Purpose of This PDQ Summary
General Information

Prognostic Factors Risk Factors Follow-up

Cellular Classification
Stage Information

TNM Definitions AJCC Stage Groupings

Treatment Option Overview

Primary Surgical Therapy Adjuvant Chemotherapy Adjuvant Radiation Therapy

Stage 0 Colon Cancer

Current Clinical Trials

Stage I Colon Cancer

Current Clinical Trials

Stage II Colon Cancer

Adjuvant Chemotherapy Current Clinical Trials

Stage III Colon Cancer

Adjuvant Chemotherapy         Chemotherapy regimens prior to 2000         Chemotherapy regimens after 2000 Current Clinical Trials

Stage IV and Recurrent Colon Cancer

Liver Metastasis Treatment of Patients With Stage IV Disease First-line Multiagent Chemotherapy The Addition of Bevacizumab to Multiagent Chemotherapy Second-line and Third-line Chemotherapy Current Clinical Trials

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Changes to This Summary (12/12/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of colon cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: Separate PDQ summaries on Colorectal Cancer Screening ⁵; Colorectal Cancer Prevention ⁶; and Genetics of Colorectal Cancer ⁷ are also available. Information about colon cancer in children is available in the PDQ summary on Unusual Cancers of Childhood Treatment ⁸.

Note: Estimated new cases and deaths from colon cancer in the United States in 2008:[1]

• New cases: 108,070.
• Deaths (colon and rectal cancers combined): 49,960.

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 ² for more information.)

Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of the patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.

The prognosis of patients with colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis.[2] Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance.[3] The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.[4-6] This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.[7-10]

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.[11-20] Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival independent of tumor stage in a population-based series of 607 patients younger than 50 years with colorectal cancer.[21] Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease rather than the age of the patient.[22-24] Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.[25]

Because of the frequency of the disease, ability to identify high-risk groups, demonstrated slow growth of primary lesions, better survival of patients with early-stage lesions, and relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults aged 50 years or older, especially for those with first-degree relatives with colorectal cancer. Groups that have a high incidence of colorectal cancer include those with hereditary conditions, such as familial polyposis, HNPCC or Lynch syndrome variants I and II, and those with a personal history of ulcerative colitis or Crohn colitis.[26,27] Together, they account for 10% to 15% of colorectal cancers. Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret.[28][Level of evidence: 3iiiA] More common conditions with an increased risk include a personal history of colorectal cancer or adenomas; first-degree family history of colorectal cancer or adenomas; and a personal history of ovarian, endometrial, or breast cancer.[29,30] These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.[31] (Refer to the PDQ summaries on Colorectal Cancer Screening ⁵ and Colorectal Cancer Prevention ⁶ for more information.)

Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.[32-35] The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented the efficacy of a standard, postoperative monitoring program.[36-40] CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:[41]

• A CEA level is not a valuable screening test for colorectal cancer because of the large numbers of false-positive and false-negative reports.
• Postoperative CEA testing should be restricted to patients who would be candidates for resection of liver or lung metastases.
• Routine use of CEA levels alone for monitoring response to treatment should not be recommended.

The optimal regimen and frequency of follow-up examinations are not well defined because the impact on patient survival is not clear, and the quality of data is poor.[38-40] New surveillance methods, including CEA immunoscintigraphy [42] and positron emission tomography,[43] are under clinical evaluation.

Gastrointestinal stromal tumors can occur in the colon. (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment ⁹ for more information.)

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ¹⁰ Last accessed October 1, 2008. 
   
   
2. Steinberg SM, Barkin JS, Kaplan RS, et al.: Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience. Cancer 57 (9): 1866-70, 1986.  [PUBMED Abstract]
   
   
3. Filella X, Molina R, Grau JJ, et al.: Prognostic value of CA 19.9 levels in colorectal cancer. Ann Surg 216 (1): 55-9, 1992.  [PUBMED Abstract]
   
   
4. Colon and rectum. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 113-124. 
   
   
5. Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.  [PUBMED Abstract]
   
   
6. Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.  [PUBMED Abstract]
   
   
7. Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.  [PUBMED Abstract]
   
   
8. Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.  [PUBMED Abstract]
   
   
9. Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.  [PUBMED Abstract]
   
   
10. Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.  [PUBMED Abstract]
    
    
11. McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999.  [PUBMED Abstract]
    
    
12. Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.  [PUBMED Abstract]
    
    
13. Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.  [PUBMED Abstract]
    
    
14. Griffin MR, Bergstralh EJ, Coffey RJ, et al.: Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60 (9): 2318-24, 1987.  [PUBMED Abstract]
    
    
15. Johnston PG, Fisher ER, Rockette HE, et al.: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12 (12): 2640-7, 1994.  [PUBMED Abstract]
    
    
16. Shibata D, Reale MA, Lavin P, et al.: The DCC protein and prognosis in colorectal cancer. N Engl J Med 335 (23): 1727-32, 1996.  [PUBMED Abstract]
    
    
17. Bauer KD, Lincoln ST, Vera-Roman JM, et al.: Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinomas. Lab Invest 57 (3): 329-35, 1987.  [PUBMED Abstract]
    
    
18. Bauer KD, Bagwell CB, Giaretti W, et al.: Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry 14 (5): 486-91, 1993.  [PUBMED Abstract]
    
    
19. Sun XF, Carstensen JM, Zhang H, et al.: Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet 340 (8832): 1369-73, 1992.  [PUBMED Abstract]
    
    
20. Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999.  [PUBMED Abstract]
    
    
21. Gryfe R, Kim H, Hsieh ET, et al.: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342 (2): 69-77, 2000.  [PUBMED Abstract]
    
    
22. Iwashyna TJ, Lamont EB: Effectiveness of adjuvant fluorouracil in clinical practice: a population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 20 (19): 3992-8, 2002.  [PUBMED Abstract]
    
    
23. Chiara S, Nobile MT, Vincenti M, et al.: Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol 42 (4): 336-40, 1998.  [PUBMED Abstract]
    
    
24. Popescu RA, Norman A, Ross PJ, et al.: Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 17 (8): 2412-8, 1999.  [PUBMED Abstract]
    
    
25. Dignam JJ, Colangelo L, Tian W, et al.: Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst 91 (22): 1933-40, 1999.  [PUBMED Abstract]
    
    
26. Thorson AG, Knezetic JA, Lynch HT: A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). Dis Colon Rectum 42 (1): 1-9, 1999.  [PUBMED Abstract]
    
    
27. Smith RA, von Eschenbach AC, Wender R, et al.: American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection. CA Cancer J Clin 51 (1): 38-75; quiz 77-80, 2001 Jan-Feb.  [PUBMED Abstract]
    
    
28. Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83 (2): 259-66, 1998.  [PUBMED Abstract]
    
    
29. Ransohoff DF, Lang CA: Screening for colorectal cancer. N Engl J Med 325 (1): 37-41, 1991.  [PUBMED Abstract]
    
    
30. Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994.  [PUBMED Abstract]
    
    
31. Winawer SJ: Screening for colorectal cancer. Cancer: Principles and Practice of Oncology Updates 2(1): 1-16, 1987. 
    
    
32. Martin EW Jr, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Ann Surg 202 (3): 310-7, 1985.  [PUBMED Abstract]
    
    
33. Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer. A meta-analysis. Ann Surg 219 (2): 174-82, 1994.  [PUBMED Abstract]
    
    
34. Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Ann Surg 220 (2): 206-11, 1994.  [PUBMED Abstract]
    
    
35. Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996.  [PUBMED Abstract]
    
    
36. Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Dis Colon Rectum 36 (7): 636-43; discussion 643-4, 1993.  [PUBMED Abstract]
    
    
37. Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270 (8): 943-7, 1993.  [PUBMED Abstract]
    
    
38. Rosen M, Chan L, Beart RW Jr, et al.: Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 41 (9): 1116-26, 1998.  [PUBMED Abstract]
    
    
39. Desch CE, Benson AB 3rd, Smith TJ, et al.: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17 (4): 1312, 1999.  [PUBMED Abstract]
    
    
40. Benson AB 3rd, Desch CE, Flynn PJ, et al.: 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 18 (20): 3586-8, 2000.  [PUBMED Abstract]
    
    
41. Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14 (10): 2843-77, 1996.  [PUBMED Abstract]
    
    
42. Lechner P, Lind P, Goldenberg DM: Can postoperative surveillance with serial CEA immunoscintigraphy detect resectable rectal cancer recurrence and potentially improve tumor-free survival? J Am Coll Surg 191 (5): 511-8, 2000.  [PUBMED Abstract]
    
    
43. Lonneux M, Reffad AM, Detry R, et al.: FDG-PET improves the staging and selection of patients with recurrent colorectal cancer. Eur J Nucl Med Mol Imaging 29 (7): 915-21, 2002.  [PUBMED Abstract]
    
    

Cellular Classification

Histologic types of colon cancer include the following:

• Adenocarcinoma (most colon cancers).
  • Mucinous (colloid) adenocarcinoma.
  • Signet ring adenocarcinoma.
• Scirrhous tumors.
• Neuroendocrine.[1] Tumors with neuroendocrine differentiation typically have a poorer prognosis than pure adenocarcinoma variants.

References

1. Saclarides TJ, Szeluga D, Staren ED: Neuroendocrine cancers of the colon and rectum. Results of a ten-year experience. Dis Colon Rectum 37 (7): 635-42, 1994.  [PUBMED Abstract]
   
   

Stage Information

Treatment decisions should be made with reference to the TNM classification [1] rather than to the older Dukes or the Modified Astler-Coller classification schema.

The American Joint Committee on Cancer (AJCC) and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.[1-3] This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.[4-7]

The AJCC has designated staging by TNM classification.[1]

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ: intraepithelial or invasion of the lamina propria*
• T1: Tumor invades submucosa
• T2: Tumor invades muscularis propria
• T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissues
• T4: Tumor directly invades other organs or structures and/or perforates visceral peritoneum**^,***

* [Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.]

** [Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.]

*** [Note: Tumor that is adherent macroscopically to other organs or structures is classified T4. If no tumor is present in the adhesion microscopically, however, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion.]

Regional lymph nodes (N)

• NX: Regional nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in one to three regional lymph nodes
• N2: Metastasis in four or more regional lymph nodes

 [Note: A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that is represents venous invasion.]

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Stage 0

• Tis, N0, M0

Stage I

• T1, N0, M0
• T2, N0, M0

Stage IIA

• T3, N0, M0

Stage IIB

• T4, N0, M0

Stage IIIA

• T1, N1, M0
• T2, N1, M0

Stage IIIB

• T3, N1, M0
• T4, N1, M0

Stage IIIC

• Any T, N2, M0

Stage IV

• Any T, any N, M1

References

1. Colon and rectum. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 113-124. 
   
   
2. Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.  [PUBMED Abstract]
   
   
3. Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.  [PUBMED Abstract]
   
   
4. Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.  [PUBMED Abstract]
   
   
5. Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.  [PUBMED Abstract]
   
   
6. Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.  [PUBMED Abstract]
   
   
7. Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.  [PUBMED Abstract]
   
   

Treatment Option Overview

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 ² for more information.)

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 ¹¹) 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.

The potential value of adjuvant chemotherapy 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 fluorouracil (5-FU)–based therapy compared with observation.[10-12] (Refer to the section on Stage II Colon Cancer ¹² for more information.)

Prior to 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Since 2000, capecitabine has been established as an equivalent alternative to 5-FU and leucovorin. The addition of oxaliplatin to 5-FU and leucovorin has been shown to improve OS compared with 5-FU and leucovorin alone. (Refer to the sections on Stage III Colon Cancer ¹³ and Stage IV and Recurrent Colon Cancer ¹⁴ for more information.)

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).[13-18] 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).[19] 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.

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. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    

Stage 0 Colon Cancer

Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.

Treatment options:

1. Local excision or simple polypectomy with clear margins.
2. Colon resection for larger lesions not amenable to local excision.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage 0 colon cancer ¹⁵. 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 ¹⁶.

Stage I Colon Cancer

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 ² for more information.)

Because of its localized nature, stage I colon cancer has a high cure rate.

Treatment options:

• Wide surgical resection and anastomosis. The role of laparoscopic techniques [1-4] in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial (NCCTG-934653 ¹¹) comparing laparoscopic-assisted colectomy (LAC) with open colectomy. The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[5][Level of evidence: 1iiC]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I colon cancer ¹⁷. 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 ¹⁶.

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. 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]
   
   

Stage II Colon Cancer

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 ² for more information.)

Treatment options:

1. Wide surgical resection and anastomosis. The role of laparoscopic techniques [1-4] in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial (NCCTG-934653 ¹¹) comparing laparoscopic-assisted colectomy (LAC) to open colectomy. The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[4][Level of evidence: 1iiC]



2. Following surgery, patients should be considered for entry into carefully controlled clinical trials such as the GRECCR-03 ¹⁸ and NCRI-QUASAR1) ¹⁹ trials, for example, which are evaluating the use of systemic or regional chemotherapy or biologic therapy. Adjuvant therapy is not indicated for most patients unless they are entered into a clinical trial.

The potential value of adjuvant chemotherapy for patients with stage II colon cancer remains controversial. Although subgroups of patients with stage II colon cancer may be at higher-than-average risk for recurrence (including those with anatomic features such as tumor adherence to adjacent structures, perforation, complete obstruction, or with biologic characteristics such as aneuploidy, high S-phase analysis, or deletion of 18q),[5-7] evidence is inconsistent that adjuvant 5-fluorouracil (5-FU)–based chemotherapy is associated with an improved overall survival (OS) compared to surgery alone.[8] Investigators from the National Surgical Adjuvant Breast and Bowel Project have indicated that the reduction in risk of recurrence by adjuvant therapy in patients with stage II disease is of similar magnitude to the benefit seen in patients with stage III disease treated with adjuvant therapy, though an OS advantage has not been established.[9]

A meta-analysis of 1,000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease-free survival (DFS) at 5 years when adjuvant therapy-treated patients treated with 5-FU-leucovorin are compared with untreated controls.[10][Level of evidence: 1iiDii];[11] Patients with stage II colon cancer remain candidates for clinical trials such as the CLB-9581 ²⁰, NSABP-C-06 ²¹, and SWOG-9415 ²² trials, for example, in which either surgery alone or 5-FU-leucovorin represent standard therapy.

Recently the Cancer Care Ontario Practice Guideline Initiative 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).[12] 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.”[13]

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.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II colon cancer ²³. 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 ¹⁶.

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. 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]
   
   
5. Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.  [PUBMED Abstract]
   
   
6. Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.  [PUBMED Abstract]
   
   
7. Merkel S, Wein A, Günther K, et al.: High-risk groups of patients with Stage II colon carcinoma. Cancer 92 (6): 1435-43, 2001.  [PUBMED Abstract]
   
   
8. Moertel CG, Fleming TR, Macdonald JS, et al.: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol 13 (12): 2936-43, 1995.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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]
    
    
11. Harrington DP: The tea leaves of small trials. J Clin Oncol 17 (5): 1336-8, 1999.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    

Stage III Colon Cancer

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 ² for more information.)

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.

Treatment options:

1. Wide surgical resection and anastomosis.

   The role of laparoscopic techniques [1-4] in the treatment of colon cancer is under evaluation in a multicenter prospective randomized trial (NCCTG-934653 ¹¹) comparing laparoscopic-assisted colectomy (LAC) with open colectomy. The quality-of-life component of this trial has been published and reported minimal short-term quality-of-life benefits with LAC.[5][Level of evidence: 1iiC]

   For patients who are not candidates for clinical trials, postoperative chemotherapy with fluorouracil (5-FU)-leucovorin for 6 months is an option. Based on preliminary results from the MOSAIC trial, adjuvant FOLFOX4 (oxaliplatin, leucovorin, and 5-FU) demonstrated prolonged 3-year survival but has not yet demonstrated an overall survival (OS) advantage.[6]




2. Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens that are now also including oxaliplatin-based and irinotecan-based chemotherapy with new targeted agents or biological therapy, alone or in combination .[7]

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.[8-11] 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.[12][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.[13][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%).[14-16]

Intergroup trial 0089 randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of four treatment arms:[17]

• 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.[17][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 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.[17]



• Treatment that includes 6–8 months of 5-FU-leucovorin is equivalent to 12 months.[18-20]



• Treatment that includes 24 weeks of adjuvant 5-FU-leucovorin is equivalent to 36 weeks of therapy.[21]



• High-dose leucovorin is equivalent to low-dose leucovorin.[22]



• 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.[23]



• An infusional deGramont LV5FU2 schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU-leucovorin.[21]

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.[24,25] A multicenter European study compared capecitabine (1250 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.[26] The study demonstrated that disease-free survival (DFS) at 3 years is equivalent for patients receiving capecitabine or 5-FU-leucovorin (HR = 0.87; P < .001).[26][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 administered for 6 months.[27] 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.[6][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. These data suggest that FOLFOX4 is a therapeutic option for patients with resected stage III colon cancer.[6]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III colon cancer ²⁴. 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 ¹⁶.

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. 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]
   
   
6. 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. 
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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. 
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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. 
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    

Stage IV and Recurrent Colon Cancer

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 ² for more information.)

Stage IV colon cancer denotes distant metastatic disease. Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information that may affect management.[1] Such approaches have not led to improvements in long-term outcome measures such as survival.

Treatment options:

1. Surgical resection of locally recurrent cancer.
2. Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.
3. Resection of liver metastases in selected metastatic patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients.[2-11]
4. Resection of isolated pulmonary or ovarian metastases in selected patients.[12]
5. Palliative radiation therapy.
6. Palliative chemotherapy.
7. Clinical trials evaluating new drugs and biological therapy.
8. Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide for a number of treatment options.

For patients with hepatic metastasis considered to be resectable (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 resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[5,7,13-16] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.[17] Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.[18-24] Radiofrequency ablation and cryosurgical ablation [25-27] remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[28,29] Patients with limited pulmonary metastases, and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly-selected patients.[12,30,31]

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine plus systemic fluorouracil (5-FU) plus leucovorin was shown to result in improved 2-year disease-free survival and overall survival (OS) (86% vs. 72%, P = .03), but did not show a significant statistical difference in median survival, compared with systemic 5-FU therapy alone.[32][Level of evidence: 1iiA] A second trial preoperatively randomized 109 patients who had one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.[33] Of those randomized, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival. While liver recurrence was decreased, median or 4-year survival was not significantly different. Further studies are required to evaluate this treatment approach and to determine if more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.[2,34-38] Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation.[39] Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Drug combinations described in this section:

• The Arbeitsgemeinschaft Internische Onkologie (AIO) or German AIO regimen (folic acid, 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 four times a year (52 weeks).
  
  
  



• The CAPOX regimen:
  • Capecitabine (1000mg/m²) twice a day on days 1 through 14 plus oxaliplatin (70mg/m²) on days 1 and 8 every 3 weeks.



• The Douillard regimen (folic acid, 5-FU, and irinotecan):
  • Irinotecan (180 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 day 1 and day 2 every 2 weeks.



• 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) administered via ambulatory pump for a period of 22 hours on day 1 and day 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 on day 1, then 5-FU (2,400–3,000 mg/m²) administered via ambulatory pump 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) administered via ambulatory pump for a period of 46 hours every 2 weeks.



• The FUFOX regimen:
  • Oxaliplatin (50mg/m²) plus leucovorin (500mg/m²) plus 5-FU (2000mg/m²) as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.



• The FUOX regimen:
  • Continuous infusion 5-FU (2250mg/m²) during 48 hours on days 1, 8, 15, 22, 29 and 36 plus oxaliplatin (85mg/m²) on days 1, 15, and 29 every 6 weeks.



• 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 XELOX regimen:
  • Oral capecitabine (1000mg/m²) twice a day for 14 days plus oxaliplatin (130mg/m²) on day 1 every 3 weeks.

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 such as the NCCTG-934653 ¹¹ trial, for example.[40-44][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.[17]

Currently, there are seven active and approved 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 in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[45,46] as well as improved survival and quality of life for patients receiving chemotherapy, compared with the best supportive care.[47-49] 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.[50] 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.[51,52][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.[53-55] 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% confidence interval [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 randomized 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.[56,57][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.

The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) ²⁵ trial evaluated several different irinotecan-based regimens in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI).[58] The study randomly assigned 430 patients and was closed early due to poor accrual. The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6m vs. 5.9m, P = .004) or CAPIRI (7.6m vs. 5.8m, P = .015). Patients who received CAPIRI had the highest grade 3 or higher rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome. After bevacizumab was approved, the BICC-C trial was amended, and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab. Although the primary endpoint, PFS, was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (not yet reached with a median follow-up of 22.6 m vs. 19.2 m, P = .007). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[58][Level of evidence: 1iiDiii] (Refer to the PDQ summary on Nausea and Vomiting ²⁶, and for information on diarrhea and dehydration refer to the Gastrointestinal Complications ²⁷ summary.)

Randomized phase III trials have addressed the equivalence of oral FUOX substituting for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[59,60] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1m for the CAPOX arm and 8.0m for the FUFOX arm (HR = 1.17; 95% CI, 0.96–1.43, P = .117), and the HR was in the prespecified equivalence range. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[59] The TTP was 8.9m versus 9.5m (P = .153) and met the prespecified range for noninferiority.[59][Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab.[61] 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 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 placebo corresponding to an HR for death = 0.66; P < .001).[61] Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had 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).[62][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 to either infusional 5-FU or supportive care.[63-66] Similarly, a phase III trial randomly assigned patients who progressed on irintocan 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).[67][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.[68][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. [69]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV colon cancer ²⁸ and recurrent colon cancer ²⁹. 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 ¹⁶.

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with cause-specific mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with carefully assessed quality of life as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.