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Adjuvant therapy for resected stage III (node-positive) colon cancer

Authors
Jeffrey W Clark, MD
Hanna K Sanoff, MD, MPH
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Approximately 95,270 new cases of colon cancer are diagnosed annually in the United States [1]. Data on global incidence are available from the World Health Organization (WHO) Globocan database.

Surgical resection is the only curative treatment for locoregional colon cancer. Outcome is most closely related to the extent of disease at presentation (table 1). Five-year survival rates according to tumor stage at diagnosis (using the older 2002 American Joint Committee on Cancer [AJCC] staging criteria [2]) for 119,363 patients with colon cancer reported to the SEER (Surveillance, Epidemiology, and End Results) database between 1991 and 2000 were as follows [3]:

Stage I (T1-2 N0) – 93 percent

Stage IIA (T3N0) – 85 percent

Stage IIB (T4N0) – 72 percent

                                    

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Literature review current through: Nov 2016. | This topic last updated: Thu Oct 27 00:00:00 GMT+00:00 2016.
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References
Top
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
  2. American Joint Committee on Cancer Staging Manual, Greene FL, Page DL, Fleming ID, et al (Eds), Springer, New York 2002. p.113.
  3. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004; 96:1420.
  4. AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th edition, Edge, SB, Byrd, DR, Compton, CC, et al (Eds) (Eds), Springer, New York 2010. p.143.
  5. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy of colorectal cancer. Why we still don't know. JAMA 1988; 259:3571.
  6. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988; 80:30.
  7. Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000; 92:388.
  8. Grem JL, Allegra CJ. Toxicity of levamisole and 5-fluorouracil in human colon carcinoma cells. J Natl Cancer Inst 1989; 81:1413.
  9. Smith RE, Colangelo L, Wieand HS, et al. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst 2004; 96:1128.
  10. Moertel CG, Fleming TR, Macdonald JS, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 1995; 122:321.
  11. Porschen R, Bermann A, Löffler T, et al. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 2001; 19:1787.
  12. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999; 17:3553.
  13. Kimmel DW, Wijdicks EF, Rodriguez M. Multifocal inflammatory leukoencephalopathy associated with levamisole therapy. Neurology 1995; 45:374.
  14. Chen TC, Hinton DR, Leichman L, et al. Multifocal inflammatory leukoencephalopathy associated with levamisole and 5-fluorouracil: case report. Neurosurgery 1994; 35:1138.
  15. Savarese DM, Gordon J, Smith TW, et al. Cerebral demyelination syndrome in a patient treated with 5-fluorouracil and levamisole. The use of thallium SPECT imaging to assist in noninvasive diagnosis--a case report. Cancer 1996; 77:387.
  16. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993; 11:1879.
  17. Punt CJ, Buyse M, Köhne CH, et al. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst 2007; 99:998.
  18. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007; 25:4569.
  19. de Gramont A, Hubbard J, Shi Q, et al. 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 2010; 28:460.
  20. Sargent D, Shi Q, Yothers G, et al. Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 2011; 47:990.
  21. Sargent DJ, Yothers G, Van Cutsem E, et al. Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients frin MOSAIC, X-ACT, PETACC-3, NSABP C06 and C-07, and C89803 (abstract #4011). J Clin Oncol 2009; 27:170s.
  22. Bayraktar S, Bayraktar UD, Rocha-Lima CM. Timing of adjuvant and neoadjuvant therapy in colorectal cancers. Clin Colorectal Cancer 2010; 9:144.
  23. Gibbs P, Handolias D, McLaughlin S, et al. Single-institution experience of adjuvant 5-fluorouracil-based chemotherapy for stage III colon cancer. Intern Med J 2008; 38:265.
  24. Hendren S, Birkmeyer JD, Yin H, et al. Surgical complications are associated with omission of chemotherapy for stage III colorectal cancer. Dis Colon Rectum 2010; 53:1587.
  25. Merkow RP, Bentrem DJ, Mulcahy MF, et al. Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer. Ann Surg 2013; 258:847.
  26. Bos AC, van Erning FN, van Gestel YR, et al. Timing of adjuvant chemotherapy and its relation to survival among patients with stage III colon cancer. Eur J Cancer 2015; 51:2553.
  27. Malietzis G, Mughal A, Currie AC, et al. Factors Implicated for Delay of Adjuvant Chemotherapy in Colorectal Cancer: A Meta-analysis of Observational Studies. Ann Surg Oncol 2015; 22:3793.
  28. Lima IS, Yasui Y, Scarfe A, Winget M. Association between receipt and timing of adjuvant chemotherapy and survival for patients with stage III colon cancer in Alberta, Canada. Cancer 2011; 117:3833.
  29. Wasserman DW, Boulos M, Hopman WM, et al. Reasons for Delay in Time to Initiation of Adjuvant Chemotherapy for Colon Cancer. J Oncol Pract 2015; 11:e28.
  30. Klein M, Azaquoun N, Jensen BV, Gögenur I. Improved survival with early adjuvant chemotherapy after colonic resection for stage III colonic cancer: A nationwide study. J Surg Oncol 2015; 112:538.
  31. Dahl O, Fluge Ø, Carlsen E, et al. 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 2009; 48:368.
  32. Czaykowski PM, Gill S, Kennecke HF, et al. Adjuvant chemotherapy for stage III colon cancer: does timing matter? Dis Colon Rectum 2011; 54:1082.
  33. Bayraktar UD, Chen E, Bayraktar S, et al. Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer 2011; 117:2364.
  34. Ahmed S, Ahmad I, Zhu T, et al. Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study. Dis Colon Rectum 2010; 53:1432.
  35. Chau I, Norman AR, Cunningham D, et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005; 16:549.
  36. André T, Quinaux E, Louvet C, et al. 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 2007; 25:3732.
  37. Quasar Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007; 370:2020.
  38. Des Guetz G, Nicolas P, Perret GY, et al. Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. Eur J Cancer 2010; 46:1049.
  39. Biagi JJ, Raphael MJ, Mackillop WJ, et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011; 305:2335.
  40. Peixoto RD, Kumar A, Speers C, et al. Effect of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer. Clin Colorectal Cancer 2015; 14:25.
  41. O'Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16:295.
  42. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 2005; 23:8671.
  43. Dencausse Y, Hartung G, Sturm J, et al. Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin. Onkologie 2002; 25:426.
  44. Des Guetz G, Uzzan B, Morere JF, et al. Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer. Cochrane Database Syst Rev 2010; :CD007046.
  45. Chambers P, Daniels SH, Thompson LC, Stephens RJ. Chemotherapy dose reductions in obese patients with colorectal cancer. Ann Oncol 2012; 23:748.
  46. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012; 30:1553.
  47. Shah MA, Renfro LA, Allegra CJ, et al. Impact of Patient Factors on Recurrence Risk and Time Dependency of Oxaliplatin Benefit in Patients With Colon Cancer: Analysis From Modern-Era Adjuvant Studies in the Adjuvant Colon Cancer End Points (ACCENT) Database. J Clin Oncol 2016; 34:843.
  48. Sanoff HK, Carpenter WR, Martin CF, et al. Comparative effectiveness of oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer. J Natl Cancer Inst 2012; 104:211.
  49. André 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.
  50. André T, Boni C, Navarro M, et al. 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 2009; 27:3109.
  51. André T, de Gramont A, Vernerey D, et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015; 33:4176.
  52. Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 2011; 29:3768.
  53. Kuebler JP, Wieand HS, O'Connell MJ, et al. 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 2007; 25:2198.
  54. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008; 26:3523.
  55. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011; 29:1465.
  56. Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol 2015; 33:3733.
  57. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 2007; 25:102.
  58. Schmoll HJ, Twelves C, Sun W, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol 2014; 15:1481.
  59. Chu MP, Hecht JR, Slamon D, et al. Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol 2016.
  60. Sun J, Ilich AI, Kim CA, et al. Concomitant Administration of Proton Pump Inhibitors and Capecitabine is Associated With Increased Recurrence Risk in Early Stage Colorectal Cancer Patients. Clin Colorectal Cancer 2016; 15:257.
  61. Zaniboni A, Labianca R, Marsoni S, et al. GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Gruppo Italiano Valutazione Interventi in Oncologia. Studio Italiano Terapia Adiuvante Colon. Cancer 1998; 82:2135.
  62. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995; 345:939.
  63. Francini G, Petrioli R, Lorenzini L, et al. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology 1994; 106:899.
  64. O'Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997; 15:246.
  65. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6:1653.
  66. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 2000; 355:1588.
  67. Poplin EA, Benedetti JK, Estes NC, et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005; 23:1819.
  68. Carrato A, Kohne C, Bedenne L, et al. Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study (abstract). J Clin Oncol 2006; 24:161s.
  69. Köhne CH, Bedenne L, Carrato A, et al. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer 2013; 49:1868.
  70. Andre T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003; 21:2896.
  71. Cassidy J, Douillard JY, Twelves C, et al. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial. Br J Cancer 2006; 94:1122.
  72. Sakamoto J, Ohashi Y, Hamada C, et al. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol 2004; 22:484.
  73. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696.
  74. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 2008; 26:2118.
  75. Hennig IM, Naik JD, Brown S, et al. Severe sequence-specific toxicity when capecitabine is given after Fluorouracil and leucovorin. J Clin Oncol 2008; 26:3411.
  76. Kim DJ, Kim TI, Suh JH, et al. Oral tegafur-uracil plus folinic acid versus intravenous 5-fluorouracil plus folinic acid as adjuvant chemotherapy of colon cancer. Yonsei Med J 2003; 44:665.
  77. Shimada Y, Hamaguchi T, Mizusawa J, et al. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer 2014; 50:2231.
  78. Sadahiro S, Tsuchiya T, Sasaki K, et al. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol 2015; 26:2274.
  79. Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 2006; 24:2059.
  80. Yoshida M, Ishiguro M, Ikejiri K, et al. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol 2014; 25:1743.
  81. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw 2008; 6 Suppl 3:S1.
  82. Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet 2011; 377:1749.
  83. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349:247.
  84. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004; 126:394.
  85. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005; 23:609.
  86. de Vos tot Nederveen Cappel WH, Meulenbeld HJ, Kleibeuker JH, et al. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer 2004; 109:468.
  87. Lanza G, Gafà R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 2006; 24:2359.
  88. Jover R, Zapater P, Castells A, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 2006; 55:848.
  89. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28:3219.
  90. Tougeron D, Mouillet G, Trouilloud I, et al. Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study. J Natl Cancer Inst 2016; 108.
  91. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007; 25:3456.
  92. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009; 27:3117.
  93. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 2009; 20:674.
  94. Allegra CJ, Yothers G, O'Connell MJ, et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol 2013; 31:359.
  95. Allegra CJ, Yothers G, O'Connell MJ, et al. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol 2009; 27:3385.
  96. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 2012; 13:1225.
  97. Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol 2016; 17:1543.
  98. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012; 307:1383.
  99. Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15:862.
  100. Adjuvant! Online program for colon cancer available online at www.adjuvantonline.com (Accessed on September 21, 2011).
  101. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004; 22:1797.
  102. Renfro LA, Grothey A, Xue Y, et al. ACCENT-based web calculators to predict recurrence and overall survival in stage III colon cancer. J Natl Cancer Inst 2014; 106.
  103. Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst 2012; 104:1635.
  104. Yothers G, O'Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol 2013; 31:4512.
  105. Portal vein chemotherapy for colorectal cancer: a meta-analysis of 4000 patients in 10 studies. Liver Infusion Meta-analysis Group. J Natl Cancer Inst 1997; 89:497.
  106. Sadahiro S, Suzuki T, Ishikawa K, et al. Prophylactic hepatic arterial infusion chemotherapy for the prevention of liver metastasis in patients with colon carcinoma: a randomized control trial. Cancer 2004; 100:590.
  107. Wolmark N, Rockette H, Wickerham DL, et al. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. J Clin Oncol 1990; 8:1466.
  108. James RD, Donaldson D, Gray R, et al. Randomized clinical trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer (AXIS). Br J Surg 2003; 90:1200.
  109. Labianca R, Fossati R, Zaniboni A, et al. Randomized trial of intraportal and/or systemic adjuvant chemotherapy in patients with colon carcinoma. J Natl Cancer Inst 2004; 96:750.
  110. Chang W, Wei Y, Ren L, et al. Randomized Controlled Trial of Intraportal Chemotherapy Combined With Adjuvant Chemotherapy (mFOLFOX6) for Stage II and III Colon Cancer. Ann Surg 2016; 263:434.
  111. Mendenhall WM, Amos EH, Rout WR, et al. Adjuvant postoperative radiotherapy for colon carcinoma. Cancer 2004; 101:1338.
  112. Czito BG, Bendell J, Willett CG. Radiation therapy for resectable colon cancer. Is there a role in the modern chemotherapy era? Oncology (Williston Park) 2006; 20:179.
  113. Gunderson LL, Sosin H, Levitt S. Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1985; 11:731.
  114. Willett CG, Goldberg S, Shellito PC, et al. Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 1999; 5:242.
  115. Willett CG, Fung CY, Kaufman DS, et al. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 1993; 11:1112.
  116. Amos EH, Mendenhall WM, McCarty PJ, et al. Postoperative radiotherapy for locally advanced colon cancer. Ann Surg Oncol 1996; 3:431.
  117. Ludmir EB, Arya R, Wu Y, et al. Role of Adjuvant Radiotherapy in Locally Advanced Colonic Carcinoma in the Modern Chemotherapy Era. Ann Surg Oncol 2016; 23:856.
  118. Martenson JA Jr, Willett CG, Sargent DJ, et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004; 22:3277.
  119. Meyerhardt JA, Mangu PB, Flynn PJ, et al. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2013; 31:4465.
  120. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003; 348:891.
  121. Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003; 348:883.
  122. Cardwell CR, Kunzmann AT, Cantwell MM, et al. Low-dose aspirin use after diagnosis of colorectal cancer does not increase survival: a case-control analysis of a population-based cohort. Gastroenterology 2014; 146:700.
  123. Walker AJ, Grainge MJ, Card TR. Aspirin and other non-steroidal anti-inflammatory drug use and colorectal cancer survival: a cohort study. Br J Cancer 2012; 107:1602.
  124. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009; 302:649.
  125. Zell JA, Ziogas A, Bernstein L, et al. Nonsteroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis. Cancer 2009; 115:5662.
  126. Coghill AE, Newcomb PA, Campbell PT, et al. Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer. Gut 2011; 60:491.
  127. Bastiaannet E, Sampieri K, Dekkers OM, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012; 106:1564.
  128. Reimers MS, Bastiaannet E, Langley RE, et al. Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med 2014; 174:732.
  129. Ng K, Meyerhardt JA, Chan AT, et al. Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 2015; 107:345.
  130. McCowan C, Munro AJ, Donnan PT, Steele RJ. Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 2013; 49:1049.
  131. Bains S, Mahic M, Cvancarova M, et al. Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study (abstract). J Clin Oncol 33, 2015 (suppl; abstr 3504). Abstract available at http://meetinglibrary.asco.org/content/146901-156 (Accessed on August 19, 2015).
  132. Li P, Wu H, Zhang H, et al. Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis. Gut 2015; 64:1419.
  133. Bains SJ, Mahic M, Myklebust TÅ, et al. Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study. J Clin Oncol 2016; 34:2501.
  134. Elwood PC, Morgan G, Pickering JE, et al. Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies. PLoS One 2016; 11:e0152402.
  135. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012; 367:1596.
  136. Paleari L, Puntoni M, Clavarezza M, et al. PIK3CA Mutation, Aspirin Use after Diagnosis and Survival of Colorectal Cancer. A Systematic Review and Meta-analysis of Epidemiological Studies. Clin Oncol (R Coll Radiol) 2016; 28:317.
  137. Nishihara R, Lochhead P, Kuchiba A, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 2013; 309:2563.
  138. http://clinicaltrials.gov/ct2/show/NCT01150045?term=celecoxib&cond=colon+cancer&lead_ex=Y&rank=3.
  139. Guercio BJ, Sato K, Niedzwiecki D, et al. Coffee Intake, Recurrence, and Mortality in Stage III Colon Cancer: Results From CALGB 89803 (Alliance). J Clin Oncol 2015; 33:3598.