Cancer of the Colon
General Information
Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of 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. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. 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. Microsatellite instability, also associated with hereditary nonpolyposis colon cancer, has 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.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. Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.
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) or Lynch SyndromeVariants I and II, and ulcerative colitis. 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. 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. 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.
Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease. However, 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. 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. 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. New surveillance methods including CEA immunoscintigraphy and positron emission tomography are under clinical evaluation.
Treatment Options
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 in the treatment of colon cancer is under evaluation in a prospective randomized trial comparing laparoscopic colectomy to open colectomy. The role of sentinel lymph node mapping is also under clinical evaluation.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.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. 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 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.
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.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. 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. 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. 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. This study also demonstrated that 6 months of 5-FU plus leucovorin is at least as effective as 12 months of 5-FU/levamisole. The NSABP C-04 study found equivalent results in overall survival for 1 year of 5-FU plus high-dose leucovorin when compared to 1 year of 5-FU plus levamisole. The addition of levamisole to 5-FU and leucovorin did not improve disease-free or overall survival. 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.
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. The preliminary results of these studies have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences. 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. 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. However, the Intergroup currently has an open trial that tests the hypothesis of perioperative systemic delivery of 5-FU chemotherapy.
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. However, a randomized trial of post-operative 5-FU plus levamisole compared to surgery alone showed no survival advantage to postoperative adjuvant chemotherapy. 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. Patients with stage II colon cancer remain candidates for clinical trials in which either surgery alone or 5-FU/leucovorin represents standard therapy.
Chemotherapy trials, typically with 5-FU-based regimens, have demonstrated increased numbers of partial responses and prolongation of the time to progression of disease, as well as improved survival and quality of life for patients receiving chemotherapy compared to best supportive care. 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.Patients should be considered candidates for clinical trials evaluating new approaches to treatment. 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. It has been approved by the Food and Drug Administration for the treatment of patients with metastatic disease that is refractory to 5-FU.
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