Colon cancer represents the second leading cause of cancer-related deaths. For patients who have undergone curative surgery, adjuvant therapy can reduce the risk of recurrence and death from relapsed or metastatic disease. Postoperative chemotherapy with a 5-fluorouracil-based regimen combined with oxaliplatin is the current standard of care for stage III patients. However, there is still controversy in stage II disease about the real impact of adjuvant monotherapy or combined therapy on survival. Better identification of a subgroup of patients with a higher risk of recurrence can select patients who might benefit from adjuvant therapy. For the elderly population, there is a well-established role for postoperative therapy, although the most appropriate regimen remains to be defined. Targeted agents for combined adjuvant therapy in stage II and III colon cancer is a promising area, but to date, there is no evidence supporting its use in this setting. Results from large prospective trials with targeted therapy have been disappointing and new drugs and strategies are needed to define the role of these types of agents in the adjuvant scenario of colon cancer.
Ades, S. ( 2009) Adjuvant chemotherapy for colon cancer in the elderly: Moving from evidence to practice. Oncology ( Williston Park) 23: 162-167.
2.
André, T., Boni, C., Mounedji-Boudiaf, L., Navarro, M., Tabernero, J., Hickish, T. et al. (2004) Oxaliplatin, 5-fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med350: 2343-2351.
3.
André, T., Boni, C., Navarro, M., Tabernero, J., Hickish, T., Topham, C. 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 Oncol27: 1-8.
4.
André, T., Colin, P., Louvet, C., Gamelin, E., Bouche, O., Achille, E. et al. (2003) Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and II colon cancer: Results of a randomized trial. J Clin Oncol21: 2896-2903.
5.
Bertagnolli, M.M., Niedzwiecki, D., Comptom, C.C., Hahn, H.P., Hall, M., Damas, B. et al. (2009) Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and leukemia Group B protocol 89803. J Clin Oncol27: 1814-1821.
6.
Chang, G.J., Rodriguez-Bigas, M.A., Skibber, J.M. and Moyer, V.A. ( 2007) Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst99: 433-441.
7.
De Dosso, S., Sessa, C. and Saletti, P. ( 2008) Adjuvant therapy for colon cancer: Present and perspectives . Cancer Treat Rev35: 160-166.
8.
de Gramont, A., Boni, C., Navarro, M., Tabernero, J., Hickish, T., Topham, C. et al. (2005) Oxaliplatin/5FU/ LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years. ASCO Annual Meeting Proceedings. J Clin Oncol23: 16S(abstract 3501).
9.
de Gramont, A., Tournigand, C., André, T., Larsen, A.K. and Louvet, C. ( 2006) Targeted agents for adjuvant therapy of colon cancer. Semin Oncol33(6 Suppl 11): S42-S45.
10.
Figueredo, A., Charette, M.L., Maroun, J., Brouwers, M.C. and Zuraw, L. ( 2004) Adjuvant therapy for stage II colon cancer: A systematic review from the cancer care Ontario program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol22: 3395-3407.
11.
Figueredo, A., Coombes, M.E. and Mukherjee, S. ( 2008) Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev16: CD005390.
12.
Gill, G., Loprinzi, C.L., Sargent, D.J., Thomé, S.D., Alberts, S.R., Haller, D.G. 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 Oncol22: 1797-1806.
13.
Goldberg, R.M., Tabah-Fisch, I., Bleiberg, H., de Gramont, A., Tournigand, C., Andre, T. et al. (2006) Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol24: 4085-4091.
14.
Gray, R., Barnwell, J., McConkey, C., Hills, R.K., Williams, N.S. and Kerr, D.J., QUASAR Collaborative Group (2007) Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet370: 2020-2029.
15.
Gryfe, R., Kim, H., Hsieh, E.T., Aronson, M.D., Holowaty, E.J., Bull, S.B. et al. (2000) Tumor microsatellite instability and clinical outcome in young patient with colorectal cancer. N Engl J Med342: 69-77.
16.
Haller, D.G., Catalano, P.J., Macdonald, J.S., O’Rourke, M.A., Frontiera, M.S., Jackson, D.V. et al. (2005) Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: Final report of Intergroup 0089. J Clin Oncol23: 8671-8678.
17.
Haller, D., Tabernero, J., Maroun, J., de Braud, F., Price, T., Van Cutsem, E. et al. (2009) First efficacy findings from a randomized phase III trial of capecitabine + oxaliplatin vs. bolus 5-FU/LV for stage III colon cancer (NO16968/XELOXA study). Eur J Cancer Suppl7: 4.
18.
Hoff, P., Clarke, S., Cunningham, D., Van Cutsem, E., Moore, M., Schmoll, H.J. et al. (2009) A three-arm phase III randomized trial of FOLFOX-4 vs. FOLFOX-4 plus bevacizumab vs. XELOX plus bevacizumab in the adjuvant treatment of patients with stage III or high-risk stage II colon cancer: Results of the interim safety analysis of the AVANT trial. Eur J Cancer Suppl7: 324.
19.
IMPACT B2; International Multicenter Pooled Analysis of B2 Colon Cancer Trials Investigators. (1999) Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol17: 1356-1363.
20.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Thun, M.J. et al. (2009) Cancer statistics. CA Cancer J Clin59: 225-249.
21.
Kerr, D., Gray, R., Quirke, P., Watson, D., Yothers, G., Lavery, I.C. et al. (2009) A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. J Clin Oncol27(Suppl; abstract 4000): 15s.
22.
Kim, G.P., Colangelo, L.H., Wieand, H.S., Paik, S., Kirsch, I.R., Wolmark, N. et al. (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol25: 767-772.
23.
Kopetz, S., Freitas, D., Calabrich, A.F. and Hoff, P.M. ( 2008) Adjuvant chemotherapy for stage II colon cancer. Oncology (Williston Park) 22: 260-270.
24.
Kuebler, J.P., Wieand, H.S., O’Connell, M.J., Smith, R.E., Colangelo, L.H., Yothers, G. 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 Oncol25: 2198-2204.
25.
Lanza, G., Gafà, R., Santini, A., Maestri, I., Guerzoni, L. and Cavazzini, L. ( 2006) Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol24: 2359-2367.
26.
Laurie, J.A., Moertel, C.G., Fleming, T.R., Wieand, H.S., Leigh, J.E., Rubin., J. et al. (1989) Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol7: 1447-1456.
27.
Le Voyer, T.E., Sigurdson, E.R., Hanlon, A.L., Mayer, R.J., Macdonald, J.S., Catalano, P.J. et al. (2003) Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial INT-0089 . J Clin Oncol21: 2912-2919.
28.
Lembersky, B.C., Wieand, H.S., Petrelli, N.J., O’Connell, M.J., Colangelo, L.H., Smith, R.E. et al. (2006) 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 Oncol24: 2059-2064.
29.
Li, M.C. and Ross, S.T. ( 1976) Chemoprophylaxis for patients with colorectal cancer. Prospective study with five-year follow-up. JAMA235: 2825-2828.
30.
Locker, G.Y., Hamilton, S., Harris, J., Jessup, J.M., Kemeny, N., Macdonald, J.S. et al. (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol24: 5313-5327.
31.
Mamounas, E., Wieand, S., Wolmark, N., Bear, H.D., Atkins, J.N., Song, K. et al. (1999) Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol17: 1349-1355.
32.
Marshall, J.L., Haller, D.G., Gramont, A., Hochster, H.S., Lenz, H.J., Ajani, J.A. et al. (2007) Adjuvant therapy for stage II and III colon cancer: Consensus report of the International Society of Gastrointestinal oncology. Gastrointest Cancer Res1: 146-154.
33.
Moertel, C.G., Fleming, T.R., Macdonald, J.S., Haller, D.G., Laurie, J.A., Goodman, P.J. et al. (1990) Levamisole and fluouroracil for adjuvant therapy of resected colon carcinoma. N Engl J Med322: 352-358.
34.
Moertel, C.G., Fleming, T.R., Macdonald, J.S., Haller, D.G., Laurie, J.A., Tangen, C.M. et al. (1995) Intergroup study of fluouroracil plus levamisole as adjuvant therapy for stage II/Dukes’ B2 colon cancer. J Clin Oncol13: 2936-2943.
35.
O’Connell, M.J., Laurie, J.A., Kahn, M., Fitzgibbons, R.J., Erlichman, C., Sheperd, L. et al. (1998) Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol16: 295-300.
36.
O’Connell, J.B., Maggard, M.A. and Ko, C.Y. ( 2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst96: 1420-1425.
37.
Popat, S., Hubner, R. and Houlston, R.S. ( 2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol23: 609-618.
38.
Poplin, E.A., Benedetti, J.K., Estes, N.C., Haller, D.G., Mayer, R.J., Goldberg, R.M. et al. (2005) 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 Oncol23: 1819-1825.
39.
Prandi, M., Lionetto, R., Bini, A., Francioni, G., Accarpio, G., Anfossi, A. et al. (2002) Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy. Results of a secondary analysis of a large scale adjuvant trial. Ann Surg235: 458-463.
40.
Quah, H.M., Chou, J.F., Gonen, M., Shia, J., Schrag, D., Landmann, R.G. et al. (2008) Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum51: 503-507.
41.
QUASAR Collaborative Group (2000) Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: A randomised trial. Lancet355: 1588-1596.
42.
Ribic, C.M., Sargent, D.J., Moore, M.J., Thibodeau, S.N., French, A.J., Goldberg, R.M. et al. (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med349: 247-257.
43.
Saltz, L.B., Niedzwiecki, D., Hollis, D., Goldberg, R.M., Hantel, A., Thomas, J.P. et al. (2007) 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 Oncol25: 3456-3461.
44.
Sargent, D.J., Goldberg, R.M., Jacobson, S.D., Macdonald, J.S., Labianca, R., Haller, D.G. et al. (2001) A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med345: 1091-1097.
45.
Schmoll, H.J., Cartwright, T., Tabernero, J., Nowacki, M.P., Figer, A., Maroun, J. et al. (2007) 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 Oncol25: 102-109.
46.
Sinicrope, F.A. and Sargent, D.J.(2009) Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol21: 369-373.
47.
Smith, R.E., Colangelo, L., Wieand, H.S., Begovic, M. and Wolmark, N. ( 2004) Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst96: 1128-1132.
48.
Sundararajan, V., Mitra, N., Jacobson, J.S., Grann, V.R., Heitjan, D.F. and Neugut, A.I. ( 2002) Survival associated with 5-fluorouracil-based adjuvant chemotherapy among elderly patients with node-positive colon cancer. Ann Intern Med136: 349-357.
49.
Takagawa, R., Fujii, S., Ohta, M., Nagano, Y., Kunisaki, C., Yamagishi, S. et al. (2008) Preoperative serum carcinoembryonic antigen level as a predictive factor of recurrence after curative resection of colorectal cancer. Ann Surg Oncol15: 3433-3439.
50.
Tejpar, T., Bosman, F., Delorenzi, M., Fiocca, R., Yan, P., Klingbiel, D. et al. (2009) Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). J Clin Oncol27: 15s(Suppl; abstract 4001).
51.
Twelves, C., Wong, A., Nowacki, M.P., Abt, M., Burris, III H., Carrato, A. et al. (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med352: 2696-2704.
52.
Van Cutsem, E., Labianca, R., Bodoky, G., Barone, C., Aranda, E., Nordlinger, B. et al. (2009) 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 Oncol27: 3117-3125.
53.
Wolmark, N., Rockette, H., Fisher, B., Wickerman, D.L., Redmond, C., Fisher, E.R. et al. (1993) 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 Oncol11: 1879-1887.
54.
Wolmark, N., Rockette, H., Mamounas, E., Jones, J., Wieand, S., Wickerman, D.L. et al. (1999) 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 Oncol17: 3553-3559.
55.
Wolmark, N., Rockette, H., Wickerham, D.L., Fisher, B., Redmond, C., Fisher, E.R. et al. (1990) Adjuvant therapy of Dukes’ A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic
56.
infusion: Preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. J Clin Oncol8: 1466-1475.
57.
Wolmark, N., Wieand, S., Kuebler, P.J., Colangelo, L., O’Connell, M.J., Yothers, G. et al. (2008) A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07. ASCO Annual Meeting Proceedings. J Clin Oncol26: 15S(abstract 4005).
58.
Wolmark, N., Yothers, G., O’Connell, M.J., Sharif, S., Atkins, J.N., Seay, T.E. et al. (2009) A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08. J Clin Oncol27: 18s(Suppl; abstract LBA4).
59.
Ychou, M., Raoul, J.L., Douillard, J.Y., Gourgou-Bourgade, S., Bugat, R., Mineur, L. et al. (2009) A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802) . Ann Oncol20: 674-680.
