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Volume 6 Issue 44 Published - 14:00 UTC 08:00 EST 13-Feb-2004 Next Update - 14:00 UTC 08:00 EST 14-Feb-2004 Editor: Susan K. Boyer, RN
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Information for practitioners: Treatment of colon cancer

Table of Contents
General Information
Adjuvant therapy
Advanced disease
Cellular Classification
Stage Information
TNM definitions
Stage 0
Stage I
Stage II
Stage III
Stage IV
Treatment Option Overview
Stage 0 Colon Cancer
Stage I Colon Cancer
Stage I (old staging: Dukes' A or Modified Astler-Coller A and B1)
Stage II Colon Cancer
Stage II (old staging: Dukes' B or Modified Astler-Coller B2 and B3)
Stage III Colon Cancer
Stage III (old staging: Dukes' C or Modified Astler-Coller C1-C3)
Stage IV Colon Cancer
Recurrent Colon Cancer
General Information

Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. It is the second most frequently diagnosed malignancy in the United States as well as the second most common cause of cancer death. Surgery is the primary form of treatment and results in cure in approximately 50% of patients. Recurrence following surgery is a major problem and often is the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis.1 Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance.2 Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with colon cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.3-5 Microsatellite instability, not only in association with hereditary nonpolyposis colon cancer, has also been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer.6 The role of prognostic and predictive markers such as tumor stage, 18q deletion, or microsatellite instability in predicting prognosis or selecting treatment for patients should be determined in prospective trials. Age greater than 65 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population.7-9

Because of the frequency of the disease, the identification of high-risk groups, the demonstrated slow growth of primary lesions, the better survival of patients with early-stage lesions, and the relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults starting at age 50 years, especially for those with first-degree relatives with colorectal cancer. There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, and ulcerative colitis.10 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.11[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.12,13 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.14 For more information on this subject, consult the PDQ summaries on screening for colorectal cancer and prevention of colorectal cancer.

Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.15 The impact of such monitoring on overall mortality of patients with recurrent colon cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program.16,17 Postoperative monitoring may detect asymptomatic recurrences that can be resected or metachronous tumors.18-20 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: that CEA is not a valuable screening test for colorectal cancer due to the large numbers of false-positive and false-negative reports; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended.21 However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor.22,23

Adjuvant therapy

The current generation of large prospective randomized trials has demonstrated consistent evidence of benefit for systemic adjuvant chemotherapy employing fluorouracil (5-FU) plus either levamisole or leucovorin. In 1990, a large intergroup trial of 5-FU/levamisole reported prolonged disease-free and overall survival in patients with stage III colon cancer, compared to patients who received no treatment after surgery.24 This benefit has persisted with continued follow-up.25

The National Surgical Adjuvant Breast and Bowel Project (NSABP) then reported a trial for stage II and III patients comparing the fluorouracil/semustine/ vincristine regimen to a weekly regimen of 5-FU plus high-dose leucovorin. This demonstrated a statistically significant benefit for 5-FU/leucovorin in both overall and disease-free survival.26 Adjuvant 5-FU plus leucovorin (in different treatment schedules) was also compared to surgery alone in 4 large randomized trials that closed prematurely in the early 1990s when surgery alone control arms were no longer felt to represent standard care for stage III patients. Three of these trials, conducted in Canada, France, and Italy, have had their primary data pooled and analyzed together. The 3-year recurrence- free and overall survival rates were also statistically significantly improved in this analysis.27,28 Taken together, about 4,000 patients have participated in the positive randomized trials comparing adjuvant chemotherapy to surgery alone with a reduction in mortality of between 22% and 33%. These results are quite clear in stage III patients but uncertain in stage II patients. Adjuvant treatment of stage III colon cancer appears to be cost- effective when costs of treatment and quality-of-life measures are taken into account.29

At this time, patients with stage III (Dukes' C) colon cancer should be considered for adjuvant therapy with 5-FU/leucovorin for 6 to 8 months.30 Regional adjuvant therapy directed at reducing liver metastasis has been tested using both portal-vein infusion 5-FU and hepatic radiation, and an early trial by Taylor showed promising results.31 The preliminary results of confirmatory trials from the NSABP, the Mayo Clinic, and the United Kingdom Large Bowel Cancer Project, however, have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences.32-34 The NSABP trial, but not the Mayo Clinic trial, showed a modest benefit in survival but no change in the incidence of liver metastases. Neither prolongation of survival nor reduction of liver recurrences was seen in a Gastrointestinal Tumor Study Group study of adjuvant hepatic radiation with 5-FU.35

Advanced disease

For locally advanced disease, the role of radiation therapy with chemotherapy in colon cancer is under clinical evaluation. Palliation may be achieved in approximately 10% to 20% of patients with 5-FU. Several studies suggest an advantage when leucovorin is added to 5-FU in terms of response rate and palliation of symptoms, but not always in terms of survival.36-42 Irinotecan (CPT-11) has been approved by the Food and Drug Administration for the treatment of patients whose tumors are refractory to 5-FU.43-46 Participation in clinical trials is appropriate. A number of other drugs are undergoing early evaluation for the treatment of colon cancer.47 Oxaliplatin plus 5-FU and leucovorin has also shown activity in 5-FU refractory patients.48,49

Some retrospective studies suggest that perioperative blood transfusions impair prognosis of patients with colorectal cancer.50,51 A small, single-institution, prospective randomized trial found the need for allogeneic transfusions following resection of colorectal cancer was an independent predictor of tumor recurrence.52 This finding was not confirmed by a large, multi-institutional, prospective randomized trial which demonstrated no benefit for autologous blood transfusions when compared to allogeneic transfusions.53 Both studies established that patients who do not require any blood transfusion have a reduced risk of recurrence, but it would be premature to change transfusion procedures based on these results as other studies have not confirmed this finding.54 There are a large number of studies correlating various clinical, pathological, and molecular parameters with prognosis, but none of these parameters has been demonstrated to be as important as pathologic stage, and none yet has a major impact on choice of, or outcome from, therapy.3,4,55-61

References:

  1. Steinberg SM, Barkin JS, Kaplan RS, et al.: Prognostic indicators of colon tumors: the Gastrointestinal Tumor Study Group experience. Cancer 57(9): 1866-1870, 1986.

  2. Filella X, Molina R, Grau JJ, et al.: Prognostic value of CA 19.9 levels in colorectal cancer. Annals of Surgery 216(1): 55-59, 1992.

  3. McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. British Journal of Cancer 79(2): 191-203, 1999.

  4. Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. New England Journal of Medicine 331(4): 213-221, 1994.

  5. Lanza G, Matteuzzi M, Gafa R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. International Journal of Cancer 79(4): 390-395, 1998.

  6. Gryfe R, Kim H, Hsieh ET, et al.: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. New England Journal of Medicine 342(2): 69-77, 2000.

  7. Fitzgerald SD, Longo WE, Daniel GL, et al.: Advanced colorectal neoplasia in the high-risk elderly patient: is surgical resection justified? Diseases of the Colon and Rectum 36(2): 161-166, 1993.

  8. Chiara S, Nobile MT, Vincenti M, et al.: Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemotherapy and Pharmacology 42(4): 336-340, 1998.

  9. Popescu RA, Norman A, Ross PJ, et al.: Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. Journal of Clinical Oncology 17(8): 2412-2418, 1999.

  10. Thorson AG, Knezetic JA, Lynch HT: A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). Diseases of the Colon and Rectum 42(1): 1-9, 1999.

  11. Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83(2): 259-266, 1998.

  12. Ransohoff DF, Lang CA: Screening for colorectal cancer. New England Journal of Medicine 325(1): 37-41, 1991.

  13. Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. New England Journal of Medicine 331(25): 1669-1674, 1994.

  14. Winawer SJ: Screening for colorectal cancer. Cancer: Principles and Practice of Oncology Updates 2(1): 1-16, 1987.

  15. Martin EW, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Annals of Surgery 202(1): 310-317, 1985.

  16. Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Diseases of the Colon and Rectum 36(7): 636-644, 1993.

  17. Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. Journal of the American Medical Association 270(8): 943-947, 1993.

  18. Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer: a meta-analysis. Annals of Surgery 219(2): 174-182, 1994.

  19. Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Annals of Surgery 220(2): 206-211, 1994.

  20. Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Diseases of the Colon and Rectum 39(3): 252-256, 1996.

  21. American Society of Clinical Oncology: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Journal of Clinical Oncology 14(10): 2843-2877, 1996.

  22. Rosen M, Chan L, Beart RW, et al.: Follow-up of colorectal cancer: a meta-analysis. Diseases of the Colon and Rectum 41(9): 1116-1126, 1998.

  23. Desch CE, Benson AB III, Smith TJ, et al.: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. Journal of Clinical Oncology 17(4): 1312-1321, 1999.

  24. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New England Journal of Medicine 322(6): 352-358, 1990.

  25. Moertel CG, Fleming TR, Macdonald JS, et al.: Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Annals of Internal Medicine 122(5): 321-326, 1995.

  26. 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. Journal of Clinical Oncology 11(10): 1879-1887, 1993.

  27. International Multicentre Pooled Analysis of Colon Cancer Trials: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345(8955): 939-944, 1995.

  28. 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. Proceedings of the American Society of Clinical Oncology 12: A-552, 190, 1993.

  29. Brown ML, Nayfield SG, Shibley LM: Adjuvant therapy for stage III colon cancer: economics returns to research and cost-effectiveness of treatment. Journal of the National Cancer Institute 86(6): 424-430, 1994.

  30. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 1990.

  31. Taylor I, Machin D, Mullee M, et al.: A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. British Journal of Surgery 72(5): 359-363, 1985.

  32. Wolmark N, Rockette H, Wickerham DL, et al.: Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. Journal of Clinical Oncology 8(9): 1466-1475, 1990.

  33. Beart RW, Moertel CG, Wieand HS, et al.: Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion: a study of the Mayo Clinic and the North Central Cancer Treatment Group. Archives of Surgery 125(7): 897-901, 1990.

  34. Nitti D, Wils J, Sahmoud T, et al.: Final results of a phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer (EORTC GITCCG 1983-1987). European Journal of Cancer 33(8): 1209-1215, 1997.

  35. The Gastrointestinal Tumor Study Group: Adjuvant therapy with hepatic irradiation plus fluorouracil in colon carcinoma. International Journal of Radiation Oncology, Biology, Physics 21(5): 1151-1156, 1991.

  36. Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Journal of Clinical Oncology 7(10): 1419-1426, 1989.

  37. Erlichman C, Fine S, Wong A, et al.: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. Journal of Clinical Oncology 6(3): 469-475, 1988.

  38. Doroshow JH, Multhauf P, Leong L, et al.: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. Journal of Clinical Oncology 8(3): 491-501, 1990.

  39. Poon MA, O'Connell MJ, Wieand HS, et al.: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. Journal of Clinical Oncology 9(11): 1967-1972, 1991.

  40. Valone FH, Friedman MA, Wittlinger PS, et al.: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group. Journal of Clinical Oncology 7(10): 1427-1436, 1989.

  41. Borner MM, Castiglione M, Bacchi M, et al.: The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Annals of Oncology 9(5): 535-541, 1998.

  42. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Journal of Clinical Oncology 10(6): 896-903, 1992.

  43. Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. Journal of Clinical Oncology 14(4): 1128-1135, 1996.

  44. Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Journal of Clinical Oncology 14(3): 709-715, 1996.

  45. 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): 1407-1412, 1998.

  46. Cunningham D, Pyrhonen 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): 1413-1418, 1998.

  47. Von Hoff DD: Promising new agents for treatment of patients with colorectal cancer. Seminars in Oncology 25(5, suppl 11): 47-52, 1998.

  48. de Gramont A, Vignoud J, Tournigand C, et al.: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. European Journal of Cancer 33(2): 214-219, 1997.

  49. Bleiberg H, de Gramont A: Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer. Seminars in Oncology 25(2 suppl 5): 32-39, 1998.

  50. Stephenson KR, Steinberg SM, Hughes KS, et al.: Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastases. Annals of Surgery 208(6): 679-687, 1988.

  51. Voogt PJ, Van de Velde CJ, Brand A, et al.: Perioperative blood transfusion and cancer prognosis: different effects of blood transfusion on prognosis of colon and breast cancer patients. Cancer 59(4): 836-843, 1987.

  52. Heiss MM, Mempel W, Delanoff C, et al.: Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. Journal of Clinical Oncology 12(9): 1859-1867, 1994.

  53. Busch OR, Hop WC, Hoynck van Papendrecht MA, et al.: Blood transfusions and prognosis in colorectal cancer. New England Journal of Medicine 328(19): 1372-1376, 1993.

  54. Donohue JH, Williams S, Cha S, et al.: Perioperative blood transfusions do not affect disease recurrence of patients undergoing curative resection of colorectal carcinoma: a Mayo/North Central Cancer Treatment Group study. Journal of Clinical Oncology 13(7): 1671-1678, 1995.

  55. Griffin MR, Bergstralh EJ, Coffey RJ, et al.: Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60(9): 2318-2324, 1987.

  56. 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. Journal of Clinical Oncology 12(12): 2640-2647, 1994.

  57. Shibata D, Reale MA, Lavin P, et al.: The DCC protein and prognosis in colorectal cancer. New England Journal of Medicine 335(23): 1727-1732, 1996.

  58. Bauer KD, Lincoln ST, Vera-Roman JM, et al.: Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinomas. Laboratory Investigation 57(3): 329-335, 1987.

  59. Bauer KD, Bagwell CB, Giaretti W, et al.: Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry 14(5): 486-491, 1993.

  60. Sun XF, Carstensen JM, Zhang H, et al.: Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet 340(8832): 1369-1373, 1992.

  61. Roth JA: p53 prognostication: pardigm or paradox? Clinical Cancer Research 5(11): 3345, 1999.
Cellular Classification
  adenocarcinoma (majority of cases)

    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. Diseases of the Colon and Rectum 37(7): 635-642, 1994.
Stage Information

Treatment decisions should be made with reference to the TNM classification,1 rather than the older Dukes' or the Modified Astler-Coller (MAC) classification schema.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.1

TNM definitions

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.

Regional lymph nodes (N)

NX: Regional nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in 1 to 3 regional lymph nodes N2: Metastasis in 4 or more regional lymph nodes

A tumor nodule greater than 3 mm in diameter in the perirectal or pericolic fat without histologic evidence of a residual node in the nodule is classified as regional perirectal or pericolic lymph node metastasis. A tumor nodule 3 mm or less in diameter is classified in the T category as a noncontiguous extension, that is T3.1

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 II

T3, N0, M0
T4, N0, M0

Stage III

Any T, N1, M0
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. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 83-90.
Treatment Option Overview

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 levels of evidence summary for more information.

Standard treatment of 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 is under evaluation in a prospective randomized trial comparing laparoscopic colectomy to open colectomy.5 When resection can be performed with clear margins, patients whose tumors extend through the bowel wall and to adjacent structures have no worse prognosis than similarly staged patients without such invasion. Surgery is also curative in 20% of patients who develop resectable metastases in the liver. Many early trials of adjuvant chemotherapy failed to show a significant improvement in either overall or disease-free survival for patients receiving treatment compared to concurrently randomized control patients receiving no adjuvant therapy.6-9 These trials employed fluorouracil (5-FU) alone or 5-FU plus 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.10[Level of evidence: 1iiA] A significant improvement in disease-free survival was observed for patients with stage III (Dukes' C) colon cancer who received 5-FU/levamisole, but overall survival benefits were of borderline statistical significance. A survival benefit of approximately 12% (49% versus 37%) was seen in patients with stage III disease treated with 5-FU/levamisole. In a large, confirmatory intergroup trial, 5-FU/levamisole prolonged disease-free and overall survival in patients with stage III colon cancer, compared to patients who received no treatment after surgery.11[Level of evidence: 1iiA] Levamisole alone did not confer these benefits. In 1990, a National Institutes of Health Consensus Panel recommended that adjuvant therapy with 5-FU/levamisole be considered for patients with stage III (Dukes' C) colon cancer.12

A study comparing 5-FU and leucovorin with fluorouracil/semustine/vincristine has demonstrated a statistically significant benefit in both survival and disease-free survival for the 5-FU/leucovorin arm.13[Level of evidence: 1iiA] The National Surgical Adjuvant Breast and Bowel Project (NSABP) regimen used 5- FU at 500 milligrams per square meter daily and high-dose leucovorin at 500 milligrams per square meter daily, both administered every seventh day for 6 weeks out of every 8 weeks for 1 year. A controlled trial of postoperative 5- FU plus leucovorin compared to surgery alone has also demonstrated a disease- free and overall survival advantage for the NCCTG regimen of 5-FU at 425 milligrams per square meter daily and low-dose leucovorin at 20 milligrams per square meter daily for 5 days repeated every 4 to 5 weeks for 6 months of chemotherapy.14[Level of evidence: 1iiA] Investigators from the International Multicentre Pooled Analysis of Colon Cancer Trials have combined data from 3 other trials for patients with stages II and III (Dukes' B and C) colon cancer using either no postoperative therapy or 5-FU at 370 to 400 milligrams per square meter plus intermediate-dose leucovorin at 200 milligrams per square meter daily for 5 days every 28 days for 6 cycles.15 A statistically significant improvement in disease-free and overall survival was demonstrated in all patients receiving adjuvant therapy.

The NCCTG performed a trial comparing 6 months to 12 months of treatment using either 5-FU and levamisole or 5-FU, levamisole, and leucovorin for patients with stages II and III (Dukes' B and C or MAC B2, B3, and C1-3) colon cancer.16[Level of evidence: 1iiA] The trial showed that for equivalent survival benefit, the 5-FU plus levamisole regimen must be given for 12 months, while the 3-drug regimen could be administered over just 6 months. An intergroup trial with 4 treatment arms, including 5-FU plus levamisole, 5-FU plus low-dose leucovorin (the NCCTG regimen), 5-FU plus high-dose leucovorin (the NSABP regimen), or 5-FU plus leucovorin plus levamisole, has been reported in preliminary fashion.17[Level of evidence: 1iiA] This study also demonstrated that 6 months of 5-FU plus leucovorin is at least as effective as 12 months of 5-FU/levamisole, as did a trial of 5-FU plus high-dose leucovorin from the NSABP.18 Mature data from NSABP C-05 suggest no survival benefit from the addition of interferon alfa-2a to 5-FU and high-dose leucovorin, but did note a substantial increase in grade 3 or higher toxic effects.19

Based on the outcomes of all of these trials, a recommendation was made at the 1997 American Society of Clinical Oncology meeting that any 1 of 3 regimens could be considered for postoperative treatment of patients with stage III colon cancer, all of which have resulted in a survival advantage over no postoperative chemotherapy. These include the NCCTG regimens of 5-FU and levamisole for 1 year, or 5-FU and low-dose leucovorin for 6 months, or the NSABP regimen of 5-FU and high-dose leucovorin for 6 months. At this time, there are insufficient data to determine if there is any advantage to the 3- drug combination of 5-FU and leucovorin and levamisole over any of the previously noted 2-drug regimens. There is also insufficient data to distinguish whether high-, intermediate-, or low-dose leucovorin is most advantageous as a modulator of 5-FU.

Based on survival benefits from an early trial of adjuvant portal-vein 5-FU infusion in patients with colon cancer, a number of confirmatory trials were conducted.20 The preliminary results of these studies have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences.21-24 However, a meta-analysis has shown a modest improvement in overall survival when patients are treated with portal- vein 5-FU infusion as compared to no postoperative therapy.25 This technique for adjuvant therapy is therefore of some historical interest and should generally not be employed because of more effective systemic adjuvant regimens administered by the more convenient peripheral intravenous route. A randomized trial by the Swiss Group for Clinical Cancer Research revealed no survival difference between systemic 5-FU versus portal-vein 5-FU infusion versus surgery alone in 769 patients with resected colon or rectal cancer.26 However, the Intergroup currently has an open trial that tests the hypothesis of perioperative systemic delivery of 5-FU chemotherapy.27

The potential value of adjuvant therapy for patients with stage II (Dukes' B or MAC B2 or B3) colon cancer also remains a controversial issue. Investigators from the NSABP have indicated that the reduction in the 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, although an overall survival advantage has not been established.28 However, a randomized trial of post-operative 5-FU plus levamisole compared to surgery alone showed no survival advantage to postoperative adjuvant chemotherapy.29 A meta-analysis of 1000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease- free survival at 5 years when adjuvant therapy treated patients treated with 5- FU/leucovorin are compared to untreated controls.30[Level of evidence: 1iiiDi];31 Patients with stage II colon cancer remain candidates for clinical trials in which either surgery alone or 5-FU/leucovorin represents standard therapy.32-34

Chemotherapy trials, typically with 5-FU-based regimens, have demonstrated increased numbers of partial responses and prolongation of the time to progression of disease,35,36 as well as improved survival and quality of life for patients receiving chemotherapy compared to best supportive care.37,38 Several trials have analyzed the activity and toxic effects of various 5-FU plus leucovorin regimens in patients 70 years of age or older as compared to younger patients. Similar quantitative and qualitative toxic effects of therapeutic outcomes have been observed for patients of all ages.39[Level of evidence: 2A,C];40[Level of evidence: 2A,C] Patients should be considered candidates for clinical trials evaluating new approaches to treatment.41,42 Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.43-46 It has been approved by the Food and Drug Administration for the treatment of patients with metastatic disease that is refractory to 5-FU.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. Bokey EL, Moore JW, Chapuis PH, et al.: Morbidity and mortality following laparoscopic-assisted right hemicolectomy for cancer. Diseases of the Colon and Rectum 39(10, Suppl): S24-S28, 1996.

  2. Franklin ME, Rosenthal D, Abrego-Medina D, et al.: Prospective comparison of open vs. laparoscopic colon surgery for carcinoma: five-year results. Diseases of the Colon and Rectum 39(10, Suppl): S35-S46, 1996.

  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. Diseases of the Colon and Rectum 39(10, Suppl): S53-S58, 1996.

  4. Marchesa P, Milsom JW, Hale JC, et al.: Intraoperative laparoscopic liver ultrasonography for staging of colorectal cancer. Diseases of the Colon and Rectum 39(10, Suppl): S73-S78, 1996.

  5. Nelson H, North Central Cancer Treatment Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Study of Laparoscopic-Assisted Colectomy vs Open Colectomy for Colon Cancer (Summary Last Modified 10/1999), NCCTG-934653, clinical trial, active, 08/15/1994.

  6. Panettiere FJ, Goodman PJ, Costanzi JJ, et al.: Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group study. Journal of Clinical Oncology 6(6): 947-954, 1988.

  7. Gastrointestinal Tumor Study Group: Adjuvant therapy of colon cancer: results of a prospectively randomized trial. New England Journal of Medicine 310(12): 737-743, 1984.

  8. Higgins GA, 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.

  9. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer: why we still don't know. Journal of the American Medical Association 259(24): 3571-3578, 1988.

  10. 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. Journal of Clinical Oncology 7(10): 1447-1456, 1989.

  11. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New England Journal of Medicine 322(6): 352-358, 1990.

  12. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 1990.

  13. 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. Journal of Clinical Oncology 11(10): 1879-1887, 1993.

  14. O'Connell MJ, Mailliard JA, Kahn MJ, et al.: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. Journal of Clinical Oncology 15(1): 246-250, 1997.

  15. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. Journal of Clinical Oncology 17(5): 1356-1363, 1999.

  16. O'Connell MJ, Laurie JA, Kahn M, et al.: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. Journal of Clinical Oncology 16(1): 295-300, 1998.

  17. Haller DG, Catalano PJ, Macdonald JS, et al.: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of INT-0089. Proceedings of the American Society of Clinical Oncology 17: A-982, 256a, 1998.

  18. Wolmark N, Rockette H, Jones J, et al.: Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Duke's B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. Journal of Clinical Oncology 17(11): 3553-3559, 1999.

  19. 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. Journal of the National Cancer Institute 90(23): 1810-1816, 1998.

  20. Taylor I, Machin D, Mullee M, et al.: A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. British Journal of Surgery 72(5): 359-363, 1985.

  21. Wolmark N, Rockette H, Wickerham DL, et al.: Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. Journal of Clinical Oncology 8(9): 1466-1475, 1990.

  22. Beart RW, Moertel CG, Wieand HS, et al.: Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion: a study of the Mayo Clinic and the North Central Cancer Treatment Group. Archives of Surgery 125(7): 897-901, 1990.

  23. Fielding LP, Hittinger R, Grace RH, et al.: Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 340(8818): 502-506, 1992.

  24. Rougier P, Sahmoud T, Nitti D, et al.: Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet 351(9117): 1677-1681, 1998.

  25. Piedbois P, Buyse M, Gray R, et al.: Portal vein infusion is an effective adjuvant treatment for patients with colorectal cancer. Proceedings of the American Society of Clinical Oncology 14: A-444, 192, 1995.

  26. Laffer U, Maibach R, Metzger U, et al.: Randomized trial of adjuvant perioperative chemotherapy in radically resected colorectal cancer (SAKK 40/87). Proceedings of the American Society of Clinical Oncology 17: 983A, 256a, 1998.

  27. Kemeny MM, Eastern Cooperative Oncology Group: Phase III Randomized Study of Curative Colon Resection With or Without Perioperative Fluorouracil in Patients with Stage IIB, IIC, or III Colon Cancer, Followed by Fluorouracil and Leucovorin Calcium for Stage IIC or III Patients (Summary Last Modified 09/1999), E-1292, clinical trial, active, 08/20/1993.

  28. 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). Journal of Clinical Oncology 17(5): 1349-1355, 1999.

  29. Moertel CG, Fleming TR, Macdonald JS, et al.: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. Journal of Clinical Oncology 13(12): 2936-2943, 1995.

  30. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. Journal of Clinical Oncology 17(5): 1356-1363, 1999.

  31. Harrington DP: The tea leaves of small trials. Journal of Clinical Oncology 17(5): 1336-1338, 1999.

  32. Colacchio TA, Cancer and Leukemia Group B: Phase III Randomized Study of Adjuvant Edrecolomab Versus No Adjuvant Therapy Following Resection in Patients With Stage II Adenocarcinoma of the Colon (Summary Last Modified 06/2000), CLB-9581, clinical trial, active, 05/31/1997.

  33. Pazdur R, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Study of Oral Uracil/Tegafur (UFT) with Leucovorin vs Fluorouracil with Leucovorin Following Resection for Stage II/III Adenocarcinoma of the Colon (Summary Last Modified 05/1999), NSABP-C-06, clinical trial, closed, 03/31/1999.

  34. Poplin EA, Southwest Oncology Group: Phase III Randomized Study of Bolus Fluorouracil and Leucovorin Calcium with Levamisole vs Continuous Infusion Fluorouracil with Levamisole as Adjuvant Therapy in Patients with High Risk Colon Cancer (Summary Last Modified 04/2000), SWOG-9415, clinical trial, closed, 12/15/1999.

  35. 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. Journal of Clinical Oncology 5(10): 1559-1565, 1987.

  36. Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Journal of Clinical Oncology 7(10): 1419-1426, 1989.

  37. 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. British Medical Journal 306(6880): 752-755, 1993.

  38. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Journal of Clinical Oncology 10(6): 904-911, 1992.

  39. Chiara S, Nobile MT, Vincenti M, et al.: Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemotherapy and Pharmacology 42(4): 336-340, 1998.

  40. Goldberg RM, Hatfield AK, Kahn M, et al.: Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. Journal of Clinical Oncology 15(11) : 3320-3329, 1997.

  41. Poon MA, O'Connell MJ, Wieand HS, et al.: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. Journal of Clinical Oncology 9(11): 1967-1972, 1991.

  42. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  43. Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. Journal of Clinical Oncology 14(4): 1128-1135, 1996.

  44. Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Journal of Clinical Oncology 14(3): 709-715, 1996.

  45. 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): 1407-1412, 1998.

  46. Cunningham D, Pyrhonen 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): 1413-1418, 1998.
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.

Stage I Colon Cancer

Stage I (old staging: Dukes' A or Modified Astler-Coller A and B1)

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

Treatment options:

Wide surgical resection and anastomosis.
Stage II Colon Cancer

Stage II (old staging: Dukes' B or Modified Astler-Coller B2 and B3)

Treatment options:

  1. Wide surgical resection and anastomosis.

  2. Following surgery, patients should be considered for entry into carefully controlled clinical trials evaluating the use of systemic or regional chemotherapy,1 radiation therapy, or biologic therapy.2 Refer to PDQ and to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with stage II colon cancer. Adjuvant therapy is not indicated for most patients unless they are entered into a clinical trial.

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 or fixation to adjacent structures (MAC stage B3), perforation, complete obstruction, or with biologic characteristics such as aneuploidy, high S-phase analysis, or deletion of 18q),3,4 there is no consistent evidence that adjuvant 5-fluorouracil-based chemotherapy is associated with an overall improved survival compared with surgery alone.5 In some trials, subset analysis of adjuvant chemotherapy has demonstrated benefits in disease-free and overall survival compared with surgery alone,6,7 but such treatment has not been considered standard for all stage II patients. Improved local control with postoperative radiation therapy has been suggested in patients with T3 and T4 tumors; an intergroup clinical trial designed to explore the role of adjuvant combined chemotherapy and radiation therapy compared with postoperative chemotherapy alone for selected patients with this high-risk stage II colon cancer was closed because of low accrual.8,9 However, preliminary results, published only in abstract form, have not suggested a survival advantage from routine postoperative adjuvant radiation therapy in this subgroup of patients.10

References:

  1. Pazdur R, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Study of Oral Uracil/Tegafur (UFT) with Leucovorin vs Fluorouracil with Leucovorin Following Resection for Stage II/III Adenocarcinoma of the Colon (Summary Last Modified 05/1999), NSABP-C-06, clinical trial, closed, 03/31/1999.

  2. Colacchio TA, Cancer and Leukemia Group B: Phase III Randomized Study of Adjuvant Edrecolomab Versus No Adjuvant Therapy Following Resection in Patients With Stage II Adenocarcinoma of the Colon (Summary Last Modified 06/2000), CLB-9581, clinical trial, active, 05/31/1997.

  3. Lanza G, Matteuzzi M, Gafa R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. International Journal of Cancer 79(4): 390-395, 1998.

  4. Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. New England Journal of Medicine 331(4): 213-221, 1994.

  5. Moertel CG, Fleming TR, Macdonald JS, et al.: Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. Journal of Clinical Oncology 13(12): 2936-2943, 1995.

  6. 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. Journal of Clinical Oncology 11(10): 1879-1887, 1993.

  7. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  8. Willett CG, Fung CY, Kaufman DS, et al.: Postoperative radiation therapy for high-risk colon carcinoma. Journal of Clinical Oncology 11(6): 1112-1117, 1993.

  9. Martenson JA, North Central Cancer Treatment Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Trial of Adjuvant 5-FU/LEV with vs without Radiotherapy in Patients with Completely Resected Adenocarcinoma of the Colon at High Risk of Locoregional Recurrence (Summary Last Modified 03/97), NCCTG-914652, clinical trial, closed, 12/17/1996.

  10. Martenson J, Willett C, Sargent D, et al.: A phase III study of adjuvant radiation therapy (RT), 5-fluorouracil (5-FU), and levamisole (LEV) vs 5-FU and LEV in selected patients with resected high risk colon cancer: initial results of Int 0130. Proceedings of the American Society of Clinical Oncology 18: A-904, 235a, 1999.
Stage III Colon Cancer

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 levels of evidence summary for more information.

Stage III (old staging: Dukes' C or Modified Astler-Coller C1-C3)

Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis: patients with 1 to 3 involved nodes have a significantly better survival than those with 4 or more involved nodes. Improved local control with postoperative radiation therapy has been suggested in patients with adherence or fixation to adjacent structures.1 Intraoperative electron beam radiation therapy, to the site of residual microscopic or gross residual disease following surgical extirpation, has also been reported to improve local control when combined with external beam radiation therapy and chemotherapy.2[Level of evidence: 3iiiDi] However, preliminary results, published only in abstract form, have not suggested a survival advantage from routine postoperative adjuvant radiation therapy in this subgroup of patients.3 (Refer to the discussion of adjuvant therapy in the treatment option overview section of this summary.)

In the late 1980s, a passive immunotherapy approach to adjuvant treatment of stage III colorectal cancer demonstrated encouraging results in a single randomized trial.4 This trial compared postoperative administration of a murine monoclonal antibody to 17-1A antigen (MOAB 17-1A), a cell surface glycoprotein of uncertain function expressed on both normal and malignant epithelial cells, to surgery alone. Treated patients appeared to have a survival benefit comparable to that seen in adjuvant chemotherapy trials, with a relative reduction in mortality of 32% (95% confidence interval (CI), 8- 51).4[Level of evidence: 1iiA] However, the small size of this trial was associated with a wide CI for the observed benefit. Therefore, this result remains to be confirmed in ongoing trials of chemotherapy with or without MOAB 17-1A in North America and chemotherapy versus MOAB 17-1A in Europe.5 Other adjuvant immunotherapeutic approaches, including autologous tumor vaccines,6 are also under clinical evaluation.

Treatment options:

  1. Wide surgical resection and anastomosis. For patients who are not candidates for clinical trials, postoperative chemotherapy with fluorouracil (5-FU)/leucovorin for 6 months. 5-FU/levamisole for 12 months may also be considered, although at least 1 trial has shown this to be inferior in survival to 6 months of 5-FU plus high-dose leucovorin.7-15 Levamisole does not appear to be a mandatory component of adjuvant therapy.9,14-16

  2. Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens, postoperative radiation therapy, or biological therapy, alone or in combination.5,17 Refer to PDQ and to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with stage III colon cancer.

References:

  1. Willett CG, Fung CY, Kaufman DS, et al.: Postoperative radiation therapy for high-risk colon carcinoma. Journal of Clinical Oncology 11(6): 1112-1117, 1993.

  2. Schild SE, Gunderson LL, Haddock MG, et al.: The treatment of locally advanced colon cancer. International Journal of Radiation Oncology, Biology, Physics 37(1): 51-58, 1997.

  3. Martenson JA, Willett C, Sargent D, et al.: A phase III study of adjuvant radiation therapy (RT), 5-flourouracil (5-FU), and levamisole (LEV) vs 5-FU and LEV in selected patients with resected high risk colon cancer. Proceedings of the American Society of Clinical Oncology 18: A904, 235a, 1999.

  4. Riethmuller G, Holz E, Schlimok G, et al.: Monoclonal antibody therapy for resected Dukes' C colorectal cancer: seven-year outcome of a multicenter randomized trial. Journal of Clinical Oncology 16(5): 1788-1794, 1998.

  5. Pazdur R, Glaxo Wellcome, Inc.: Phase III Randomized Study of Adjuvant MOAB 17-1A plus 5-FU-Based Chemotherapy vs 5-FU-Based Chemotherapy Alone for Surgically Resected Stage III Adenocarcinoma of the Colon (Summary Last Modified 08/1999), GW-157-001, clinical trial, closed, 07/06/1999.

  6. Benson AB, Eastern Cooperative Oncology Group: Phase III Comparison of Adjuvant 5-FU/LEV vs 5-FU/LEV plus Autologous Tumor Cell Vaccination in Patients with Potentially Curatively Resected Stage C1-3 Adenocarcinoma of the Colon (Summary Last Modified 11/94), E-1290, clinical trial, closed, 01/03/1996.

  7. Moertel CG, Fleming TR, Macdonald JS, et al.: Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Annals of Internal Medicine 122(5): 321-326, 1995.

  8. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 1990.

  9. Wolmark N, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Comparison of 5-FU/CF vs 5-FU/LEV vs 5-FU/CF/LEV as Adjuvant Therapy Following Potentially Curative Resection of Dukes' B and C Carcinoma of the Colon (Summary Last Modified 06/89), NSABP-C-04, clinical trial, closed, 12/31/1990.

  10. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  11. Wolmark N, Rockette H, Wickerham DL, et al.: Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. Journal of Clinical Oncology 8(9): 1466-1475, 1990.

  12. Beart RW, Moertel CG, Wieand HS, et al.: Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion: a study of the Mayo Clinic and the North Central Cancer Treatment Group. Archives of Surgery 125(7): 897-901, 1990.

  13. Fielding LP, Hittinger R, Grace RH, et al.: Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 340(8818): 502-506, 1992.

  14. Piedbois P, Buyse M, Gray R, et al.: Portal vein infusion is an effective adjuvant treatment for patients with colorectal cancer. Proceedings of the American Society of Clinical Oncology 14: A-444, 192, 1995.

  15. 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. Journal of Clinical Oncology 5(10): 1559-1565, 1987.

  16. Haller DG, Eastern Cooperative Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Adjuvant Low-Dose CF/5-FU vs High-Dose CF/5-FU vs Low-Dose CF/5-FU/LEV vs 5-FU/LEV Following Curative Resection in Selected Patients with Dukes' B2 and C Carcinoma of the Colon (Summary Last Modified 06/97), EST-2288, clinical trial, closed, 07/30/1992.

  17. 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. Annals of Oncology 4(Suppl 2): S21-S28, 1993.
Stage IV Colon Cancer

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 levels of evidence summary for more information.

Stage IV colon cancer denotes distant metastatic disease. Local regional approaches to treating liver metastases include hepatic resection and/or intraarterial administration of chemotherapy with implantable infusion ports or pumps. For patients with limited (3 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40%.1-5 For those patients with hepatic metastases deemed unresectable (due to factors such as location, distribution, excessive number), cryosurgical ablation has been associated with long-term tumor control.6 Prognostic variables that predict a favorable outcome for cryotherapy are similar to those for hepatic resection and include low preoperative carcinoembryonic antigen level, absence of extrahepatic disease, negative margin, and lymph node negative primary.7[Level of evidence: 3iiiA] Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.8,9 Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.10,11 The role of additional systemic therapy 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 and overall survival (86% versus 72%, P=.03) compared to systemic 5-FU therapy alone.12[Level of evidence: 1iiA] Further follow-up is required to confirm these findings and to determine whether more effective combination chemotherapy alone may provide similar results compared to 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.13-18 Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CALGB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intraarterial chemotherapy with hepatic irradiation, especially employing focal radiation of metastatic lesions, is under evaluation.19 Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

In stage IV and recurrent colon cancer, chemotherapy has been used for palliation, with 5-FU-based treatment considered to be standard.20,21 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin22-28 or methotrexate.29,30 Randomized clinical trials show that interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy.31,32 Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.33,34 The benefits of continuous infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.35 Oral fluoropyrimidines are also being evaluated in phase II-III trials.36,37 Oral regimens using prodrugs of 5-FU or inhibitors of dihydropyrimidine dehydrogenase (DPD) (GW 776C85) pharmacologically simulate continuous infusion and are under clinical evaluation. The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and the toxic effects profile of the chosen regimen, as well as cost and quality-of-life issues.38 In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous-infusion or bolus administration.39

DPD is the rate-limiting enzyme in the degradation pathway for 5-FU. While genetic polymorphism commonly results in considerable individual variability in levels of this enzyme, between 0.5% and 3% of the population are severely DPD deficient. Severe mucositis, neutropenia, diarrhea, and cerebellar dysfunction can result in toxic deaths among patients who are DPD deficient. Standard testing for DPD is not widely available, but one study found that patients with a pretreatment ratio of dihydrouracil to uracil of 1.8 or less were at risk of increased 5-FU toxic effects.40-42

Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.43-45 It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.46 Another drug, Tomudex, is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin.47[Level of evidence: 1iiA]48 A number of other drugs are undergoing early evaluation for the treatment of colon cancer.49 Oxaliplatin plus 5-FU and leucovorin has also shown activity in previously untreated and 5-FU refractory patients.50-52

Patients with advanced colon cancer who have relapsed after either adjuvant therapy or treatment for advanced disease with 5-FU and leucovorin may be considered for additional therapy. A number of approaches have been used in the treatment of such patients, including retreatment with 5-FU and treatment with CPT-11.53 Patients retreated with bolus or infusional 5-FU following adjuvant 5-FU therapy or discontinuation of 5-FU in responding patients with metastatic disease have response rates and response durations similar to previously untreated patients.53[Level of evidence: 2B] CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5- FU. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.54[Levels of evidence: 1iiA,1iiC];55[Levels of evidence: 1iiA,1iiC]

Treatment options:

  1. Surgical resection/anastomosis or bypass of obstructing primary lesions in selected cases.

  2. Surgical resection of isolated metastases (liver, lung, ovaries).1,3,13,10,56-59

  3. Chemotherapy.

  4. Clinical trials evaluating new drugs and biologic therapy.

  5. Radiation therapy.

References:

  1. Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. British Journal of Surgery 77(11): 1241-1246, 1990.

  2. Steele G, Bleday R, Mayer RJ, et al.: A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group protocol 6584. Journal of Clinical Oncology 9(7): 1105-1112, 1991.

  3. Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110(1): 13-29, 1991.

  4. Pedersen IK, Burcharth F, Roikjaer O, et al.: Resection of liver metastases from colorectal cancer: indications and results. Diseases of the Colon and Rectum 37(11): 1078-1082, 1994.

  5. Harmon KE, Ryan JA Jr, Biehl TR, et al.: Benefits and safety of hepatic resection for colorectal metastases. American Journal of Surgery 177(5), 402-404, 1999.

  6. Jarnagin WR, Fong Y, Ky A, et al.: Liver resection for metastatic colorectal cancer: assessing the risk of occult irresectable disease. Journal of the American College of Surgeons 188(1): 33-42, 1999.

  7. Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Annals of Surgery 228(2): 201-208, 1998.

  8. Thomas DS, Nauta RJ, Rodgers JE, et al.: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Cancer 71(6): 1977-1981, 1993.

  9. Ravikumar TS: Interstitial therapies for liver tumors. Surgical Oncology Clinics of North America 5(2): 365-377, 1996.

  10. Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. Journal of Clinical Oncology 14(7): 2047-2053, 1996.

  11. McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Annals of Thoracic Surgery 53(5): 780-786, 1992.

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