About Medicine OnLine
MOL HomeLibrariesDoseCalcOncology News
ForumsSearchCancer LinksGlossary

Information Libraries: Colon Cancer

Important: This information is intended for use by doctors and other health care professionals. If you are a cancer patient, your doctor can explain how it applies to you, or you can call the Cancer Information Service at 1-800-422-6237. CancerNet also contains PDQ information for patients; see the CancerNet Clinical Cancer Information for Patients from PDQ for more information. This information is produced and provided by the National Cancer Institute (NCI).


Table Of Contents

GENERAL INFORMATION

(Separate statements containing information on screening for colorectal cancer and prevention of colorectal cancer are also available in PDQ.)

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 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 two 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) and of carbohydrate antigen 19-9 (CA 19-9) have a negative prognostic significance.[2] Age greater than 70 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.[3]

Because of the frequency of the disease (approximately 160,000 new cases of colon and rectal cancer per year), the identification of high-risk groups, the demonstrated slow growth of primary lesions, the better survival of 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, especially those with first-degree relatives with colorectal cancer.[4]

Careful screening of high-risk populations (patients with panulcerative colitis, previous colon cancer, a family history of colon or female genital cancer, or a history of sporadic colon polyps) should include periodic stool occult blood evaluation and appropriate radiologic and endoscopic studies. Specific genetic alterations have been recognized in the two major conditions predisposing familial colorectal cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.[5,6] As practical assays are developed and validated, such detectable genetic abnormalities may be used in the future to screen members of high-risk families, particularly those with familial adenomatous polyposis.[7] For more information on this subject, consult the PDQ statements on screening and prevention of colorectal cancer.

Following treatment for colon cancer, periodic determinations of serum CEA levels, radiographic and laboratory studies, and physical examination may lead to the earlier identification and management of recurrent disease.[8] 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.[9,10] Postoperative monitoring should be reserved primarily for detection of asymptomatic recurrences that can be curatively resected and for early detection of metachronous tumors.[11-13]


Adjuvant therapy

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.[14-17]

A subsequent generation of large prospective randomized trials, however, hademonstrated consistent evidence of benefit for systemic adjuvant chemotherapy employing fluorouracil plus either levamisole or leucovorin. The first positive trial employed a regimen that is no longer used. In 1988, the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated improved disease-free survival and an overall survival benefit of 8% at 5 years of follow-up for patients with stages II and III (Dukes' B and C and Modified Astler-Coller [MAC] B2, B3, and C1-C3) treated with postoperative MOF chemotherapy consisting of fluorouracil (5-FU), semustine (methyl-CCNU), and vincristine.[18] However, after 8 years of follow-up, this benefit was no longer apparent. 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.[19] This benefit has persisted with continued follow-up.[20] Levamisole alone did not confer these benefits, and it was not clear whether 5-FU/levamisole was effective in stage II patients.

The NSABP then reported a trial for stage II and III patients comparing the original MOF 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.[21] 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 event-free and overall survival rates were also statistically significantly improved in this analysis.[22,23] 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 for stage III colon cancer appears to be cost-effective when costs of treatment and quality-of-life measures are taken into account.[24]

At this time, patients with stage III (Dukes' C) colon cancer should be considered for adjuvant therapy with 5-FU/levamisole, with 5-FU/leucovorin, or with one of the other regimens now being studied in clinical trials.[25] Regional adjuvant therapy directed at reducing liver metastasis has been tested using both portal vein infusion of 5-FU and hepatic radiation, and an early trial by Taylor showed promising results.[26] 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.[27-29] 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.[30]


Advanced disease

For locally advanced disease, the role of radiation therapy in colon cancer is under clinical evaluation. There is no standard therapy for advanced colon cancer and no evidence that chemotherapy improves survival, although short-term palliation may be achieved in approximately 10%-20% of patients with 5-FU. Several studies suggest an advantage when leucovorin or methotrexate is added to 5-FU in terms of response rate and palliation of symptoms, but not always in terms of survival.[31-35]

Some retrospective studies suggest that perioperative blood transfusions impair prognosis of patients with colorectal cancer.[36,37] 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.[38] 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.[39] 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.[40]

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. 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.
  4. Cannon-Albright LA, Skolnick MH, Bishop DT, et al.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. New England Journal of Medicine 319(9): 533-537, 1988.
  5. Peltomaki P, Aaltonen LA, Sistonen P, et al.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260(5109): 810-812, 1993.
  6. Aaltonen LA, Peltomaki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 260(5109): 812-816, 1993.
  7. Powell SM, Petersen GM, Krush AJ, et al.: Molecular diagnosis of familial adenomatous polyposis. New England Journal of Medicine 329(27): 1982-1987, 1993.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Annals of Surgery 220(2): 206-211, 1994.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. Wolmark N, Fisher B, Rockette H, et al.: Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01 [Prior Annotation Incorrect]. Journal of the National Cancer Institute 80(1): 30-36, 1988.
  19. 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.
  20. 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.
  21. 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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 11(10): 1879-1887, 1993.
  22. International Multicentre Pooled Analysis of Colon Cancer Trials: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345(8955): 939-944, 1995.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 8(9): 1466-1475, 1990.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.

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 are usually made in reference to the older Dukes or the Modified Astler-Coller (MAC) classification schema.[1]

Stages should preferably be defined by TNM classification.[2]


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 the nonperitonealized pericolic tissues

T4: Tumor directly invades other organs or structures and/or perforates the

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 of other organs or structures includes invasion of other segments of colorectum by way of serosa (e.g., 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 pericolic lymph nodes
N2: Metastasis in 4 or more pericolic lymph nodes
N3: Metastasis in any lymph node along the course of a named vascular trunk

and/or metastasis to apical node(s) (when marked by the surgeon)
Distant metastasis (M)

MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis


Stage 0

Stage 0 is defined as the following TNM grouping:

Tis, N0, M0
(carcinoma in situ)

Stage I

Stage I is defined as any of the following TNM groupings:

T1, N0, M0
T2, N0, M0

Stage I may be equivalent to Dukes' A or MAC A or B1. Tumor is limited to bowel wall (mucosa, muscularis mucosae, submucosa, and muscularis propria).


Stage II

Stage II is defined as any of the following TNM groupings:

T3, N0, M0
T4, N0, M0

Stage II may be equivalent to Dukes' B or MAC B2 or B3. Tumor has spread to extramural tissue.


Stage III

Stage III is defined as any of the following TNM groupings:

any T, N1, M0
any T, N2, M0
any T, N3, M0

Stage III may be equivalent to Dukes' C or MAC C1-C3. Regional nodes are involved.


Stage IV

Stage IV is defined as the following TNM grouping:

any T, any N, M1

Note: Dukes' B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) prognostic groups as is Dukes' C (any T, N1, M0 and any T, N2 or N3, M0).

References:

  1. Cohen AM, Minsky BD, Schilsky RL: Colon cancer. In: DeVita VT, Hellman S, Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology. Philadelphia: JB Lippincott Company, 4th Edition, 1993, pp 929-977.
  2. Colon and rectum. In: American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia: JB Lippincott Company, 4th ed., 1992, 75-82.
  3. Zinkin LD: A critical review of the classifications and staging of colorectal cancer. Diseases of the Colon and Rectum 26(1): 37-43, 1983.
  4. Eisenberg B, Decosse JJ, Harford F, et al.: Carcinoma of the colon and rectum: the natural history reviewed in 1704 patients. Cancer 49(6): 1131-1134, 1982.
  5. Olson RM, Perencevich NP, Malcolm AW, et al.: Patterns of recurrence following curative resection of adenocarcinoma of the colon and rectum. Cancer 45(12): 2969-2974, 1980.
  6. Newland RC, Chapuis PH, Pheils MT, et al.: The relationship of survival to staging and grading of colorectal carcinoma: a prospective study of 503 cases. Cancer 47(6): 1424-1429, 1981.

TREATMENT OPTION OVERVIEW

Standard treatment for colon cancer has been surgical resection of the primary and regional lymph nodes for localized disease. 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.[1-4] In 1988, a large prospective trial of adjuvant therapy by the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated improved disease-free survival and an overall survival benefit of 8% for stages II and III (Dukes' B and C or MAC B2, B3, and C1-C3) patients treated with postoperative chemotherapy consisting of fluorouracil (5-FU), semustine (methyl-CCNU), and vincristine (MOF).[5] A follow-up study comparing 5-FU and leucovorin with MOF has demonstrated a statistically significant benefit in both survival and disease-free survival for the 5-FU/leucovorin arm.[6]

Another randomized trial compared surgical resection alone with postoperative levamisole or 5-FU/levamisole started within five weeks of surgery.[7] A significant improvement in disease-free survival was observed for stage III (Dukes' C or MAC C1-C3) colorectal carcinoma receiving 5-FU/levamisole, bu overall survival benefits were of borderline statistical significance. A survival benefit of approximately 12% (37% versus 49%) was seen in patients with stage III disease. In addition, in a large intergroup trial, 5-FU/levamisole has been reported to prolong disease-free and overall survival in patients with stage III colon cancer, compared to patients who received no treatment after surgery.[8] Levamisole alone did not confer these benefits. With 5-year survival rates of 70%-80% and nearly half of the deaths due to causes other than cancer, stage II (Dukes' B, Astler-Coller B2 and B3) patients should be offered adjuvant chemotherapy only in the context of a clinical trial.[2,9]

At this time, patients with stage III (Dukes' C) colon cancer should be considered for adjuvant therapy with 5-FU/levamisole.[10] Based on survival benefits from an early trial of adjuvant portal-vein 5-FU infusion in patients with colorectal cancer, a number of groups have sought to confirm these data.[11] The preliminary results of these confirmatory trials have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences.[12-14] However, a meta-analysis has shown a modest improvement in overall survival.[15] There is no standard chemotherapy for patients with widespread metastatic disease, but trials with 5-FU and leucovorin have demonstrated increased numbers of partial responses and prolongation of the time to progression of disease.[16,17] These patients should be considered candidates for clinical trials evaluating new approaches to treatment.[18-20]

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. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Wolmark N, Fisher B, Rockette H, et al.: Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01 [Prior Annotation Incorrect]. Journal of the National Cancer Institute 80(1): 30-36, 1988.
  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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 11(10): 1879-1887, 1993.
  7. 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.
  8. 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.
  9. Nauta R, Stablein DM, Holyoke ED: Survival of patients with stage B2 colon carcinoma: the Gastrointestinal Tumor Study Group experience. Archives of Surgery 124(2): 180-182, 1989.
  10. 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.
  11. 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.
  12. 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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 8(9): 1466-1475, 1990.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. Wadler S, Lembersky B, Atkins M, et al.: Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group Study. Journal of Clinical Oncology 9(10): 1806-1810, 1991.
  19. 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.
  20. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

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 or 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 or 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, radiotherapy, or biologic therapy. Refer to the PDQ protocol file for active protocols 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), there is no consistent evidence that adjuvant 5-FU plus levamisole is associated with an overall improved survival compared with surgery alone.[1] In some trials, subset analysis of adjuvant chemotherapy has demonstrated benefits in disease-free and overall survival compared with surgery alone,[2,3] but such treatment has not been considered standard for all stage II patients. Improved local control with postoperative radiotherapy has been reported in patients with B3 tumors; an intergroup protocol is exploring the role of adjuvant combined chemotherapy and radiotherapy compared with postoperative chemotherapy alone for selected patients with this high-risk stage II colon cancer.[4,5]

References:

  1. 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.
  2. 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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 11(10): 1879-1887, 1993.
  3. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.
  4. Willett CG, Tepper JE, Skates SJ, et al.: Adjuvant postoperative radiation therapy for colonic carcinoma. Annals of Surgery 206(6): 694-698, 1987.
  5. 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 06/96), NCCTG-914652, clinical trial, active, 10/16/92.

STAGE III COLON CANCER


Stage III or Dukes' C or Modified Astler-Coller C1-C3

Stage III colon cancer denotes lymph node involvement. Recent studies have indicated that the number of lymph nodes involved affects prognosis: patients with 1-3 involved nodes have a significantly better survival than those with 4 or more involved nodes. Improved local control with postoperative radiotherapy has been suggested in patients with adherence or fixation to adjacent structures.[1] (Refer to discussion of adjuvant therapy in the treatment overview.)

In the late 1980s, a passive immunotherapy approach to adjuvant treatment of stage III colorectal cancer yielded encouraging results in a single randomized German trial of moderate size.[2] This trial tested postoperative administration of a murine monoclonal antibody to 17-1a antigen, a cell surface glycoprotein of uncertain function expressed on both normal and malignant epithelial cells. Treated patients appeared to have a survival benefit comparable to that seen in adjuvant chemotherapy trials. However, the small size of this trial was associated with a wide confidence interval for the observed benefit. Therefore, this result remains to be confirmed. Other adjuvant immunotherapeutic approaches, including autologous tumor vaccines,[3] are also under investigation.

Treatment options:

1. Wide surgical resection and anastomosis. For patients who are not protocol candidates, postoperative chemotherapy with fluorouracil (5-FU)/levamisole should be given.[4-7] Studies of adjuvant chemotherapy with 5-FU/leucovorin with or without levamisole, have been completed. Although one trial has shown that 5-FU/leucovorin is superior to MOF,[8] there is no data to suggest that 5-FU/leucovorin is better than the standard regimen of 5-FU/levamisole. Whether 5-FU/leucovorin, with or without levamisole, is better than the standard regimen of 5-FU/levamisole is unknown at this time but has been addressed in recently completed randomized-controlled trials.[6,9]
2. Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens, postoperative radiotherapy, or biological therapy, alone or in combination.[10] Refer to the PDQ protocol file for active protocols for patients with stage III colon cancer.

References:

  1. Willett CG, Tepper JE, Skates SJ, et al.: Adjuvant postoperative radiation therapy for colonic carcinoma. Annals of Surgery 206(6): 694-698, 1987.
  2. Riethmuller G, Schneider-Gadicke E, Schlimok G, et al.: Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet 343(8907): 1177-1183, 1994.
  3. 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, 01/03/96.
  4. 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.
  5. 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.
  6. 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, 12/31/90.
  7. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.
  8. 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 [Prior Annotation Incorrect]. Journal of Clinical Oncology 11(10): 1879-1887, 1993.
  9. 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 03/92), EST-2288, clinical trial, closed, 07/30/92.
  10. 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

Stage IV colon cancer (added by Turnbull, 1967) denotes distant metastatic disease. Evidence suggests that resection of limited hepatic or pulmonary metastases may enhance survival in some patients if resection results in no clinically apparent residual tumor.[1-5] The administration of chemotherapy intra-arterially with improved implantable infusion ports and pumps is one approach to the treatment of liver metastases.[6] Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced a higher overall response rate but no consistent improvement in survival.[7-9] Several studies show increased local toxicity, including liver function abnormalities and fatal biliary sclerosis. In addition, local ablative techniques for elimination of liver metastases have been used, including cryosurgery, embolization, ultrasound, and interstitial radiotherapy.[10]

In stage IV and recurrent colon cancer, chemotherapy has been used for palliation, with fluorouracil (5-FU)-based treatment considered to be standard.[11] Combination chemotherapy has not been shown to be more effective than 5-FU alone. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin,[12-18] methotrexate,[19] or other agents.[20-24] Interferon alfa appears to add toxicity but no clinical benefit to 5-FU therapy.[25,26] Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, again with variable effects on median survival. The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and the toxicity profile of the chosen regimen, as well as cost and quality-of-life issues.[27] CPT-11 (irinotecan) is a topoisomerase-I inhibitor with phase II activity in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.[28,29] Diarrhea is the dose-limiting toxicity of CPT-11. The drug is still investigational. Another investigational drug, Tomudex, is a specific thymidylate synthase inhibitor. In phase II and III trials, the activity of Tomudex appears equivalent to 5-FU with leucovorin. Both Tomudex and CPT-11 await further evaluation in the United States to establish their respective roles in the management of metastatic colorectal cancer.

Treatment options:

1. Surgical resection/anastomosis or bypass of obstructing primary lesions in selected cases.
2. Surgical resection of isolated metastases (liver, lung, ovaries).[1,3,5,6,30,31]
3. Palliative radiotherapy.
4. Palliative chemotherapy.
5. Clinical trials investigating new drugs and biologic 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. 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.
  6. Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. Journal of Clinical Oncology 8(11): 1885-1893, 1990.
  7. Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Annals of Internal Medicine 107(4): 459-465, 1987.
  8. Chang AE, Schneider PD, Sugarbaker PH, et al.: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Annals of Surgery 206(6): 685-693, 1987.
  9. Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion floxuridine in patients with liver metastases from colorectal carcinoma:long-term results of a prospective randomized trial. Journal of Clinical Oncology 10(7): 1112-1118, 1992.
  10. 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.
  11. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Buroker TR, O'Connell MJ, Wieand HS, et al.: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Journal of Clinical Oncology 12(1): 14-20, 1994.
  18. Jager E, Heike M, Bernhard H, et al.: Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Journal of Clinical Oncology 14(8): 2274-2279, 1996.
  19. The Advanced Colorectal Cancer Meta-Analysis Project: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Journal of Clinical Oncology 12(5): 960-969, 1994.
  20. Kemeny N, Younes A, Seiter K, et al.: Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma: assessment of activity and toxicity. Cancer 66(12): 2470-2475, 1990.
  21. Wadler S, Lembersky B, Atkins M, et al.: Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group Study. Journal of Clinical Oncology 9(10): 1806-1810, 1991.
  22. Pazdur R, Ajani JA, Patt YZ, et al.: Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. Journal of Clinical Oncology 8(12): 2027-2031, 1990.
  23. The Corfu-A Study Group: Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. Journal of Clinical Oncology 13(4): 921-928, 1995.
  24. Hill M, Norman A, Cunningham D, et al.: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. Journal of Clinical Oncology 13(6): 1297-1302, 1995.
  25. Kosmidis PA, Tsavaris N, Skarlos D, et al.: Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Journal of Clinical Oncology 14(10): 2682-2687, 1996.
  26. Greco FA, Figlin R, York M, et al.: Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. Journal of Clinical Oncology 14(10): 2674-2681, 1996.
  27. Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. Journal of Clinical Oncology 13(6): 1303-1311, 1995.
  28. 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.
  29. 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.
  30. Adson MA, van Heerden JA, Wagner JS, et al.: Resection of hepatic metastases from colorectal cancer. Archives of Surgery 119(6): 647-651, 1984.
  31. Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. Annals of Surgery 202(2): 203-208, 1985.
  32. Kemeny N: Review of regional therapy of liver metastases in colorectal cancer. Seminars in Oncology 19(2, Suppl 3): 155-162, 1992.

  33. Kemeny N, Cohen A, Seiter K, et al.: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer. Journal of Clinical Oncology 11(2): 330-335, 1993.

RECURRENT COLON CANCER

Treatment of recurrent colon cancer depends upon the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. Unique approaches to treating liver metastases include resection of metastases and/or intra-arterial chemotherapy using improved implantable infusion ports and pumps.[1-3] Hepatic intra-arterial chemotherapy with floxuridine has produced a higher overall response rate but no consistent improvement in survival, even when combined with resection of hepatic metastases.[1,4] Several studies show increased local toxicity, including liver function abnormalities and fatal biliary sclerosis.[5-7] Local ablative techniques for elimination of liver metastases have been used, including cryosurgery, embolization, and ultrasound techniques.[8,9] However, some evidence suggests that survival may be enhanced in some patients if resection results in no remaining measurable tumor.[10-12] Locally recurrent colon cancer, such as a suture line recurrence, may be resectable, particularly if an inadequate prior operation was performed. Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly-selected patients.[13,14]

In stage IV and recurrent colon cancer, chemotherapy has been used for palliation, with fluorouracil (5-FU)-based treatment considered to be standard.[15] Combination chemotherapy has not been shown to be more effective than 5-FU alone. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin,[16-22] methotrexate,[23] or other agents.[24-28] Interferon alfa appears to add toxicity but no clinical benefit to 5-FU therapy.[29,30] Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, again with variable effects on median survival. The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and the toxicity profile of the chosen regimen, as well as cost and quality-of-life issues.[31] CPT-11 (irinotecan) is a topoisomerase-I inhibitor with phase II activity in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.[32,33] Diarrhea is the dose-limiting toxicity of CPT-11. The drug is still investigational. Another investigational drug, Tomudex, is a specific thymidylate synthase inhibitor. In phase II and III trials, the activity of Tomudex appears equivalent to 5-FU with leucovorin. Both Tomudex and CPT-11 await further evaluation in the United States to establish their respective roles in the management of metastatic colorectal cancer.

Treatment options:

1. Resection of liver metastases in selected patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%).[1,10,12,34-37]
2. Resection of isolated pulmonary or ovarian metastases.
3. Palliative radiotherapy.
4. Palliative chemotherapy.[16-19,21,38]
5. Biological therapy protocols.
6. Chemotherapy protocols in phase I and II clinical trials, mostly relating to biochemical modulation of fluoropyridines and continuous-infusion schedules.[39,40]

References:

  1. Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. Journal of Clinical Oncology 8(11): 1885-1893, 1990.
  2. Kemeny N, Cohen A, Seiter K, et al.: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer. Journal of Clinical Oncology 11(2): 330-335, 1993.
  3. 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.
  4. Meta-Analysis Group in Cancer: Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Journal of the National Cancer Institute 88(5): 252-258, 1996.
  5. Chang AE, Schneider PD, Sugarbaker PH, et al.: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Annals of Surgery 206(6): 685-693, 1987.
  6. Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Annals of Internal Medicine 107(4): 459-465, 1987.
  7. Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. Journal of Clinical Oncology 10(7): 1112-1118, 1992.
  8. Ravikumar TS, Steele G, Kane R, et al.: Experimental and clinical observations on hepatic cryosurgery for colorectal metastases. Cancer Research 51(23, Part 1): 6323-6327, 1991.
  9. 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.
  10. 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.
  11. 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.
  12. Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110(1):13-29, 1991.
  13. McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Annals of Thoracic Surgery 53(5): 780-786, 1992.
  14. 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.
  15. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Buroker TR, O'Connell MJ, Wieand HS, et al.: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Journal of Clinical Oncology 12(1): 14-20, 1994.
  22. Jager E, Heike M, Bernhard H, et al.: Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Journal of Clinical Oncology 14(8): 2274-2279, 1996.
  23. The Advanced Colorectal Cancer Meta-Analysis Project: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Journal of Clinical Oncology 12(5): 960-969, 1994.
  24. Wadler S, Lembersky B, Atkins M, et al.: Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group Study. Journal of Clinical Oncology 9(10): 1806-1810, 1991.
  25. Kemeny N, Younes A, Seiter K, et al.: Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma: assessment of activity and toxicity. Cancer 66(12): 2470-2475, 1990.
  26. Pazdur R, Ajani JA, Patt YZ, et al.: Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. Journal of Clinical Oncology 8(12): 2027-2031, 1990.
  27. The Corfu-A Study Group: Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. Journal of Clinical Oncology 13(4): 921-928, 1995.
  28. Hill M, Norman A, Cunningham D, et al.: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. Journal of Clinical Oncology 13(6): 1297-1302, 1995.
  29. Kosmidis PA, Tsavaris N, Skarlos D, et al.: Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Journal of Clinical Oncology 14(10): 2682-2687, 1996.
  30. Greco FA, Figlin R, York M, et al.: Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. Journal of Clinical Oncology 14(10): 2674-2681, 1996.
  31. Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. Journal of Clinical Oncology 13(6): 1303-1311, 1995.
  32. 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.
  33. 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.
  34. Adson MA, van Heerden JA, Wagner JS, et al.: Resection of hepatic metastases from colorectal cancer. Archives of Surgery 119(6): 647-651, 1984.
  35. Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. Annals of Surgery 202(2): 203-208, 1985.
  36. Gayowski TJ, Iwatsuki S, Madariaga JR, et al.: Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 116(4): 703-711, 1994.
  37. Fernandez-Trigo V, Shamsa F, Sugarbaker PH, et al.: Repeat liver resections from colorectal metastasis. Surgery 117(3): 296-304, 1995.
  38. Poon MA, O'Connell MJ, Moertel CG, et al.: Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. Journal of Clinical Oncology 7(10): 1407-1418, 1989.
  39. Wadler S, Wiernik PH: Clinical update on the role of fluorouracil and recombinant interferon alfa-2a in the treatment of colorectal carcinoma. Seminars in Oncology 17(1, Suppl 1): 16-21, 1990.
  40. Grem JL, Jordan E, Robson ME, et al.: Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. Journal of Clinical Oncology 11(9): 1737-1745, 1993.

Return to Colon Library Index  | Top

About Medicine OnLine
MOL HomeLibrariesDoseCalcOncology News
ForumsSearchCancer LinksGlossary