansmann U, Siassi M et al (2001) The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 16:298–304PubMedCrossRefGoogle Scholar
  34. 34.
    Nagtegaal I, Quirke P (2008) What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26:303–312PubMedCrossRefGoogle Scholar
  35. 35.
    NCCN Clinical Practice Guidelines in Oncology (2011) Rectal Cancer. Version 4.2011. Accessed Dec 2011
  36. 36.
    Rödel C, Arnold D, Becker H et al (2010) Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer. Is it time for a randomized phase III trial? Strahlenther Onkol 186:658–664PubMedCrossRefGoogle Scholar
  37. 37.
    Rödel C, Liersch T, Hermann R et al (2007) Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:668–674Google Scholar
  38. 38.
    Roh M, Colangelo L, O’Connell M et al (2009) Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124–5130PubMedCrossRefGoogle Scholar
  39. 39.
    Russo A, Borger D, Ryan D et al (2011) Mutational analysis and clinical correlation of 185 consecutive metastatic colorectal patients: similarities and differences between colon and rectal cancers patients. J Clin Oncol 29(suppl; asbtract 3536)Google Scholar
  40. 40.
    Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740PubMedCrossRefGoogle Scholar
  41. 41.
    Sebag-Montefiore D, Rutten H, Rullier E et al (2009) Three-year survival results of CORE (Capecitabine, Oxaliplatin, Radiotherapy, and Excision) study after postoperative chemotherapy in patients with locally advanced rectal adenocarcinoma. ASCO GI Meeting. Abstracts 447Google Scholar
  42. 42.
    Smith N, Barbachano Y, Norman A et al (2008) Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer. Br J Surg 95:229–236PubMedCrossRefGoogle Scholar
  43. 43.
    Valentini V, Grimelius B (2010) Rectal cancer radiotherapy: Towards European consensus. Acta Oncol 49:1206–1216PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Carlos Fernandez-Martos
    • 1
  • Xabier Garcia de Albeniz
    • 2
  1. 1.Medical Oncology DepartmentFundacion Instituto Valenciano de OncologiaValenciaSpain
  2. 2.Channing Laboratory, Cubicle 346FBrigham and Women’s HospitalBostonUSA

Personalised recommendations