Access the full text.
Sign up today, get DeepDyve free for 14 days.
D. Kerr, R. Gray, P. Quirke, D. Watson, G. Yothers, I. Lavery, M. Lee, M. O’connell, S. Shak, N. Wolmark (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 15_suppl
M. Alikhan, Vijay Phooskooru, M. Kohli (2004)
Re: Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01.Journal of the National Cancer Institute, 96 23
H. Quah, J. Chou, M. Gonen, J. Shia, D. Schrag, R. Landmann, J. Guillem, P. Paty, L. Temple, W. Wong, M. Weiser (2008)
Identification of Patients with High-Risk Stage II Colon Cancer for Adjuvant TherapyDiseases of the Colon & Rectum, 51
G. Lanza, R. Gafà, A. Santini, I. Maestri, Laura Guerzoni, L. Cavazzini (2006)
Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24 15
B. Lembersky, H. Wieand, N. Petrelli, M. O’connell, L. Colangelo, Roy Smith, T. Seay, J. Giguere, M. Marshall, A. Jacobs, L. Colman, A. Soran, G. Yothers, N. Wolmark (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24 13
N. Wolmark, H. Rockette, D. Wickerham, B. Fisher, C. Redmond, E. Fisher, M. Potvin, R. Davies, J. Jones, A. Robidoux (1990)
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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 8 9
E. Mamounas, S. Wieand, N. Wolmark, H. Bear, J. Atkins, K. Song, Judy Jones, H. Rockette (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)Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 17 5
A. Jemal, R. Siegel, Elizabeth Ward, Y. Hao, Jiaquan Xu, M. Thun (2009)
Cancer Statistics, 2009CA: A Cancer Journal for Clinicians, 59
R. Takagawa, Syoichi Fujii, Mitsuyoshi Ohta, Y. Nagano, C. Kunisaki, S. Yamagishi, Shun-ichi Osada, Y. Ichikawa, H. Shimada (2008)
Preoperative Serum Carcinoembryonic Antigen Level as a Predictive Factor of Recurrence After Curative Resection of Colorectal CancerAnnals of Surgical Oncology, 15
L. Saltz, D. Niedzwiecki, D. Hollis, R. Goldberg, A. Hantel, James Thomas, A. Fields, R. Mayer (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 25 23
J. Laurie, C. Moertel, T. Fleming, H. Wieand, John Leigh, J. Rubin, J. Gerstner, J. Krook, J. Malliard, D. Twito, R. Morton, K. Tschetter, J. Barlow (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 7 10
N. Dubrawsky (1989)
Cancer statisticsCA: A Cancer Journal for Clinicians, 39
T. Voyer, E. Sigurdson, A. Hanlon, R. Mayer, J. Macdonald, P. Catalano, D. Haller (2003)
Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 21 15
R. Labianca, S. Marsoni, G. Pancera, V. Torri, A. Zaniboni, C. Erlichman, J. Pater, L. Shepherd, B. Zee, J. Seitz, C. Milan, J. Pignon (1995)
Efficacy of adjuvant fluorouracil and folinic acid in colon cancer International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigatorsThe Lancet, 345
A. Gramont, C. Tournigand, T. André, A. Larsen, C. Louvet (2006)
Targeted agents for adjuvant therapy of colon cancer.Seminars in oncology, 33 6 Suppl 11
N. Wolmark, H. Rockette, E. Mamounas, Judy Jones, S. Wieand, D. Wickerham, H. Bear, J. Atkins, N. Dimitrov, A. Glass, Edwin Fisher, B. Fisher (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 17 11
M. Saif (2006)
Targeted agents for adjuvant therapy of colon cancer.Clinical colorectal cancer, 6 1
V. Sundararajan, N. Mitra, J. Jacobson, V. Grann, D. Heitjan, A. Neugut (2002)
Survival Associated with 5-FluorouracilBased Adjuvant Chemotherapy among Elderly Patients with Node-Positive Colon CancerAnnals of Internal Medicine, 136
T. André, P. Colin, C. Louvet, E. Gamelin, O. Bouché, E. Achille, N. Colbert, C. Boaziz, P. Piedbois, N. Tubiana-Mathieu, A. Boutan-Laroze, M. Flesch, M. Buyse, A. Gramont (2003)
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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 21 15
S. Dosso, C. Sessa, P. Saletti (2009)
Adjuvant therapy for colon cancer: present and perspectives.Cancer treatment reviews, 35 2
J. Kuebler, H. Wieand, M. O’connell, Roy Smith, L. Colangelo, G. Yothers, N. Petrelli, M. Findlay, T. Seay, J. Atkins, J. Zapas, J. Goodwin, L. Fehrenbacher, R. Ramanathan, B. Conley, P. Flynn, G. Soori, L. Colman, E. Levine, K. Lanier, N. Wolmark (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 25 16
Carolyn Seib, F. Rocha, D. Hwang, B. Shoji (2009)
Gastrosplenic fistula from Hodgkin's lymphoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 20
E. Mitry (1990)
Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.The New England journal of medicine, 323 3
T. André, C. Boni, M. Navarro, J. Tabernero, T. Hickish, C. Topham, A. Bonetti, P. Clingan, J. Bridgewater, F. Rivera, A. Gramont (2009)
Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 19
G. Chang, M. Rodriguez-Bigas, J. Skibber, V. Moyer (2007)
Lymph node evaluation and survival after curative resection of colon cancer: systematic review.Journal of the National Cancer Institute, 99 6
H. Schmoll, T. Cartwright, J. Tabernero, M. Nowacki, A. Figer, J. Maroun, T. Price, R. Lim, E. Cutsem, Young-Suk Park, J. Mckendrick, C. Topham, Gemma Soler-González, F. Braud, M. Hill, F. Sirzén, D. Haller (2006)
Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 25 1
C. Moertel, T. Fleming, J. Macdonald, D. Haller, J. Laurie, C. Tangen, J. Ungerleider, W. Emerson, D. Tormey, J. Glick (1995)
Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 13 12
S. Tejpar, F. Bosman, Mauro Delorenzi, Roberto Fiocca, Pu Yan, D. Klingbiel, Daniel Dietrich, E. Cutsem, Roberto Labianca, A. Roth (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).Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 15_suppl
N. Wolmark, S. Wieand, P. Kuebler, L. Colangelo, M. O’connell, G. Yothers (2005)
A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07Journal of Clinical Oncology, 26
S. Popat, R. Hubner, R. Houlston (2005)
Systematic review of microsatellite instability and colorectal cancer prognosis.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 23 3
N. Wolmark, G. Yothers, M. O’connell, S. Sharif, J. Atkins, T. Seay, L. Feherenbacher, S. O'reilly, C. Allegra (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 18_suppl
Quasar Group (2007)
Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised studyThe Lancet, 370
E. Poplin, J. Benedetti, N. Estes, D. Haller, R. Mayer, R. Goldberg, G. Weiss, S. Rivkin, J. Macdonald (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 23 9
E. Cutsem, R. Labianca, G. Bodoky, C. Barone, E. Aranda, B. Nordlinger, C. Topham, J. Tabernero, T. André, A. Sobrero, E. Mini, R. Greil, F. Costanzo, L. Collette, L. Cisar, Xiaoxi Zhang, D. Khayat, C. Bokemeyer, A. Roth, D. Cunningham (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 19
S. Gill, C. Loprinzi, D. Sargent, S. Thomé, S. Alberts, D. Haller, J. Benedetti, G. Francini, L. Shepherd, Jean Seitz, R. Labianca, Wei Chen, S. Cha, Michael Heldebrant, R. Goldberg (2004)
Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22 10
M. Bertagnolli, D. Niedzwiecki, C. Compton, H. Hahn, M. Hall, Beatrice Damas, S. Jewell, R. Mayer, R. Goldberg, L. Saltz, R. Warren, M. Redston (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 11
M. Li, S. Ross (1976)
Chemoprophylaxis for patients with colorectal cancer. Prospective study with five-year follow-up.JAMA, 235 26
J. Marshall, D. Haller, A. Gramont, H. Hochster, H. Lenz, J. Ajani, R. Goldberg (2007)
Adjuvant Therapy for Stage II and III Colon Cancer: Consensus Report of the International Society of Gastrointestinal Oncology.Gastrointestinal cancer research : GCR, 1 4
M. Prandi, R. Lionetto, A. Bini, G. Francioni, G. Accarpio, A. Anfossi, Ezio Ballario, G. Becchi, S. Bonilauri, A. Carobbi, P. Cavaliere, D. Garcea, L. Giuliani, Eugenio Morziani, F. Mosca, A. Mussa, M. Pasqualini, D. Poddie, Federico Tonetti, Luciano Zardo, R. Rosso (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 TrialAnnals of Surgery, 235
J. O'connell, M. Maggard, C. Ko (2005)
Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging.Journal of the National Cancer Institute, 96 19
C. Twelves, A. Wong, M. Nowacki, M. Abt, H. Burris, A. Carrato, J. Cassidy, A. Cervantes, J. Fagerberg, V. Georgoulias, F. Husseini, D. Jodrell, P. Koralewski, H. Kröning, J. Maroun, N. Marschner, J. Mckendrick, M. Pawlicki, R. Rosso, J. Schüller, J. Seitz, B. Štabuc, J. Tujakowski, G. Hazel, J. Zaluski, W. Scheithauer (2005)
Capecitabine as adjuvant treatment for stage III colon cancer.The New England journal of medicine, 352 26
R. Goldberg, I. Tabah-Fisch, H. Bleiberg, A. Gramont, C. Tournigand, T. André, M. Rothenberg, E. Green, D. Sargent (2006)
Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24 25
A. Figueredo, M. Charette, J. Maroun, M. Brouwers, L. Zuraw (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 22 16
D. Sargent, R. Goldberg, S. Jacobson, J. Macdonald, R. Labianca, D. Haller, L. Shepherd, J. Seitz, G. Francini (2001)
A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.The New England journal of medicine, 345 15
F. Sinicrope, D. Sargent (2009)
Clinical implications of microsatellite instability in sporadic colon cancersCurrent Opinion in Oncology, 21
B. Fisher (2005)
National Surgical Adjuvant Breast and Bowel Project
S. Kopetz, D. Freitas, A. Calabrich, P. Hoff (2008)
Adjuvant chemotherapy for stage II colon cancer.Oncology, 22 3
D. Haller, P. Catalano, J. Macdonald, M. O'Rourke, M. Frontiera, D. Jackson, R. Mayer (2005)
Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 23 34
R Williamson (1987)
Gastrointestinal oncologyGut, 28
A. Figueredo, M. Coombes, S. Mukherjee (2008)
Adjuvant therapy for completely resected stage II colon cancer.The Cochrane database of systematic reviews, 3
S. Ades (2009)
Adjuvant chemotherapy for colon cancer in the elderly: moving from evidence to practice.Oncology, 23 2
R. Gryfe, Hyeja Kim, E. Hsieh, M. Aronson, E. Holowaty, S. Bull, M. Redston, S. Gallinger (2000)
Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.The New England journal of medicine, 342 2
Wei Chua, Sarah Randall, M. McKay, Lisa Horvath, Stephen Clarke, M. Molloy (2009)
Targeted plasma proteome profiling for early prediction of chemotherapy response and toxicity in colorectal cancer (CRC).Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 15_suppl
Roy Smith, L. Colangelo, H. Wieand, M. Begovic, N. Wolmark (2004)
Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01.Journal of the National Cancer Institute, 96 15
C. Ribic, D. Sargent, M. Moore, S. Thibodeau, A. French, R. Goldberg, S. Hamilton, P. Laurent-Puig, R. Gryfe, L. Shepherd, D. Tu, M. Redston, S. Gallinger (2003)
Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.The New England journal of medicine, 349 3
N. Wolmark, H. Rockette, B. Fisher, D. Wickerham, C. Redmond, Edwin Fisher, J. Jones, E. Mamounas, L. Ore, N. Petrelli (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 11 10
D. Haller, J. Tabernero, J. Maroun, F. Braud, T. Price, E. Cutsem, M. Hill, F. Gilberg, K. Rittweger, H. Schmoll (2009)
5LBA 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)Ejc Supplements, 7
R. Gray, D. Kerr, C. McConkey, N. Williams, R. Hills (2000)
Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trialThe Lancet, 355
M. Ychou, J. Raoul, J. Douillard, S. Gourgou-Bourgade, R. Bugat, L. Mineur, F. Viret, Y. Bécouarn, O. Bouché, E. Gamelin, M. Ducreux, T. Conroy, J. Seitz, L. Bedenne, A. Kramar (2009)
A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).Annals of oncology : official journal of the European Society for Medical Oncology, 20 4
G. Locker, S. Hamilton, J. Harris, J. Jessup, N. Kemeny, J. Macdonald, M. Somerfield, D. Hayes, R. Bast (2006)
ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24 33
A. Gramont, C. Boni, M. Navarro, J. Tabernero, T. Hickish, C. Topham, A. Bonetti, P. Clingan, J. Marceau-suissa, C. Lorenzato, T. André (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 yearsJournal of Clinical Oncology, 23
(2009)
A three-arm phase III randomized trial of FOLFOX-4 vs. FOLFOX-4 plus bevacizumab vs. XELOX plus beva
M. O’connell, J. Laurie, M. Kahn, R. Fitzgibbons, C. Erlichman, L. Shepherd, C. Moertel, W. Kocha, R. Pazdur, H. Wieand, J. Rubin, A. Vukov, J. Donohue, J. Krook, A. Figueredo (1998)
Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 16 1
George Kim, L. Colangelo, H. Wieand, S. Paik, I. Kirsch, N. Wolmark, C. Allegra (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.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 25 7
T. André, C. Boni, L. Mounedji-Boudiaf, M. Navarro, J. Tabernero, T. Hickish, C. Topham, M. Zaninelli, P. Clingan, J. Bridgewater, I. Tabah-Fisch, A. Gramont (2004)
Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.The New England journal of medicine, 350 23
Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Combination therapy in high-risk stage II (2010) 2(4) 261272 DOI: 10.1177/ or stage III colon cancer: current practice ! The Author(s), 2010. Reprints and permissions: and future prospects http://www.sagepub.co.uk/ journalsPermissions.nav Diogo Assed Bastos, Suilane Coelho Ribeiro, Daniela de Freitas and Paulo M. Hoff Abstract: 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. Keywords: adjuvant chemotherapy, colon cancer, combined therapy, high-risk stage II, stage III Introduction adjuvant treatment. Patients with stage II disease Correspondence to: Paulo M. Hoff, MD, FACP At least one million new cases of colon cancer are represent about 25% of cases and have a 5-year Oncology Center, Hospital diagnosed every year worldwide. It represents one overall survival (OS) ranging from 84.7% for Sı´rio-Libaneˆs, Adma Jafet Street, 91, Sao Paulo of the most common neoplasms and the second T3N0 (IIa) to 72.2% for T4N0 (IIb). Stage III 0138-050, Brazil leading cause of death for cancer, accounting for patients are stratified into three subgroups with phoff@hsl.org.br 9% of total cancer fatalities [Jemal et al. 2009]. different 5-year OS: 83.4% for IIIa (T1-2N1), Diogo Assed Bastos Oncology Center, Hospital Approximately 7580% of newly diagnosed 64.1% for IIIb (T3-4N1), and 44.3% for IIIc Sırio-Libanes, Sao Paulo, ´ ˆ patients have localized or regional tumors and (T0-4N2) [O’Connell et al. 2004]. Of note, sur- Brazil surgery remains the unique curative treatment vival from stage IIb colon cancer is statistically Suilane Coelho Ribeiro Oncology Center, Hospital for these patients. However, up to 50% of patients inferior to stage IIIa tumors, whether this is due Sı´rio-Libaneˆs, Sao Paulo, will relapse after surgical resection and ultimately to widespread use of adjuvant therapy in stage III Brazil and Department of Oncology, die of metastatic disease [De Dosso et al. 2008; disease remains unclear. Cancer Institute of the Kopetz et al. 2008; Marshall et al. 2007; State of Sao Paulo, University of Sao Paulo, de Gramont et al. 2005]. The objective of adju- Despite the general agreement on postoperative Sao Paulo, Brazil vant postoperative chemotherapy is to reduce the chemotherapy for stage III colon cancer, there is Daniela de Freitas risk of recurrence and improve a patient’s out- still debate on this approach for stage II tumors. Oncology Center, Hospital Sı´rio-Libaneˆs, Sao Paulo, come by eliminating any occult, viable tumor Recently, several high-risk features have been Brazil cells that may have remained after surgery. identified to guide therapeutic decision on adju- vant therapy in this setting and probably high-risk The prognosis of colon cancer is directly related to stage II patients may benefit from treatment. the risk of recurrence, which is better predicted by pathologic staging. Stage I colon cancer patients Based on available current data, combination have a 5-year survival rate of approximately 93% therapy is the standard treatment for stage III and therefore these patients do not benefit from colon cancer. However, there is still controversy http://tam.sagepub.com 261 Therapeutic Advances in Medical Oncology 2 (4) about whether or not combined therapy can compared with 5-FU/lev. The National Surgical improve outcome in high-risk stage II patients Adjuvant Breast and Bowel Project (NSABP) and also in the elderly population. This review C-04 trial showed a superiority of 5-FU/LV for addresses the current debate over the use of com- both OS and disease-free survival (DFS), with a bined adjuvant chemotherapy in high-risk stage 13% and 10% relative risk reduction for DFS and II and stage III colon cancer. OS, respectively. For stage II disease there was a reduction in recurrence rate of 22% suggesting a Historical perspective potential role of adjuvant 5-FU/LV in this setting. The first solid evidence of benefit from adjuvant These results supported the routine use of adju- chemotherapy for colon cancer emerged in 1990. vant 5-FU/LV as adjuvant treatment in stage III The Intergroup 0035 trial of 5-fluorouracil patients and a potential role of this approach for (5-FU) plus levamisole (lev) compared with lev stage II patients [Wolmark et al. 1999]. alone or observation demonstrated a 41% relative reduction in recurrence rate and a significant sur- Another important trial was the Intergroup 0089 vival advantage for patients on the 5-FU/lev arm, trial, which compared the efficacy of 5-FU/LV and with a median 5-year OS of 60% for adjuvant 5-FU/lev and also compared two regimens of chemotherapy versus 46.7% and 49% for obser- 5FU/LV, the 5-FU/high-dose LV (Roswell Park) vation and lev alone, respectively (p¼ 0.0007) and the 5-FU/low-dose LV regimen (Mayo [Moertel et al. 1995, 1990]. Clinic) (Table 1). There were four treatment arms in this trial: 5-FU/lev (12-month protocol), After these results, successive trials have demon- 5-FU/high-dose LV (Roswell Park, 7 months), strated the superiority of 5-FU/leucovorin (LV) 5-FU/low-dose LV (Mayo, 6 months), and Table 1. Adjuvant chemotherapy protocols used in clinical trials. Protocol Drugs/doses/schedule References 5-FU/LV LV 20 mg/m /day iv for 5 days every 4 weeks, for six [Haller et al. 2005] Mayo Clinic cycles 5-FU 425 mg/m /day iv for 5 days every 4 weeks, for six cycles 5-FU/LV LV 500 mg/m iv, 6 weekly courses every 8 weeks, for [Haller et al. 2005] Roswell Park three to four cycles 5-FU 500 mg/m iv, 6 weekly courses every 8 weeks, for three to four cycles QUASAR LV 25 mg/day iv for 5 days every 4 weeks, forsix [Gray et al. 2007] cycles 5-FU 370 mg/m /day iv for 5 days every 4 weeks, for six cycles FLOX LV 500 mg/m iv, 6 weekly courses every 8 weeks, for [Kuebler et al. 2007] three cycles 5-FU 500 mg/m iv, 6 weekly courses every 8 weeks, for three cycles Oxaliplatin 85 mg/m iv on days 1, 15 and 29 of each cycle 5-FU/LV2 LV 200 mg/m iv every 2 weeks, for six cycles [Andre´ et al. 2004] 2 2 5-FU 400 mg/m iv bolus followed by 600mg/m iv 22 h infusion for 2 consecutive days every 2 weeks, for six cycles FOLFOX4 LV 200 mg/m iv every 2 weeks, for six cycles [Andre´ et al. 2004] 2 2 5-FU 400 mg/m iv bolus followed by 600 mg/m iv 22 h infusion for 2 consecutive days every 2 weeks, for six cycles Oxaliplatin 85 mg/m every 2 weeks, for six cycles mFOLFOX6 LV 400 mg/m iv every 2 weeks, for six cycles [Wolmark et al. 2009] 2 2 5-FU 400 mg/m iv bolus followed by 2400 mg/m iv 46 h infusion every 2 weeks, for six cycles Oxaliplatin 85 mg/m every 2 weeks, for six cycles XELOX Capecitabine 1000 mg/m twice daily for 14 days every 3 [Schmoll et al. 2007] weeks, for eight cycles Oxaliplatin 130 mg/m every 3 weeks, for eight cycles 5-FU, 5-fluorouracil; iv, intravenously; LV, leucovorin. 262 http://tam.sagepub.com DA Bastos, SC Ribeiro et al. 5-FU/LV/lev (6 months). After a 10-year follow Combination therapy up, results for both 5-year DFS and OS were Oxaliplatin and irinotecan are known active similar in all treatment arms [Haller et al. 2005]. drugs for metastatic colorectal cancer and both were tested as combined therapy with 5-FU/LV At that time, bolus 5-FU/LV (the Roswell Park in the adjuvant treatment of colon cancer. or Mayo Clinic regimen) was considered the Oxaliplatin. Benefit for combination therapy standard adjuvant therapy for stage III colon with oxaliplatin in the adjuvant setting was first cancer. Since then, the availability of active che- demonstrated in the MOSAIC trial [Andre ´ et al. motherapy agents, outcome improvement with 2004]. In this study, 2246 stage II (40%) and combination chemotherapy, and redefinition of stage III (60%) patients were randomized to clinical benefit for high-risk stage II colon receive 5-FU/LV infusion regimen alone or plus cancer and for the elderly population have mod- oxaliplatin 85 mg/m (FOLFOX4 regimen). ified the understanding and management of adju- Overall, the 5-year DFS was significantly higher vant therapy for colon cancer. in the FOLFOX arm than in the 5-FU/LV mono- therapy group, with 73.3% versus 67.4% Adjuvant therapy for stage III colon cancer (p¼ 0.003, HR, 0.80). For stage III patients, the 5-year DFS was 66.4% for FOLFOX4 and Monotherapy regimens 58.9% for the 5-FU/LV arm, with a significant As previously mentioned, several studies have risk reduction of 22% (Figure 1). The advantage established adjuvant therapy with 5FU/LV as the favoring the combined treatment regimen was standard for patients with stage III colon cancer observed in all subgroups of stage III colon [Haller et al. 2005; Wolmark et al. 1999]. cancer, with a reduction in risk of recurrence of Although there was no established standard 7% in patients with stage III N1 disease and 12% dosing schedule for 5-FU/LV or defined treatment in patients with stage III N2 disease. The 6-year duration, important concepts could be learned update of the MOSAIC trial demonstrated that from available trials. It has been demonstrated the addition of oxaliplatin resulted in an OS that 6 months of 5-FU/LV treatment was equiva- advantage of 2.5% (p¼ 0.046) and 4.2% lent to 12 months of 5-FU/lev or 5-FU/LV/lev (p¼ 0.023) for the entire study population and [Haller et al. 2005; O’Connell et al. 1998], stage III patients, respectively [Andre et al. low-dose LV was as effective as high-dose LV in 2009] (Figure 2). Together with DFS and OS combination with bolus 5-FU [QUASAR benefit, the combined treatment arm had a Collaborative Group, 2000], and regimens of higher incidence of grade 3/4 toxicities in the 5-FU administered by continuous infusion or MOSAIC trial. The addition of oxaliplatin to those combining bolus and infusional 5-FU are 5-FU/LV was associated with an increase in neu- better tolerated and have similar efficacy com- tropenia (41% versus 4.7%), febrile neutropenia pared with bolus 5-FU regimens [Poplin et al. (1.8% versus 0.2%), diarrhea (10.8% versus 2005; Andre ´ et al. 2003]. 6.7%), vomiting (5.9% versus 1.4%), allergy (3% versus 0.2%), and neuropathy (12.4% Oral fluoropyrimidines were also tested as versus 0%), but no increase in mortality. monotherapy in the adjuvant setting. In a large randomized phase III trial, capecitabine was The second trial that demonstrated better out- compared with bolus 5-FU/LV (Mayo regimen) comes with combined therapy was the NSABP for stage III colon cancer. The results demon- C-07 [Kuebler et al. 2007]. In this trial 2407 strated superiority in relapse-free survival in the patients with stage II (29%) or III colon cancer capecitabine arm (hazard ratio [HR], 0.86; were randomized to three cycles of bolus weekly p¼ 0.04) and also a trend toward superior DFS 5-FU/LV alone or with oxaliplatin (FLOX (HR, 0.87; p¼ 0.052) and OS (HR, 0.84; regimen). Four-year DFS significantly favored p¼ 0.07) for capecitabine versus bolus 5-FU/LV the oxaliplatin group (73.2% versus 67%), with a [Twelves et al. 2005]. In the NSABP C-06 trial, 20% risk reduction in recurrence rate (p< 0.004). which evaluated tegafur-uracil (UFT) in the In a preliminary report from the 2008 American adjuvant treatment for stage II and III colon Society of Clinical Oncology (ASCO) meeting, cancer, UFT/folinic acid (FA) achieved similar there was a trend toward better OS in the FLOX DFS and OS as compared with bolus 5-FU/FA arm (5-year survival 80% versus 78%, HR, 0.85) [Lembersky et al. 2006]. [Wolmark et al. 2008]. http://tam.sagepub.com 263 Therapeutic Advances in Medical Oncology 2 (4) 80% 74.2% 72.4% FOLFOX 70% FOLFOX 66.4% + BEV 64.2% FOLFOX 60.8% p = 0.25 60.6% 58.9% CAP 60% HR 0.90 57% p = 0.005 5-FU/lev 5-FU/LV 5-FU p = 0.05 HR 0.78 53% F/U 36mo 5-FU/LV HR 0.87 p = 0.0001 F/U 5yr 50% HR 0.60 5-FU/lev p = 0.04 F/U 3yr 43.8% HR 0.87 F/U 7yr Control F/U 5yr 40% 30% 20% 10% 0% INT-0035 NSABP C-04 X-ACT MOSAIC NSABP C-08 Trials of adjuvant therapy Figure 1. Disease-free survival for stage III colon cancer in landmark clinical trials of adjuvant therapy. BEV, bevacizumab; FOLFOX, 5-fluorouracil plus oxaliplatin; 5-FU, 5-fluorouracil; F/U, follow up; HR, hazard ratio; lev, levamisole; LV, leucovorin; yr, years. INT-0035 [Moertel et al. 1995]; NSABP C-04 [Wolmark et al. 1999]; X-ACT [Twelves et al. 2005]; MOSAIC [Andre´ et al. 2009]; NSABP C-08 [Wolmark et al. 2009]. 90% 81.3% 80% 77.6% CAP 72.9% 5-FU/LV p = 0.07 68.7% 70% 67% FOLFOX HR 0.84 63% 5-FU/LV 5-FU/LV p = 0.023 F/U 3yr 60.2% HR 0.80 60% 5-FU/lev p = 0.07 5-FU/lev HR 0.90 F/U 6yr p = 0.0007 50% 46.7% F/U 5yr HR 0.67 Control F/U 7yr 40% 30% 20% 10% 0% INT-0035 NSABP C-04 X-ACT MOSAIC Trials of adjuvant therapy Figure 2. Overall survival for stage III colon cancer in landmark clinical trials of adjuvant therapy. FOLFOX, 5-fluorouracil plus oxaliplatin; 5-FU, 5-fluorouracil; F/U, follow up; HR, hazard ratio; lev, levamisole; LV, leucovorin; yr, years. INT-0035 [Moertel et al. 1995]; NSABP C-04 [Wolmark et al. 1999]; X-ACT [Twelves et al. 2005]; MOSAIC [Andre´ et al. 2009]. 264 http://tam.sagepub.com Disease free survival Overall survival DA Bastos, SC Ribeiro et al. Overall, the toxicity of FOLFOX4 was lower than setting. Also, patients with microsatellite instabil- the FLOX regimen, with the exception of grade 3 ity did not benefit from combined treatment with sensory neuropathy, possibly because of the lower irinotecan in a recent subgroup analysis of the cumulative dose of oxaliplatin used in NSABP PETACC-3 trial [Tejpar et al. 2009]. C-07 as compared with the MOSAIC trial. Based on the above-mentioned results, adjuvant Conversely, gastrointestinal toxicity was more irinotecan-combined chemotherapy cannot be frequent in the FLOX regimen, possibly due to considered a standard approach for resected the different administration schedule of 5-FU/LV colon cancer patients. There is controversy in the NSABP C-07 (bolus 5-FU/LV) and about whether patients with microsatellite insta- MOSAIC trial (infusional 5-FU) (Table 1). For these reasons, there is a general agreement that bility can benefit from combined treatment with irinotecan and this approach cannot be recom- FOLFOX should be the regimen of choice, although FLOX could be used in patients for mended until more conclusive data are presented. whom ambulatory infusional therapy is not available. Adjuvant therapy for stage II colon cancer As previously discussed, combined adjuvant The first efficacy results of a phase III trial of chemotherapy has been considered a standard combination adjuvant therapy with capecitabine approach for stage III colon cancer. Despite the and oxaliplatin (XELOX trial) were recently pre- fact that patients with stage II disease have sented [Haller et al. 2009; Schmoll et al. 2007]. been included in several adjuvant trials (Figures 2 In this trial, 1886 stage III colon cancer patients and 3), the benefit of chemotherapy after resec- were randomized to receive either XELOX or tion in these patients has not been definitively bolus 5-FU/LV (Mayo Clinic or Roswell Park), established. Better identification of a subgroup and after a median follow up of 57 months, the of patients with a higher risk of recurrence can XELOX arm had a superior DFS (68.4% versus select patients who might benefit from adjuvant 62.3%, HR, 0.80, p¼ 0.0045), and also a man- therapy. ageable toxicity profile. Definition of high-risk stage II colon cancer Irinotecan. Despite documented efficacy of Stage II colon cancer patients are a heteroge- irinotecan for the treatment of metastatic colon neous population in terms of prognosis. These cancer, trials of adjuvant therapy using this drug patients have a relatively good outcome after have failed to demonstrate improvement in DFS surgery, with an OS of 7285% and the role of and OS. adjuvant chemotherapy in this setting is still controversial [Kopetz et al. 2008]. The first trial of irinotecan in the adjuvant setting was the CALGB 89803. In this trial, 1264 stage Therefore, a better stratification of patients based III patients were randomized to 5-FU/high-dose on high-risk features should select a subgroup of LV alone or with irinotecan (IFL regimen) and no patients with a higher risk of recurrence that DFS or OS benefit was demonstrated [Saltz et al. might benefit from adjuvant therapy. On the 2007]. Of note, there were significantly higher other hand, this stratification may spare low-risk rates of toxicities and treatment-related mortality patients from receiving cytotoxic chemotherapy. in the IFL group (2.8% versus 1%). Interestingly, a recent subgroup analysis of this trial showed an The well-known prognostic histological features apparent benefit of adding irinotecan in the adju- in stage II disease are T4 tumor, perforation or vant therapy of patients with microsatellite insta- obstruction, poorly differentiated histology, lym- bility [Bertagnolli et al. 2009]. phovascular invasion [Quah et al. 2008; O’Connell et al. 2004], fewer than 12 sampled Owing to a better toxicity profile than the IFL lymph nodes [Chang et al. 2007; Le Voyer et al. regimen in the metastatic scenario, the 2003; Prandi et al. 2002], and a high preoperative FOLFIRI regimen was evaluated for adjuvant carcinoembryonic antigen level [Takagawa et al. treatment of colon cancer in two randomized 2008]. These factors have an important negative trials [Van Cutsem et al. 2009; Ychou et al. impact on survival and these patients have a 2009]. Both the PETACC-3 trial and ACCORD 5-year OS of about 60%, similar to that of trial have also failed to demonstrate benefit from stage III patients [Quah et al. 2008; O’Connell adding irinotecan to 5-FU/FL in the adjuvant et al. 2004]. Therefore, adjuvant treatment is http://tam.sagepub.com 265 Therapeutic Advances in Medical Oncology 2 (4) 100% 90% 87.4% 84.7% 84.7% 83.7% 81.9% FOLFOX 79.9% 79% 5-FU/LV FOLFOX 80% + BEV FOLFOX Control 75% 5-FU/LV 5-FU/lev p = 0.76 71% 71% p = 0.25 p = 0.35 5-FU/LV HR 0.82 70% HR 0.84 HR 0.82 p = 0.10 Control 5-FU/lev HR 0.69 p = 0.04 F/U 5.5yr F/U 36mo F/U 5yr HR 0.78 60% F/U 7yr F/U 5yr 50% 40% 30% 20% 10% 0% INT-0035 NSABP C-04 QUASAR MOSAIC NSABP C-08 Trials of adjuvant therapy Figure 3. Disease-free survival for stage II colon cancer in landmark clinical trials of adjuvant therapy. BEV, bevacizumab; FOLFOX, 5-fluorouracil plus oxaliplatin; 5-FU, 5-fluorouracil; F/U, follow-up; HR, hazard ratio; lev, levamisole; LV, leucovorin; yr, years. INT-0035 [Moertel et al. 1995]; NSABP C-04 [Wolmark et al. 1999]; QUASAR [Gray et al. 2007]; MOSAIC [Andre ´ et al. 2009]; NSABP C-08 [Wolmark et al. 2009]. often recommended for patients with one or utility as a prognostic tool remains to be defined. more of these features, although its efficacy in There are other molecular factors increasingly this high-risk group has never been prospectively being evaluated for predicting outcome in stage validated. II colon cancer, but the isolated use of these mar- kers to assess prognosis or select patients for In addition to the well-recognized clinical and adjuvant chemotherapy cannot yet be rec- pathologic high-risk characteristics, molecular ommended, as stated previously [Locker et al. markers can also provide prognostic information. 2006]. The ongoing ECOG E5202 trial is evalu- Microsatellite instability (MSI) is a measure of ating the role of molecular markers to select DNA repair mechanisms, which when disrupted patients for adjuvant therapy or observation lead to replication errors in repetitive nucleotide and the results are waited to define better this regions (called microsatellites), and the high- controversial matter. frequency MSI (MSI-H) is associated with a better survival compared with MSI-stable Recently, a quantitative multigene real-time poly- (MSI-S) tumors [Gryfe et al. 2000]. Although merase chain reaction assay provided a validated there are conflicting results about the role of colon cancer recurrence score that was an inde- MSI in the outcome of patients treated with adju- pendent predictor of individualized recurrence vant chemotherapy, most studies support the risk for stage II colon cancer patients following concept that adjuvant therapy is less beneficial surgery [Kerr et al. 2009], but its use in clinical for MSI-H tumors [Sinicrope and Sargent, practice has not yet been defined. 2009; Kim et al. 2007; Lanza et al. 2006; Popat et al. 2005; Ribic et al. 2003]. Monotherapy regimens An early prospective trial of adjuvant therapy for Other important candidate molecular prognostic colorectal cancer reported an important benefit markers are those related to chromosomal insta- of short-term 5-FU for stage II patients, with a bility, particularly the loss of heterozygosity of the 5-year DFS of 82% compared with 59% in long arm of chromosome 18 (18q LOH). This is patients who did not receive adjuvant treatment highly prevalent in sporadic colon cancer but its (p< 0.02) [Li and Ross, 1976]. However, these 266 http://tam.sagepub.com Disease free survival DA Bastos, SC Ribeiro et al. dramatic results have never been reproduced by B2 (T3-4N0) patients [IMPACT B2, 1999]. A other trials. total of 998 patients randomized to treatment with 5-FU/LV or observation were analyzed Subgroup analyses from the initial NSABP trials after a 5.8-year follow-up period. The 5-year failed to show a statistically significant improve- OS rate was 82% on the 5-FU/LV arm versus ment in the outcomes of stage II patients treated 80% with observation alone (nonsignificant) with adjuvant chemotherapy [Smith et al. 2004; and the HR at 5 years was 0.83 (90% confidence Wolmark et al. 1999, 1993, 1990]. interval [CI], 0.721.07) for DFS and 0.86 (90% CI, 0.681.07) for OS. The first study to report data separately for stage II patients evaluated adjuvant treatment with A second study evaluated the benefit of adjuvant 5-FU/lev versus observation [Laurie et al. 1989]. treatment in the NSABP C-01C-04 trials There was a trend towards improved DFS in the [Mamounas et al. 1999]. In this analysis there 5-FU/lev arm (59% versus 73%; p¼ 0.10). was a 30% relative reduction in mortality for However, there was no OS benefit with adjuvant stage II patients (p< 0.05), favoring the more chemotherapy in this small stage II trial. effective treatment arms, with a corresponding decrease in risk of recurrence. Of note, the ben- The subsequent Intergroup 0035 trial evaluated efit in mortality occurred irrespective of the pres- the impact of 5-FU/lev in 1247 stage II and stage ence or absence of adverse prognostic factors and III patients. However, it was underpowered to also this survival advantage was similar for stage demonstrate benefit in stage II patients, as only II and III colon cancer. 318 of these patients were studied. In this study, patients receiving 5-FU/lev were part of a trend On a pooled analyses of 3302 patients from seven towards a reduced rate of recurrence (71% versus randomized trials of 5-FU-based adjuvant ther- 79% for observation and 5-FU/lev, respectively, apy for stage II and III colon cancer, the only p¼ 0.10), with similar OS in the final report independent prognostic factors for DFS and OS [Moertel et al. 1995, 1990]. were nodal status, tumor (T) stage and histologi- cal grade [Gill et al. 2004]. Univariate analysis In the QUASAR trial, 3239 patients (2146 [66%] demonstrated a 4% absolute risk reduction in with stage II colon cancer) with no clear indica- DFS (HR, 0.82, p¼ 0.049) but no improvement tion for adjuvant chemotherapy were randomized in mortality was observed (80% versus 81%, to treatment with 5-FU/LV or observation [Gray p¼ 0.1127). When adjusted for T-stage, nodal et al. 2007]. After a median follow up of 5.5 status and grade, there was a 35% reduction in years, the relative risk of recurrence and death the risk of recurrence (HR, 0.65; 95% CI, from any cause with chemotherapy versus obser- 0.580.73) and a 30% reduction in the risk of vation alone was 0.82 (p¼ 0.008) and 0.78 death (HR, 0.73; 95% CI, 0.630.79) with (p¼ 0.001), respectively. The authors concluded adjuvant chemotherapy. that the absolute benefit from an 18% relative reduction in mortality in this trial would be A systematic review focused on stage II patients 5.4% in patients with high-risk features and was conducted by the Cancer Care Ontario 3.6% in those without, which might both be Program in Evidence-based Care [Figueredo considered sufficient to justify adjuvant chemo- et al. 2004]. This review, which included 37 therapy in this patient group. However, the inclu- trials and 11 meta-analyses and was able to pool sion of rectal cancer patients, administration of data from 4187 patients, found a risk ratio of 0.87 four 5-FU-based regimens and the lack of a for adjuvant chemotherapy (95% CI, 0.751.01, central pathologic review make these results p¼ 0.07), representing a trend towards an questionable. improvement in OS. Meta-analyses. Several meta-analyses had been Combination therapy published evaluating the role of adjuvant therapy The MOSAIC trial demonstrated indubitable for colon cancer, including stage II patients, with benefit in terms of DFS and OS for stage III conflicting results. colon patients. For stage II colon cancer, which represented 40% of the enrolled patients The IMPACT B2 study evaluated five trials that (n¼ 899), 3-year DFS was 87% in the had individual patient data for modified Dukes FOLFOX4 arm compared with 84.3% in the http://tam.sagepub.com 267 Therapeutic Advances in Medical Oncology 2 (4) 5-FU/LV group (HR, 0.80; 95% CI, 0.561.15) subgroups (including age over 70 years), without [Andre et al. 2004]. Moreover, subgroup analysis an increase in adverse events in the elderly pop- of patients with high-risk features (T4 stage, per- ulation [Sargent et al. 2001]. Additional data foration or obstruction, poorly differentiated supporting survival benefit for postoperative che- tumor, lymphovascular invasion, fewer than 10 motherapy for elderly patients was provided from sampled lymph nodes) revealed a trend toward a series of 4768 stage III colon cancer patients improvement in DFS for the combined treatment aged over 65 years. Although only 52% of eligible group (82.1% versus 74.9%; HR, 0.74; 95% CI, patients received therapy, the use of 5-FU-based 0.521.06). However, the 6-year updated results chemotherapy was associated with a significant of the MOSAIC trial showed no OS benefit by 34% reduction in mortality [Sundararajan et al. adding oxaliplatin for stage II patients regardless 2002]. A pooled analysis of 1567 patients of their risk stratification [Andre ´ et al. 2009]. (614 aged over 70 years) from four trials of the FOLFOX regimen showed similar benefits for all Similar results from the NSABP C-07 trial age subgroups [Goldberg et al. 2006]. demonstrated an overall benefit of the addition of oxaliplatin to 5-FU/LV but failed to demon- In contrast to the above described results, recent strate an improvement in the stage II patient pop- analyses of data from the ACCENT database, ulation [Kuebler et al. 2007]. with more than 12,500 patients enrolled in phase III trials of intravenous 5-FU compared Recently, a large meta-analysis of adjuvant ther- with combination therapy or oral fluoropyrimi- apy for completely resected stage II colon cancer dines, conclusively showed that patients aged evaluated more than 7000 stage II patients over 70 years do not receive the same benefit included in 33 trials and 17 meta-analyses. The from combination and/or oral FU as those pooled risk ratio for OS and DFS were 0.96 under 70 years old. (95% CI, 0.881.05) and 0.83 (95% CI, 0.750.92), respectively. Although there was no Targeted agents for adjuvant therapy improvement in OS in the pooled analysis, adju- Monoclonal antibodies against vascular endothe- vant treatment significantly improved DFS of lial growth factor and epidermal growth factor stage II colon cancer in this large database receptor (EGFR) are been increasingly recog- [Figueredo et al. 2008]. nized as important components of systemic ther- apy for metastatic colon cancer. Trials of targeted There is an ongoing trial that started on March therapy combined with chemotherapy in the 2008 with an estimated enrollment of 9500 adjuvant setting have also been conducted patients, which will prospectively evaluate the [de Gramont et al. 2006]. role of combination chemotherapy after surgery in treating patients with high-risk stage II or stage The NSABP C-08 trial results were reported in III colorectal cancer. The results are expected the 2009 ASCO meeting [Wolmark et al. 2009]. and may definitively demonstrate the benefit of In this trial, 2672 stage II (25%) and III patients treatment in this patient population. were randomized to receive modified FOLFOX6 (mFOLFOX6) alone or plus bevacizumab Adjuvant therapy in the elderly population (BEV). At a median follow up of 36 months, Incidence of colon cancer increases with age and there was no significant DFS benefit for the addi- the median age at diagnosis is 72 years. This tion of BEV (3-year DFS 77.4% versus 75.5%, patient population usually has more significant HR for progression 0.89; 95% CI, 0.761.04). comorbidities and a higher incidence of noncancer-related deaths [Ades, 2009]. Thus, In the recently completed phase III AVANT trial, the risks and benefits must be weighted when high-risk stage II or stage III patients were ran- considering adjuvant chemotherapy for the domized to FOLFOX4 versus FOLFOX4 plus elderly colon cancer patient. BEV versus XELOX plus BEV. The safety analy- sis of this study was recently presented [Hoff et al. In a pooled analysis of seven phase III trials with 2009] and the efficacy results are expected soon. 3351 patients, adjuvant therapy was associated with a 24% relative reduction in mortality (71% In addition, two phase III randomized trials versus 64%, p< 0.001) and a 32% reduction in (NCCTG/Intergroup N0147 and PETACC-8) cancer recurrence (p< 0.001) for all age are ongoing in evaluating the anti-EGFR 268 http://tam.sagepub.com DA Bastos, SC Ribeiro et al. antibody, cetuximab, for the adjuvant treatment Targeted agents of stage III colon cancer. Preliminary data To date, there is still no role for targeted drugs in released to the press in November 2009 (unpub- the adjuvant treatment of colon cancer. Results of lished) of the NCCTG/Intergroup N0147 trial ongoing trials may demonstrate benefit and fur- indicated that the trial was negative, and that ther data are waited to define better the utility of the endpoints could not be achieved. Therefore, these promising drugs on adjuvant setting. at this time there seems to be no benefit from the addition of cetuximab to chemotherapy in the Perspectives adjuvant setting of wild-type K-ras stage III Despite the important evolution and better colon cancer patients. The final report with the understanding of the role of adjuvant therapy in official results of this trial is expected soon. stage II and III colon cancer, there are still several questions to be answered. Results of ongoing large prospective clinical trials are expected to Recommendations refine the management and improve survival in this highly prevalent disease. Stage III colon cancer For resected stage III colon cancer, adjuvant che- Conflicts of interest statement motherapy based on combined 5-FU/LV and PMH serves on advisory boards and receives oxaliplatin regimens should be the current stan- research support from Sanofi-Aventis and Roche. dard of care because of the demonstrated benefit in DFS and OS for this patient population. To date there is no study directly comparing References XELOX, FLOX, and FOLFOX and, therefore, Ades, S. (2009) Adjuvant chemotherapy for colon there is no evidence to support recommendation cancer in the elderly: Moving from evidence to of one specific protocol. practice. Oncology (Williston Park) 23: 162167. Andre ´, T., Boni, C., Mounedji-Boudiaf, L., Navarro, Stage II colon cancer M., Tabernero, J., Hickish, T. et al. (2004) Oxaliplatin, 5-fluorouracil and leucovorin as adjuvant treatment for Adjuvant therapy should not be routinely recom- colon cancer. N Engl J Med 350: 23432351. mended for unselected stage II colon cancer patients. However, because of a possible small Andre ´, T., Boni, C., Navarro, M., Tabernero, J., absolute benefit with monotherapy, postoperative Hickish, T., Topham, C. et al. (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin chemotherapy can be offered for medically fit as adjuvant treatment in stage II or III colon cancer in high-risk stage II patients (T4 disease, fewer the MOSAIC trial. J Clin Oncol 27: 18. than 12 sampled lymph nodes, obstruction or Andre ´, T., Colin, P., Louvet, C., Gamelin, E., Bouche, perforated tumor, lymphovascular invasion, O., Achille, E. et al. (2003) Semimonthly versus poorly differentiated histology). In this setting, monthly regimen of fluorouracil and leucovorin monotherapy appears to have a better riskben- administered for 24 or 36 weeks as adjuvant therapy in efit ratio and is the current recommendation, but stage II and II colon cancer: Results of a randomized trial. J Clin Oncol 21: 28962903. combined therapy with oxaliplatin can also be discussed for selected cases. Bertagnolli, M.M., Niedzwiecki, D., Comptom, C.C., Hahn, H.P., Hall, M., Damas, B. et al. (2009) Microsatellite instability predicts improved response to Elderly patients adjuvant therapy with irinotecan, fluorouracil, and There is a general agreement that adjuvant ther- leucovorin in stage III colon cancer: Cancer and apy should be routinely offered for elderly leukemia Group B protocol 89803. J Clin Oncol 27: 18141821. patients. The optimal regimen for these patients is uncertain. Based on the recent results of the Chang, G.J., Rodriguez-Bigas, M.A., Skibber, J.M. ACCENT database, patients over 70 years old do and Moyer, V.A. (2007) Lymph node evaluation and survival after curative resection of colon cancer: not benefit from combined oxaliplatin-based systematic review. J Natl Cancer Inst 99: 433441. therapy. Therefore, we do not recommend rou- tine use of combined adjuvant chemotherapy for De Dosso, S., Sessa, C. and Saletti, P. (2008) Adjuvant therapy for colon cancer: Present and elderly colon cancer patients. However, the perspectives. Cancer Treat Rev 35: 160166. riskbenefit ratio of combined treatment can be discussed and eventually recommended in very de Gramont, A., Boni, C., Navarro, M., Tabernero, J., high-risk and otherwise healthy older patients. Hickish, T., Topham, C. et al. (2005) Oxaliplatin/5FU/ http://tam.sagepub.com 269 Therapeutic Advances in Medical Oncology 2 (4) LV in the adjuvant treatment of stage II and stage III IMPACT B2; International Multicenter Pooled colon cancer: Efficacy results with a median follow-up Analysis of B2 Colon Cancer Trials Investigators. of 4 years. ASCO Annual Meeting Proceedings. J Clin (1999) Efficacy of adjuvant fluorouracil and folinic Oncol 23: 16S(abstract 3501). acid in B2 colon cancer. J Clin Oncol 17: 13561363. de Gramont, A., Tournigand, C., Andre ´, T., Larsen, A.K. and Louvet, C. (2006) Targeted agents for Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Thun, adjuvant therapy of colon cancer. Semin Oncol M.J. et al. (2009) Cancer statistics. CA Cancer J Clin 33(6 Suppl 11): S42S45. 59: 225249. Figueredo, A., Charette, M.L., Maroun, J., Brouwers, Kerr, D., Gray, R., Quirke, P., Watson, D., Yothers, M.C. and Zuraw, L. (2004) Adjuvant therapy for stage G., Lavery, I.C. et al. (2009) A quantitative multigene II colon cancer: A systematic review from the cancer RT-PCR assay for prediction of recurrence in stage II care Ontario program in evidence-based care’s gas- colon cancer: Selection of the genes in four large stu- trointestinal cancer disease site group. J Clin Oncol dies and results of the independent, prospectively 22: 33953407. designed QUASAR validation study. J Clin Oncol 27(Suppl; abstract 4000): 15s. Figueredo, A., Coombes, M.E. and Mukherjee, S. (2008) Adjuvant therapy for completely resected stage Kim, G.P., Colangelo, L.H., Wieand, H.S., Paik, S., II colon cancer. Cochrane Database Syst Rev Kirsch, I.R., Wolmark, N. et al. (2007) Prognostic and 16: CD005390. predictive roles of high-degree microsatellite instability in colon cancer: A National Cancer Institute-National Gill, G., Loprinzi, C.L., Sargent, D.J., Thome, S.D., Surgical Adjuvant Breast and Bowel Project Alberts, S.R., Haller, D.G. et al. (2004) Pooled ana- Collaborative Study. J Clin Oncol 25: 767772. lysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? Kopetz, S., Freitas, D., Calabrich, A.F. and Hoff, P.M. J Clin Oncol 22: 17971806. (2008) Adjuvant chemotherapy for stage II colon cancer. Oncology (Williston Park) 22: 260270. Goldberg, R.M., Tabah-Fisch, I., Bleiberg, H., de Gramont, A., Tournigand, C., Andre, T. et al. (2006) Kuebler, J.P., Wieand, H.S., O’Connell, M.J., Smith, Pooled analysis of safety and efficacy of oxaliplatin plus R.E., Colangelo, L.H., Yothers, G. et al. (2007) fluorouracil/leucovorin administered bimonthly in Oxaliplatin combined with weekly bolus fluorouracil elderly patients with colorectal cancer. J Clin Oncol and leucovorin as surgical adjuvant chemotherapy for 24: 40854091. stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 25: 21982204. Gray, R., Barnwell, J., McConkey, C., Hills, R.K., Williams, N.S. and Kerr, D.J., QUASAR Collaborative Lanza, G., Gafa ` , R., Santini, A., Maestri, I., Guerzoni, Group (2007) Adjuvant chemotherapy versus obser- L. and Cavazzini, L. (2006) Immunohistochemical test vation in patients with colorectal cancer: A randomised for MLH1 and MSH2 expression predicts clinical study. Lancet 370: 20202029. outcome in stage II and III colorectal cancer patients. J Clin Oncol 24: 23592367. Gryfe, R., Kim, H., Hsieh, E.T., Aronson, M.D., Holowaty, E.J., Bull, S.B. et al. (2000) Tumor micro- Laurie, J.A., Moertel, C.G., Fleming, T.R., Wieand, satellite instability and clinical outcome in young H.S., Leigh, J.E., Rubin., J. et al. (1989) Surgical patient with colorectal cancer. N Engl J Med adjuvant therapy of large-bowel carcinoma: An evalu- 342: 6977. ation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Haller, D.G., Catalano, P.J., Macdonald, J.S., O’Rourke, M.A., Frontiera, M.S., Jackson, D.V. et al. Treatment Group and the Mayo Clinic. J Clin Oncol (2005) Phase III study of fluorouracil, leucovorin, and 7: 14471456. levamisole in high-risk stage II and III colon cancer: Le Voyer, T.E., Sigurdson, E.R., Hanlon, A.L., Mayer, Final report of Intergroup 0089. J Clin Oncol R.J., Macdonald, J.S., Catalano, P.J. et al. (2003) 23: 86718678. Colon cancer survival is associated with increasing Haller, D., Tabernero, J., Maroun, J., de Braud, F., number of lymph nodes analyzed: A secondary survey Price, T., Van Cutsem, E. et al. (2009) First efficacy of intergroup trial INT-0089. J Clin Oncol findings from a randomized phase III trial of capeci- 21: 29122919. tabine þ oxaliplatin vs. bolus 5-FU/LV for stage III Lembersky, B.C., Wieand, H.S., Petrelli, N.J., colon cancer (NO16968/XELOXA study). Eur J O’Connell, M.J., Colangelo, L.H., Smith, R.E. et al. Cancer Suppl 7: 4. (2006) Oral uracil and tegafur plus leucovorin com- Hoff, P., Clarke, S., Cunningham, D., Van Cutsem, E., pared with intravenous fluorouracil and leucovorin in Moore, M., Schmoll, H.J. et al. (2009) A three-arm stage II and III carcinoma of the colon: Results from phase III randomized trial of FOLFOX-4 vs. National Surgical Adjuvant Breast and Bowel Project FOLFOX-4 plus bevacizumab vs. XELOX plus beva- Protocol C-06. J Clin Oncol 24: 20592064. cizumab in the adjuvant treatment of patients with Li, M.C. and Ross, S.T. (1976) Chemoprophylaxis for stage III or high-risk stage II colon cancer: Results of the interim safety analysis of the AVANT trial. Eur J patients with colorectal cancer. Prospective study with Cancer Suppl 7: 324. five-year follow-up. JAMA 235: 28252828. 270 http://tam.sagepub.com DA Bastos, SC Ribeiro et al. Locker, G.Y., Hamilton, S., Harris, J., Jessup, J.M., QUASAR Collaborative Group (2000) Comparison of Kemeny, N., Macdonald, J.S. et al. (2006) ASCO fluorouracil with additional levamisole, higher-dose 2006 update of recommendations for the use of tumor folinic acid, or both, as adjuvant chemotherapy for markers in gastrointestinal cancer. J Clin Oncol colorectal cancer: A randomised trial. Lancet 24: 53135327. 355: 15881596. Mamounas, E., Wieand, S., Wolmark, N., Bear, H.D., Ribic, C.M., Sargent, D.J., Moore, M.J., Thibodeau, Atkins, J.N., Song, K. et al. (1999) Comparative effi- S.N., French, A.J., Goldberg, R.M. et al. (2003) Tumor microsatellite-instability status as a predictor of cacy of adjuvant chemotherapy in patients with Dukes’ benefit from fluorouracil-based adjuvant chemother- B versus Dukes’ C colon cancer: Results from four apy for colon cancer. N Engl J Med 349: 247257. National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Saltz, L.B., Niedzwiecki, D., Hollis, D., Goldberg, Oncol 17: 13491355. R.M., Hantel, A., Thomas, J.P. et al. (2007) Irinotecan fluorouracil plus leucovorin is not superior to fluor- Marshall, J.L., Haller, D.G., Gramont, A., Hochster, ouracil plus leucovorin alone as adjuvant treatment H.S., Lenz, H.J., Ajani, J.A. et al. (2007) Adjuvant for stage III colon cancer: Results of CALGB 89803. therapy for stage II and III colon cancer: Consensus J Clin Oncol 25: 34563461. report of the International Society of Gastrointestinal oncology. Gastrointest Cancer Res 1: 146154. Sargent, D.J., Goldberg, R.M., Jacobson, S.D., Macdonald, J.S., Labianca, R., Haller, D.G. et al. Moertel, C.G., Fleming, T.R., Macdonald, J.S., (2001) A pooled analysis of adjuvant chemotherapy for Haller, D.G., Laurie, J.A., Goodman, P.J. et al. (1990) resected colon cancer in elderly patients. N Engl J Med Levamisole and fluouroracil for adjuvant therapy of 345: 10911097. resected colon carcinoma. N Engl J Med 322: 352358. Schmoll, H.J., Cartwright, T., Tabernero, J., Nowacki, M.P., Figer, A., Maroun, J. et al. (2007) Phase III trial Moertel, C.G., Fleming, T.R., Macdonald, J.S., of capecitabine plus oxaliplatin as adjuvant therapy for Haller, D.G., Laurie, J.A., Tangen, C.M. et al. (1995) stage III colon cancer: A planned safety analysis in Intergroup study of fluouroracil plus levamisole as 1,864 patients. J Clin Oncol 25: 102109. adjuvant therapy for stage II/Dukes’ B2 colon cancer. J Clin Oncol 13: 29362943. Sinicrope, F.A. and Sargent, D.J. (2009) Clinical implications of microsatellite instability in sporadic O’Connell, M.J., Laurie, J.A., Kahn, M., Fitzgibbons, colon cancers. Curr Opin Oncol 21: 369373. R.J., Erlichman, C., Sheperd, L. et al. (1998) Prospectively randomized trial of postoperative adju- Smith, R.E., Colangelo, L., Wieand, H.S., Begovic, vant chemotherapy in patients with high-risk colon M. and Wolmark, N. (2004) Randomized trial of cancer. J Clin Oncol 16: 295300. adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst O’Connell, J.B., Maggard, M.A. and Ko, C.Y. (2004) 96: 11281132. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. Sundararajan, V., Mitra, N., Jacobson, J.S., Grann, J Natl Cancer Inst 96: 14201425. V.R., Heitjan, D.F. and Neugut, A.I. (2002) Survival associated with 5-fluorouracil-based adjuvant chemo- Popat, S., Hubner, R. and Houlston, R.S. (2005) therapy among elderly patients with node-positive Systematic review of microsatellite instability and colon cancer. Ann Intern Med 136: 349357. colorectal cancer prognosis. J Clin Oncol 23: 609618. Takagawa, R., Fujii, S., Ohta, M., Nagano, Y., Kunisaki, C., Yamagishi, S. et al. (2008) Preoperative Poplin, E.A., Benedetti, J.K., Estes, N.C., Haller, serum carcinoembryonic antigen level as a predictive D.G., Mayer, R.J., Goldberg, R.M. et al. (2005) Phase factor of recurrence after curative resection of color- III Southwest Oncology Group 9415/Intergroup 0153 ectal cancer. Ann Surg Oncol 15: 34333439. randomized trial of fluorouracil, leucovorin, and leva- misole versus fluorouracil continuous infusion and Tejpar, T., Bosman, F., Delorenzi, M., Fiocca, R., levamisole for adjuvant treatment of stage III and Yan, P., Klingbiel, D. et al. (2009) Microsatellite high-risk stage II colon cancer. J Clin Oncol instability (MSI) in stage II and III colon cancer 23: 18191825. treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). J Prandi, M., Lionetto, R., Bini, A., Francioni, G., Clin Oncol 27: 15s(Suppl; abstract 4001). Accarpio, G., Anfossi, A. et al. (2002) Prognostic evaluation of stage B colon cancer patients is improved Twelves, C., Wong, A., Nowacki, M.P., Abt, M., by an adequate lymphadenectomy. Results of a sec- Burris, III H., Carrato, A. et al. (2005) Capecitabine as ondary analysis of a large scale adjuvant trial. Ann Surg adjuvant treatment for stage III colon cancer. N Engl J 235: 458463. Med 352: 26962704. Quah, H.M., Chou, J.F., Gonen, M., Shia, J., Schrag, Van Cutsem, E., Labianca, R., Bodoky, G., Barone, D., Landmann, R.G. et al. (2008) Identification of C., Aranda, E., Nordlinger, B. et al. (2009) patients with high-risk stage II colon cancer for adju- Randomized phase III trial comparing biweekly infu- vant therapy. Dis Colon Rectum 51: 503507. sional fluorouracil/leucovorin alone or with irinotecan http://tam.sagepub.com 271 Therapeutic Advances in Medical Oncology 2 (4) in the adjuvant treatment of stage III colon cancer: infusion: Preliminary results of National Surgical PETACC-3. J Clin Oncol 27: 31173125. Adjuvant Breast and Bowel Project Protocol C-02. J Clin Oncol 8: 14661475. Wolmark, N., Rockette, H., Fisher, B., Wickerman, Wolmark, N., Wieand, S., Kuebler, P.J., Colangelo, L., D.L., Redmond, C., Fisher, E.R. et al. (1993) The O’Connell, M.J., Yothers, G. et al. (2008) A phase III benefit of leucovorin-modulated fluorouracil as post- trial comparing FULV to FULV þ oxaliplatin in stage operative adjuvant therapy for primary colon cancer: II or III carcinoma of the colon: Survival results of Results from National Surgical Adjuvant Breast and NSABP Protocol C-07. ASCO Annual Meeting Bowel Project protocol C-03. J Clin Oncol Proceedings. J Clin Oncol 26: 15S(abstract 4005). 11: 18791887. Wolmark, N., Yothers, G., O’Connell, M.J., Sharif, S., Wolmark, N., Rockette, H., Mamounas, E., Jones, J., Atkins, J.N., Seay, T.E. et al. (2009) A phase III trial Wieand, S., Wickerman, D.L. et al. (1999) Clinical comparing mFOLFOX6 to mFOLFOX6 plus bevaci- trial to assess the relative efficacy of fluorouracil and zumab in stage II or III carcinoma of the colon: Results leucovorin, fluorouracil and levamisole, and fluorour- of NSABP Protocol C-08. J Clin Oncol 27: 18s(Suppl; acil, leucovorin, and levamisole in patients with Dukes’ abstract LBA4). B and C carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project C-04. Ychou, M., Raoul, J.L., Douillard, J.Y., Gourgou- J Clin Oncol 17: 35533559. Bourgade, S., Bugat, R., Mineur, L. et al. (2009) A phase III randomised trial of LV5FU2 þ irinotecan Wolmark, N., Rockette, H., Wickerham, D.L., Fisher, Visit SAGE journals online versus LV5FU2 alone in adjuvant high-risk colon http://tam.sagepub.com B., Redmond, C., Fisher, E.R. et al. (1990) Adjuvant cancer (FNCLCC Accord02/FFCD9802). Ann Oncol therapy of Dukes’ A, B, and C adenocarcinoma of 20: 674680. the colon with portal-vein fluorouracil hepatic 272 http://tam.sagepub.com
Therapeutic Advances in Medical Oncology – SAGE
Published: May 13, 2010
Keywords: adjuvant chemotherapy; colon cancer; combined therapy; high-risk stage II; stage III
You can share this free article with as many people as you like with the url below! We hope you enjoy this feature!
Read and print from thousands of top scholarly journals.
Already have an account? Log in
Bookmark this article. You can see your Bookmarks on your DeepDyve Library.
To save an article, log in first, or sign up for a DeepDyve account if you don’t already have one.
Copy and paste the desired citation format or use the link below to download a file formatted for EndNote
Access the full text.
Sign up today, get DeepDyve free for 14 days.
All DeepDyve websites use cookies to improve your online experience. They were placed on your computer when you launched this website. You can change your cookie settings through your browser.