Will Adjuvant Chemotherapy Improve Outcome After Preoperative Chemoradiation?

  • Bengt Glimelius
  • Peter Nygren


Adjuvant systemic chemotherapy is standard therapy in many patients with colon cancer since it can prevent recurrences and thus improve survival. The benefits, shown in randomized trials, are sufficiently large for routine use if the recurrence risk is at least reasonably high. Since colon and rectal cancer are regarded as one disease entity essentially separated only by an arbitrary anatomical border, adjuvant chemotherapy should improve outcome also in rectal cancer. Thus, the role of adjuvant chemotherapy in rectal cancer following chemoradiotherapy and surgery is frequently extrapolated from colon cancer without too much consideration of the scientific support for this approach. However, there are biological differences beyond anatomical location between these tumour types; the preoperative (chemo)radiotherapy adds complexity with bearing on the role of adjuvant chemotherapy and, most disturbingly, there is lack of convincing data showing a benefit from adjuvant chemotherapy in rectal cancer. This is particularly the case after preoperative chemoradiation. There is a great need for well-designed trials to answer the fundamental question whether adjuvant chemotherapy in rectal cancer provides any benefit after preoperative chemoradiation.


Overall Survival Colon Cancer Rectal Cancer Adjuvant Chemotherapy Total Mesorectal Excision 
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  1. 1.
    Aamodt R, Jonsdottir K, Andersen SN et al (2009) Differences in protein expression and gene amplification of cyclins between colon and rectal adenocarcinomas. Gastroenterol Res Pract 2009:285830PubMedGoogle Scholar
  2. 2.
    Alberts SR, Sargent DJ, Smyrk TC et al (2010) Adjuvant mFOLFOX6 with or without cetuximab in KRAS wild-type patients with resected stage III colon cancer: results from NCCTG intergroup phase III trial N0147. J Clin Oncol 28:A3507CrossRefGoogle Scholar
  3. 3.
    Allegra CJ, Yothers G, O’Connell MJ et al (2011) Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 29:11–16PubMedCrossRefGoogle Scholar
  4. 4.
    Andre T, Boni C, Navarro M et al (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 27:3109–3116PubMedCrossRefGoogle Scholar
  5. 5.
    Biagi JJ, Raphael M, King WD et al (2011) The impact of time to adjuvant chemotherapy on survival in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 29(suppl 4):A364Google Scholar
  6. 6.
    Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123PubMedCrossRefGoogle Scholar
  7. 7.
    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 radio(chemo)therapy? A Systematic Review of Randomized Trials. Ann Oncol 21:1743–1750PubMedCrossRefGoogle Scholar
  8. 8.
    Bujko K, Nowacki MP, Nasierowska-Guttmejer A et al (2006) Long-term results of a randomised trial comparing preoperative short-course radiotherapy vs preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215–1223PubMedCrossRefGoogle Scholar
  9. 9.
    Cafiero F, Gipponi M, Peressini A et al (2000) Preliminary analysis of a randomized clinical trial of adjuvant postoperative RT vs. postoperative RT plus 5-FU and levamisole in patients with TNM stage II-III resectable rectal cancer. J Surg Oncol 75:80–88PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Cionini L, Manfredi B, Sainato A et al (2001) Randomized study of postoperative chemotherapy after preoperative chemoradiation in locally advanced rectal cancer. Preliminary results. Eur J Cancer 37:S300 (Abstr)CrossRefGoogle Scholar
  12. 12.
    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? J Clin Oncol 25:4379–4386PubMedCrossRefGoogle Scholar
  13. 13.
    Dahl O, Fluge O, Carlsen E et al (2009) Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group. Acta Oncol 48:368–376PubMedCrossRefGoogle Scholar
  14. 14.
    De Gramont A, Van Cutsem E, Tabernero J et al (2011) AVANT: results from a randomized three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX alone as adjuvant treatment for colon cancer. J Clin Oncol 29(suppl 4):A 362Google Scholar
  15. 15.
    de Gramont A, Hubbard J, Shi Q et al (2010) Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the 20,800 patient ACCENT data set. J Clin Oncol 28:460–465PubMedCrossRefGoogle Scholar
  16. 16.
    Des Guetz G, Nicolas P, Perret GY et al (2010) Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. Eur J Cancer 46:1049–1055PubMedCrossRefGoogle Scholar
  17. 17.
    Dewdney A, Capdevila J, Glimelius B et al (2011) Expert-C: a randomized phase II European multicenter trial of neoadjuvant chemotherapy (CAPOX) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined, high-risk rectal cancer. Proc Am Soc Clin Oncol; J Clin Oncol 29:suppl abstract 3513Google Scholar
  18. 18.
    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
  19. 19.
    Fietkau R, Barten M, Klautke G et al (2006) Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 49:1284–1292PubMedCrossRefGoogle Scholar
  20. 20.
    Figueredo A, Coombes, ME, Mukherjee S (2008) Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev (3): CD005390Google Scholar
  21. 21.
    Folkesson J, Birgisson H, Påhlman L et al (2005) Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23:5644–5650PubMedCrossRefGoogle Scholar
  22. 22.
    Fountzilas G, Zisiadis A, Dafni U et al (1999) Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 10:671–676PubMedCrossRefGoogle Scholar
  23. 23.
    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
  24. 24.
    Gastrointestinal Tumor Study Group (1985) Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312:1465–1472CrossRefGoogle Scholar
  25. 25.
    Glimelius B (2010) Adjuvant chemotherapy in rectal cancer – an issue or a non-issue? Ann Oncol 21:1739–1741PubMedCrossRefGoogle Scholar
  26. 26.
    Glimelius B, Dahl O, Cedermark B et al (2005) Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Acta Oncol 44:904–912PubMedGoogle Scholar
  27. 27.
    Gray R, McConkey C (2008) Adjuvant chemotherapy for rectal cancer: authors’ reply. Lancet 371:1503CrossRefGoogle Scholar
  28. 28.
    Hafstrom L, Rudenstam CM, Domellof L (1985) A randomized trial of oral 5-fluorouracil versus placebo as adjuvant therapy in colorectal cancer Dukes’ B and C: results after 5 years observation time. Br J Surg 72:138–141PubMedCrossRefGoogle Scholar
  29. 29.
    Hafström L, Domellöf L, Rudenstam CM et al (1990) Adjuvant chemotherapy with 5-fluorouracil, vincristine and CCNU for patients with Dukes’ C colorectal cancer. The Swedish Gastrointestinal Tumour Adjuvant Therapy Group. Br J Surg 77:1345–1348PubMedCrossRefGoogle Scholar
  30. 30.
    Haller DG, Tabernero J, Maroun J et al (2011) Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 29:1465–1471PubMedCrossRefGoogle Scholar
  31. 31.
    Hamaguchi T, Shirao K, Moriya Y et al (2011) Final results of randomized trials by the national surgical adjuvant study of colorectal cancer (NSAS-CC). Cancer Chemother Pharmacol 67:587–596PubMedCrossRefGoogle Scholar
  32. 32.
    Hojo K, Kajitani T (1986) Adjuvant chemotherapy of colorectal cancer – results of prospective randomized trials. Gan To Kagaku Ryoho 13:3063–3073PubMedGoogle Scholar
  33. 33.
    Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252PubMedCrossRefGoogle Scholar
  34. 34.
    Khrizman P, Niland JC, ter 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; abstr 3515Google Scholar
  35. 35.
    Kuebler JP, Wieand HS, O’Connell MJ et al (2007) Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:2198–2204PubMedCrossRefGoogle Scholar
  36. 36.
    Kusters M, Valentini V, Calvo FA 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 21:1279–1284PubMedCrossRefGoogle Scholar
  37. 37.
    Mansour EG, Lefkopoulou M, Johnson R et al (1991) A comparison of postoperative adjuvant chemotherapy, radiotherapy or combination therapy in potentially curable resectable rectal carcinoma. An ECOG study Est 4276. Proc Am Soc Clin Oncol 10:154 abstrGoogle Scholar
  38. 38.
    McAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28:4022–4028PubMedCrossRefGoogle Scholar
  39. 39.
    Minoo P, Zlobec I, Peterson M et al (2010) Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol 37:707–718PubMedCrossRefGoogle Scholar
  40. 40.
    National Comprehensive Cancer Network (2011) Rectal cancer. NCCN clinical practice guidelines in oncology Version 3Google Scholar
  41. 41.
    NCI (1991) Clinical announcement. Adjuvant therapy of rectal cancer. National Cancer Institute, BethesdaGoogle Scholar
  42. 42.
    Pahlman L, Bohe M, Cedermark B et al (2007) The Swedish rectal cancer registry. Br J Surg 94:1285–1292PubMedCrossRefGoogle Scholar
  43. 43.
    Quasar Collaborative Group, Gray R, Barnwell J et al (2007) Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:2020–2029PubMedCrossRefGoogle Scholar
  44. 44.
    Ragnhammar P, Brorsson B, Nygren P et al (2001) A prospective study of the use of chemotherapy in Sweden and assessment of the use in relation to scientific evidence. Acta Oncol 40:391–411PubMedCrossRefGoogle Scholar
  45. 45.
    Sakamoto J, Hamada C, Kodaira S et al (1999) Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials. Jpn J Clin Oncol 29:78–86PubMedCrossRefGoogle Scholar
  46. 46.
    Sakamoto J, Hamada C, Yoshida S et al (2007) An individual patient data meta-analysis of adjuvant therapy with uracil-tegafur (UFT) in patients with curatively resected rectal cancer. Br J Cancer 96:1170–1177PubMedCrossRefGoogle Scholar
  47. 47.
    Slattery ML, Wolff E, Hoffman MD et al (2011) MicroRNAs and colon and rectal cancer: differential expression by tumor location and subtype. Genes Chromosomes Cancer 50:196–206PubMedCrossRefGoogle Scholar
  48. 48.
    Swedish Rectal Cancer Trial (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980–987CrossRefGoogle Scholar
  49. 49.
    Taal BG, Van Tinteren H, Zoetmulder FA (2001) Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer 85:1437–1443PubMedCrossRefGoogle Scholar
  50. 50.
    Tiefenthal M, Nilsson PJ, Johansson R et al (2011) The effects of short-course preoperative irradiation on local recurrence rate and survival in rectal cancer: a population-based nationwide study. Dis Colon Rectum 54:672–680PubMedCrossRefGoogle Scholar
  51. 51.
    Valentini V, Glimelius B (2010) Rectal cancer radiotherapy: towards European consensus. Acta Oncol 49:1206–1216PubMedCrossRefGoogle Scholar
  52. 52.
    Valentini V, van Stiphout RG, Lammering G 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 29:3163–3172PubMedCrossRefGoogle Scholar
  53. 53.
    van de Velde CJH (2010) Chronicle/PROCTOR/SCRIPT trials. European Multidisciplinary Colorectal Cancer Congress, Nice, 28–30 Mar, 2010, Oral presentationGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Radiology, Oncology and Radiation ScienceUniversity of Uppsala, Akademiska sjukhusetUppsalaSweden
  2. 2.Department of Oncology and PathologyKarolinska InstitutetStockholmSweden

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