Stage III Colon Cancer Treatment
Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis; patients with one to three involved nodes have a significantly better survival than those with four or more involved nodes.
Standard Treatment Options for Stage III Colon Cancer
Standard treatment options for stage III colon cancer include the following:
Surgery for stage III colon cancer is wide surgical resection and anastomosis.
Evidence (laparoscopic techniques):
The role of laparoscopic techniques [1-4] in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653, now closed) comparing laparoscopic-assisted colectomy (LAC) with open colectomy.
- Three-year recurrence rates and 3-year overall survival (OS) rates were similar in the two groups. (Refer to the Primary Surgical Therapy section in the Treatment Option Overview section of this summary for more information.)
- The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[Level of evidence: 1iiC]
Drug combinations described in this section include the following:
- The FOLFOX4 regimen (oxaliplatin, leucovorin, and fluorouracil [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) intravenous bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on day 1 and day 2 every 2 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 North Central Cancer Treatment Group (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 National Surgical Adjuvant Breast and Bowel Project (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.
Chemotherapy regimens prior to 2000
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.[6-9] These trials employed 5-FU alone or 5-FU-semustine (methyl-CCNU).
Evidence (5-FU alone and 5-FU-semustine):
- The NCCTG conducted a randomized trial comparing surgical resection alone with postoperative levamisole or 5-FU-levamisole.[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.[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.
- The completed Intergroup trial 0089 (INT-0089) randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of the following four treatment arms:
- 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 OS 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.[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 with 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 INT-0089, multiple studies have refined the use of 5-FU-leucovorin in the adjuvant setting and can be summarized as follows:
- Levamisole is unnecessary when using leucovorin.
- Treatment that includes 6 to 8 months of 5-FU-leucovorin is equivalent to 12 months of therapy.[16-18]
- Treatment that includes 24 weeks of adjuvant 5-FU-leucovorin is equivalent to 36 weeks of therapy.
- High-dose leucovorin is equivalent to low-dose leucovorin.
- A meta-analysis of seven trials revealed no significant difference in efficacy or toxicity among patients 70 years or younger compared with patients older than 70 years.
- An infusional deGramont LV5FU2 schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU-leucovorin.
Chemotherapy regimens after 2000
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.[22,23]
For patients with stage III colon cancer, capecitabine provides equivalent outcome to intravenous 5-FU and leucovorin.
- A multicenter European study compared capecitabine (1,250 mg/m2) administered twice daily for days 1 to 14, then given every 21 days for eight cycles against the Mayo Clinic schedule of 5-FU and low-dose leucovorin for patients with stage III colon cancer.
- The study demonstrated that DFS at 3 years is equivalent for patients receiving capecitabine or 5-FU-leucovorin (hazard ratio [HR], 0.87; P < .001).[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 completed Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC [NCT00275210]) study, the toxic effects and efficacy of FOLFOX4 were compared with the same 5-FU-leucovorin regimen without oxaliplatin administered for 6 months. Based on results from the MOSAIC trial, adjuvant FOLFOX4 demonstrated prolonged OS for patients with stage III colon cancer compared with patients receiving 5-FU-leucovorin without oxaliplatin.
- 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 initially reported, there was no difference in OS.[Level of evidence: 1iiDii]
- Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS = 78.5% vs. 76.0%; HR, 0.84; 95% confidence interval [CI], 0.71–1.00). On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX4 and 68.7% in the patients receiving 5-FU-leucovorin (HR, 0.80; 95% CI, 0.65–0.97, P = .023).[Level of evidence: 1iiA]
- 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).
FOLFOX has become the reference standard for the next generation of clinical trials for patients with stage III colon cancer.
Treatment Options Under Clinical Evaluation
Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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.
- 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]
- 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]
- 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]
- 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.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- André T, Boni C, Navarro M, et al.: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27 (19): 3109-16, 2009. [PUBMED Abstract]
- Rougier P, Nordlinger B: Large scale trial for adjuvant treatment in high risk resected colorectal cancers. Rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Ann Oncol 4 (Suppl 2): 21-8, 1993. [PUBMED Abstract]