Primary Surgical Therapy
Adjuvant Chemotherapy
        Chemotherapy regimens prior to 2000
        Chemotherapy regimens after 2000
        Adjuvant therapy for patients with stage II disease
Adjuvant Radiation Therapy
Treatment of Patients With Stage IV Disease
First-line Multiagent Chemotherapy
The Addition of Bevacizumab to Multiagent Chemotherapy
Second-line and Third-line Chemotherapy

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• The Arbeitsgemeinschaft Internische Onkologie (AIO) or German AIO regimen (folic acid, fluorouracil [5-FU], and irinotecan):
  • Irinotecan (100 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (500 mg/m²) administered as a 2-hour infusion on day 1; followed by 5-FU (2,000 mg/m²) intravenous (IV) bolus via ambulatory pump administered for a period of 24 hours on a weekly basis 4 times in a year (52 weeks).



• The deGramont or LV5FU2 regimen (leucovorin and 5-FU):
  • Leucovorin (400 mg/m²) in a 2-hour infusion, followed by a 5-FU (400 mg/m²) bolus and 2 or 3 g/m² of continuous infusion for 46 hours.



• The FOLFOX4 regimen (oxaliplatin, leucovorin, and 5-FU):
  • Oxaliplatin (85 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m²) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m²) IV bolus, then 5-FU (600 mg/m²) via ambulatory pump administered for a period of 22 hours on days 1 and 2 every 2 weeks.



• The FOLFOX6 regimen (oxaliplatin, leucovorin, and 5-FU):
  • Oxaliplatin (85–100 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m²) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m²) IV bolus administered on day 1, then 5-FU (2,400-3,000 mg/m²) via ambulatory pump administered for a period of 46 hours every 2 weeks.



• The FOLFIRI regimen (folic acid, 5-FU, and irinotecan):
  • Irinotecan (180 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m²) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m²) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m²) via ambulatory pump administered for a period of 46 hours every 2 weeks.



• The IFL or Saltz regimen (irinotecan, 5-FU, and leucovorin):
  • Irinotecan (125 mg/m²), 5-FU (500 mg/m²) IV bolus, and leucovorin (20 mg/m²) IV bolus administered weekly for 4 out of 6 weeks.



• The Levamisole regimen (5-FU and levamisole):
  • Bolus 5-FU (450 mg/m² per day) on days 1 to 5, then weekly 28 days later plus levamisole (50 mg) administered orally 3 times a day for 3 days every 2 weeks.



• The Mayo Clinic or NCCTG regimen (5-FU and low-dose leucovorin):
  • Bolus 5-FU-(450 mg/m²)-leucovorin (20 mg/m²) administered daily for 5 days every 28 days.



• The Roswell Park or NSABP regimen (5-FU and high-dose leucovorin):
  • Bolus 5-FU-(500 mg/m²)-leucovorin (500 mg/m²) administered weekly for 6 consecutive weeks every 8 weeks.

Standard treatment for patients with colon cancer has been open surgical resection of the primary and regional lymph nodes for localized disease. The role of laparoscopic techniques [1-4] in the treatment of colon cancer has been examined in two studies. A multicenter prospective randomized noninferiority trial (NCCTG-934653) compared laparoscopic-assisted colectomy (LAC) to open colectomy in 872 patients. At a median follow-up of 4.4 years, 3-year recurrence rates (16% LAC vs. 18% open colectomy; hazard ratio [HR] for recurrence = 0.86; 95% confidence interval [CI], 0.63–1.17; P = .32) and 3-year overall survival (OS) rates (86% LAC vs. 85% open colectomy; HR for death in LAC = 0.91; 95% CI, 0.68–1.21; P = .51) were similar in both groups for all stages of disease evaluated.[5][Level of evidence: 1iiA]. Tumor recurrence in surgical incisions was less than 1% for both groups. Decreased hospital stay (5 days LAC vs. 6 days open colectomy, P < .001) and decreased use of analgesics were reported in the LAC group. A 21% conversion rate from LAC to open procedure was shown. This study excluded patients with locally advanced disease, transverse colon and rectal tumor locations, and perforated lesions. Each of the 66 surgeons participating in the trial had performed at least 20 LACs and were accredited for study participation after independent videotape review assured appropriate oncologic and surgical principles were maintained.[5] The quality-of-life component of this trial was published separately and minimal short-term quality-of-life benefits with LAC were reported.[6][Level of evidence: 1iiC] One small, single-institution randomized study of 219 patients showed that the LAC procedure was independently associated with reduced tumor recurrence on multivariate analysis.[7][Level of evidence: 1iiB] The role of sentinel lymph node mapping is also under clinical evaluation.[8,9]

Surgery is curative in 25% to 40% of highly selected patients who develop resectable metastases in the liver and lung. Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

Prior to 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Many of the early randomized studies of 5-FU in the adjuvant setting failed to show a significant improvement in survival for patients.[10-13] These trials employed 5-FU alone or 5-FU-semustine (methyl-CCNU). The North Central Cancer Treatment Group (NCCTG) conducted a randomized trial comparing surgical resection alone with postoperative levamisole or 5-FU-levamisole.[14][Level of evidence: 1iiA] A significant improvement in disease-free survival (DFS) was observed for patients with stage III colon cancer who received 5-FU-levamisole, but OS benefits were of borderline statistical significance. An absolute survival benefit of approximately 12% (49% vs. 37%) was seen in patients with stage III disease treated with 5-FU-levamisole.

In a large, confirmatory intergroup trial, 5-FU-levamisole prolonged DFS and OS in patients with stage III colon cancer compared with patients who received no treatment after surgery.[15][Level of evidence: 1iiA] Levamisole alone did not confer these benefits. Subsequent studies tested the combination of 5-FU-leucovorin in the adjuvant treatment of patients with resected carcinoma of the colon. Results of multiple randomized trials that have enrolled more than 4,000 patients comparing adjuvant chemotherapy with 5-FU-leucovorin to surgery or 5-FU-semustine-vincristine demonstrate a relative reduction in mortality of between 22% and 33% (3-year OS of 71% to 78% increased to 75% to 84%).[16-18]

Intergroup trial 0089 randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of four treatment arms:[19]

• The Mayo Clinic regimen administered for a total of six cycles.
• The Roswell Park regimen administered for a total of four cycles.
• The Mayo Clinic regimen administered with levamisole for six cycles.
• The levamisole regimen administered for a total of 1 year.

Five-year overall survival ranged from 49% for the Mayo Clinic regimen with levamisole to 60% for the Mayo Clinic regimen, and there were no statistically significant differences among treatment arms.[19][Level of evidence: 1iiA] A preliminary report in November 1997 demonstrated a statistically significant advantage for OS for the Mayo Clinic regimen with levamisole compared to the levamisole regimen. This difference became insignificant with longer follow-up. Overall, grade 3 or greater toxicity occurred more frequently for the Mayo Clinic regimen and the Mayo Clinic regimen with levamisole. In addition, the Mayo Clinic regimen was significantly more toxic with levamisole than without levamisole. The death rate for all four regimens ranged from 0.5% to 1%. Because of its ease of use and its good toxicity profile, the Roswell Park regimen became the preferred adjuvant regimen used in the United States and was often the control arm in subsequent randomized studies.

In addition to Intergroup 0089, multiple studies have refined the use of adjuvant 5-FU-leucovorin in the adjuvant setting and can be summarized:

• Levamisole is unnecessary when using leucovorin.[19]



• Treatment that includes 6–8 months of 5-FU-leucovorin is equivalent to 12 months.[20-22]



• Treatment that includes 24 weeks of adjuvant 5-FU-leucovorin is equivalent to 36 weeks of therapy.[23]



• High-dose leucovorin is equivalent to low-dose leucovorin.[24]



• A meta-analysis of 7 trials revealed no significant difference in efficacy or toxicity among patients 70 years or younger compared with patients older than 70 years.[25]



• An infusional deGramont LV5FU2 schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU-leucovorin.[23]

Capecitabine is an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU with the last step occurring in the tumor cell. For patients with metastatic colon cancer, two studies have demonstrated the equivalence of capecitabine to 5-FU-leucovorin.[26,27] A multicenter European study compared capecitabine (1250 mg/m²) administered twice daily for days 1 to 14, then given every 21 days for 8 cycles to the Mayo Clinic schedule of 5-FU and low-dose leucovorin for patients with stage III colon cancer.[28] The study demonstrated that DFS at 3 years is equivalent for patients receiving capecitabine or 5-FU-leucovorin (HR = 0.87; P < .001).[28][Level of evidence: 1iiDii] Hand-foot syndrome and hyperbilirubinemia were significantly more common for patients receiving capecitabine, but diarrhea, nausea or vomiting, stomatitis, alopecia, and neutropenia were significantly less common. Of patients receiving capecitabine, 57% required a dose modification. For patients with stage III colon cancer in whom treatment with 5-FU-leucovorin is planned, capecitabine is an equivalent alternative.

Oxaliplatin has significant activity when combined with 5-FU-leucovorin in patients with metastatic colorectal cancer. In the 2,246 patients with resected stage II or stage III colon cancer in the MOSAIC study, the toxic effects and efficacy of FOLFOX4 were compared with the same 5-FU-leucovorin regimen without oxaliplatin when administered for 6 months.[29] The preliminary results of the study with 37 months of follow-up demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX4. When reported, there was no difference in overall survival.[30][Level of evidence: 1iiDii] Patients treated with FOLFOX4 experienced more frequent toxic effects consisting mainly of neutropenia (41% > grade 3) and reversible peripheral sensorial neuropathy (12.4% > grade 3). These results are still preliminary, and information is lacking with regard to OS. Nevertheless, these data suggest that FOLFOX4 is a therapeutic option for patients with resected stage III colon cancer.[30]

The potential value of adjuvant therapy for patients with stage II colon cancer is controversial. Pooled analyses and meta-analyses have suggested a 2% to 4% improvement in OS for patients treated with adjuvant 5-FU-based therapy compared with observation.[31-33]

Recently, the Cancer Care Ontario Practice Guideline Initiative (CCOPGI) Gastrointestinal Cancer Disease Site Group undertook a meta-analysis of the English language published literature consisting of randomized trials where adjuvant chemotherapy was compared with observation for patients with stage II colon cancer. The mortality risk ratio was 0.87 (95% CI, 0.75–1.01; P = .07).[34] Based on these data, the American Society of Clinical Oncology issued a guideline stating, “direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer.”[35]

Features in patients with stage II colon cancer that are associated with an increased risk of recurrence include inadequate lymph node sampling, T4 disease, involvement of the visceral peritoneum, and a poorly differentiated histology. The decision to use adjuvant chemotherapy for patients with stage II colon cancer is complicated and requires thoughtful consideration for both patients and their physicians.

While combined modality therapy with chemotherapy and radiation therapy has a significant role in the management of patients with rectal cancer (below the peritoneal reflection), the role of adjuvant radiation therapy for patients with colon cancer (above the peritoneal reflection) is not well defined. Patterns-of-care analyses and single-institution retrospective reviews suggest a role for radiation therapy in certain high-risk subsets of colon cancer patients (T4, tumor location in immobile sites, local perforation, obstruction, and residual disease postresection).[36-41] Such observations led to the development of a phase III randomized intergroup study designed to test the benefit of adding radiation therapy to surgery and chemotherapy with 5-FU-levamisole for selected high-risk colon cancer patients (T4; or T3, N1–N2 ascending and/or descending colon).[42] This clinical trial closed early secondary to inadequate patient accrual, and analysis of 222 enrolled patients (the original goal was 700 patients) demonstrated no relapse or OS benefit for the group receiving radiation therapy, though the sample size and statistical power were inadequate to exclude benefit. Adjuvant radiation therapy, has no current standard role in the management of patients with colon cancer following curative resection, though it may have a role for patients with residual disease.

Treatment of patients with recurrent or advanced colon cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment. For patients with hepatic metastasis considered to be resectable (i.e., based on limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative margin resection has been associated with 5-year survival rates of 25% to 40% in nonrandomized studies.[6,12-15][Level of evidence: 3iiiDiv] Better surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.[43]

Currently, there are seven active and approved chemotherapy drugs for patients with metastatic colorectal cancer: 5-FU, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab. When 5-FU was the only active chemotherapy drug, trials including patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[44,45] as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.[46-48] Several trials have analyzed the activity and toxic effects of various 5-FU-leucovorin regimens using different doses and administration schedules and showed essentially equivalent results with a median survival time in the 12-month range.[49] Prior to the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU-leucovorin.[26,27][Level of evidence: 1iiA]

Three randomized studies demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[50-52] Intergroup study N9741 then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced an improved PFS (median, 6.9 months vs. 8.7 months, P = .014; HR = 0.74; 95% CI, 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR = 0.66; 95% CI, 0.54–0.82) compared with patients randomly assigned to IFL.[Level of evidence: 1iiA] Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively.[53,54][Level of evidence: 1iiDiii] PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.

Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab.[55] The patients randomly assigned to IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL and bevacizumab as compared with 6.2 months in the group given IFL and a placebo; HR for disease progression = 0.54; P < .001) and OS (20.3 months in the group given IFL and bevacizumab as compared with 15.6 months in the group given IFL and a placebo corresponding to an HR for death = 0.66; P < .001).[55] Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who progressed on 5-FU-leucovorin and irinotecan to either FOLFOX or FOLFOX and bevacizumab. Preliminary data demonstrated that patients randomly assigned to FOLFOX and bevacizumab experienced a statistically significant improvement in PFS (7.4 vs. 5.5 months; P = .003) and OS (12.5 vs. 10.7 months; P = .002).[56][Level of evidence: 1iiA] Based on these two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[57-60] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU-leucovorin to either infusional 5-FU, oxaliplatin, or FOLFOX4. Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P < .001).[61][Level of evidence: 1iiDiii]

Erbitux is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of either erbitux or irinotecan and erbitux. The median TTP for patients receiving erbitux was 1.5 months, and the median TTP for patients receiving irinotecan and erbitux was 4.2 months.[62][Level of evidence: 3iiiDiv] On the basis of this study, erbitux was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial that has not yet been published, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced an improved OS. Despite the preliminary nature of this study, the FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[63]

References

1. Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Dis Colon Rectum 39 (10 Suppl): S24-8, 1996.  [PUBMED Abstract]
   
   
2. Franklin ME Jr, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma. Five-year results. Dis Colon Rectum 39 (10 Suppl): S35-46, 1996.  [PUBMED Abstract]
   
   
3. Fleshman JW, Nelson H, Peters WR, et al.: Early results of laparoscopic surgery for colorectal cancer. Retrospective analysis of 372 patients treated by Clinical Outcomes of Surgical Therapy (COST) Study Group. Dis Colon Rectum 39 (10 Suppl): S53-8, 1996.  [PUBMED Abstract]
   
   
4. Schwenk W, Böhm B, Müller JM: Postoperative pain and fatigue after laparoscopic or conventional colorectal resections. A prospective randomized trial. Surg Endosc 12 (9): 1131-6, 1998.  [PUBMED Abstract]
   
   
5. Clinical Outcomes of Surgical Therapy Study Group.: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350 (20): 2050-9, 2004.  [PUBMED Abstract]
   
   
6. Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.  [PUBMED Abstract]
   
   
7. Lacy AM, García-Valdecasas JC, Delgado S, et al.: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 359 (9325): 2224-9, 2002.  [PUBMED Abstract]
   
   
8. Esser S, Reilly WT, Riley LB, et al.: The role of sentinel lymph node mapping in staging of colon and rectal cancer. Dis Colon Rectum 44 (6): 850-4; discussion 854-6, 2001.  [PUBMED Abstract]
   
   
9. Bilchik AJ, Nora DT, Sobin LH, et al.: Effect of lymphatic mapping on the new tumor-node-metastasis classification for colorectal cancer. J Clin Oncol 21 (4): 668-72, 2003.  [PUBMED Abstract]
   
   
10. Panettiere FJ, Goodman PJ, Costanzi JJ, et al.: Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol 6 (6): 947-54, 1988.  [PUBMED Abstract]
    
    
11. Adjuvant therapy of colon cancer--results of a prospectively randomized trial. Gastrointestinal Tumor Study Group. N Engl J Med 310 (12): 737-43, 1984.  [PUBMED Abstract]
    
    
12. Higgins GA Jr, Amadeo JH, McElhinney J, et al.: Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report. Cancer 53 (1): 1-8, 1984.  [PUBMED Abstract]
    
    
13. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer. Why we still don't know. JAMA 259 (24): 3571-8, 1988.  [PUBMED Abstract]
    
    
14. Laurie JA, Moertel CG, Fleming TR, et al.: 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 Oncol 7 (10): 1447-56, 1989.  [PUBMED Abstract]
    
    
15. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.  [PUBMED Abstract]
    
    
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 11 (10): 1879-87, 1993.  [PUBMED Abstract]
    
    
17. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 345 (8955): 939-44, 1995.  [PUBMED Abstract]
    
    
18. O'Connell M, Mailliard J, Macdonald J, et al.: An intergroup trial of intensive course 5FU and low dose leucovorin as surgical adjuvant therapy for high risk colon cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-552, 190, 1993. 
    
    
19. 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 23 (34): 8671-8, 2005.  [PUBMED Abstract]
    
    
20. Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90 (23): 1810-6, 1998.  [PUBMED Abstract]
    
    
21. 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 17 (11): 3553-9, 1999.  [PUBMED Abstract]
    
    
22. Okuno SH, Woodhouse CL, Loprinzi CL, et al.: Phase III placebo-controlled clinical trial evaluation of glutamine for decreasing mucositis in patients receiving 5FU (fluorouracil)-base chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-256, 1998. 
    
    
23. 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 21 (15): 2896-903, 2003.  [PUBMED Abstract]
    
    
24. Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 355 (9215): 1588-96, 2000.  [PUBMED Abstract]
    
    
25. Sargent DJ, Goldberg RM, Jacobson SD, et al.: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345 (15): 1091-7, 2001.  [PUBMED Abstract]
    
    
26. Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.  [PUBMED Abstract]
    
    
27. Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.  [PUBMED Abstract]
    
    
28. Twelves C, Wong A, Nowacki MP, et al.: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352 (26): 2696-704, 2005.  [PUBMED Abstract]
    
    
29. André T, Boni C, Mounedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350 (23): 2343-51, 2004.  [PUBMED Abstract]
    
    
30. De Gramont A, Banzi M, Navarro M, et al.: Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1015, 2003. 
    
    
31. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17 (5): 1356-63, 1999.  [PUBMED Abstract]
    
    
32. 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 22 (10): 1797-806, 2004.  [PUBMED Abstract]
    
    
33. Mamounas E, Wieand S, Wolmark N, et al.: 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 Oncol 17 (5): 1349-55, 1999.  [PUBMED Abstract]
    
    
34. Figueredo A, Charette ML, Maroun J, et al.: 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 Oncol 22 (16): 3395-407, 2004.  [PUBMED Abstract]
    
    
35. Benson AB 3rd, Schrag D, Somerfield MR, et al.: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22 (16): 3408-19, 2004.  [PUBMED Abstract]
    
    
36. Willett C, Tepper JE, Cohen A, et al.: Local failure following curative resection of colonic adenocarcinoma. Int J Radiat Oncol Biol Phys 10 (5): 645-51, 1984.  [PUBMED Abstract]
    
    
37. Willett C, Tepper JE, Cohen A, et al.: Obstructive and perforative colonic carcinoma: patterns of failure. J Clin Oncol 3 (3): 379-84, 1985.  [PUBMED Abstract]
    
    
38. 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 11 (4): 731-41, 1985.  [PUBMED Abstract]
    
    
39. Willett CG, Fung CY, Kaufman DS, et al.: Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 11 (6): 1112-7, 1993.  [PUBMED Abstract]
    
    
40. 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 5 (4): 242-7, 1999 Jul-Aug.  [PUBMED Abstract]
    
    
41. Schild SE, Gunderson LL, Haddock MG, et al.: The treatment of locally advanced colon cancer. Int J Radiat Oncol Biol Phys 37 (1): 51-8, 1997.  [PUBMED Abstract]
    
    
42. 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 22 (16): 3277-83, 2004.  [PUBMED Abstract]
    
    
43. Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23 (9): 2038-48, 2005.  [PUBMED Abstract]
    
    
44. Petrelli N, Herrera L, Rustum Y, et al.: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5 (10): 1559-65, 1987.  [PUBMED Abstract]
    
    
45. Petrelli N, Douglass HO Jr, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 7 (10): 1419-26, 1989.  [PUBMED Abstract]
    
    
46. Scheithauer W, Rosen H, Kornek GV, et al.: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306 (6880): 752-5, 1993.  [PUBMED Abstract]
    
    
47. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 10 (6): 904-11, 1992.  [PUBMED Abstract]
    
    
48. Buyse M, Thirion P, Carlson RW, et al.: Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356 (9227): 373-8, 2000.  [PUBMED Abstract]
    
    
49. Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13 (6): 1303-11, 1995.  [PUBMED Abstract]
    
    
50. Saltz LB, Cox JV, Blanke C, et al.: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343 (13): 905-14, 2000.  [PUBMED Abstract]
    
    
51. de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18 (16): 2938-47, 2000.  [PUBMED Abstract]
    
    
52. Douillard JY, Cunningham D, Roth AD, et al.: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355 (9209): 1041-7, 2000.  [PUBMED Abstract]
    
    
53. Tournigand C, André T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22 (2): 229-37, 2004.  [PUBMED Abstract]
    
    
54. Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.  [PUBMED Abstract]
    
    
55. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.  [PUBMED Abstract]
    
    
56. Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005. 
    
    
57. Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.  [PUBMED Abstract]
    
    
58. Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14 (3): 709-15, 1996.  [PUBMED Abstract]
    
    
59. Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352 (9138): 1407-12, 1998.  [PUBMED Abstract]
    
    
60. Cunningham D, Pyrhönen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352 (9138): 1413-8, 1998.  [PUBMED Abstract]
    
    
61. Rothenberg ML, Oza AM, Bigelow RH, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21 (11): 2059-69, 2003.  [PUBMED Abstract]
    
    
62. Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 (4): 337-45, 2004.  [PUBMED Abstract]
    
    
63. Van Cutsem E, Peeters M, Siena S, et al.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 (13): 1658-64, 2007.  [PUBMED Abstract]
    
    

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