Colon cancer is a major public health problem. The primary treatment is resection. For patients with early-stage disease, surgery results in excellent survival rates. In contrast, patients with locally advanced tumors arising in "anatomically immobile" segments of large bowel have a less satisfactory outcome, in part secondary to compromised surgical clearance. Patterns-of-failure analyses suggest that for tumors that invade adjacent organs, exhibit perforation or fistula, or are subtotally resected, local failure rates exceed 30%. Multiple single-institution retrospective studies have shown improved local control and possibly survival with the addition of external irradiation and/or intraoperative radiation. In contrast, a recent Intergroup trial failed to show any benefit by the addition of adjuvant radiation therapy combined with chemotherapy. Interpretation of this trial's results is handicapped by low patient accrual. With the advent of novel and more effective systemic therapies for metastatic colon cancer, current and future clinical research will address the efficacy of these agents in the adjuvant setting. Adjuvant radiation therapy should be considered in patients with colon cancer at high risk for local failure.
Colorectal cancer remains a major worldwide health problem. In the United States alone it is estimated that there will be 145,290 patients diagnosed with colon cancer and 54,200 deaths this year. Worldwide, approximately 1 million new cases per year are diagnosed, with 529,000 deaths.
Most colon cancers arise in the mucosa, and more than 90% are adenocarcinomas. These tumors invade from the mucosa through the bowel wall into surrounding tissues. Lymphatic channel and subsequent lymph node involvement is common. Hematogenous metastases occur primarily in the lung and liver. In contrast to other gastrointestinal malignancies, colon cancer has little propensity to spread longitudinally within the bowel wall.
Clinical Manifestation and Staging
Colon cancer frequently produces minimal or no symptoms, highlighting the importance of screening programs. Many symptoms related to colon cancer are nonspecific, including changes in bowel habits, intermittent abdominal pain, weakness, and nausea and vomiting. Location of a malignancy within the colon influences clinical presentation. Specifically, right-sided colon cancers are frequently exophytic and may be associated with iron deficiency anemia due to occult blood loss. Over recent decades, the incidence of cancer of the right colon has increased and accounts for approximately one-third of large bowel cancers. Many of these are diagnosed at a later stage. Cancer of the left or sigmoid colon is often deeply invasive, annular, and accompanied by obstructive symptoms and rectal bleeding.
For patients with potentially resectable disease, pretreatment evaluation should include colonoscopy to establish pathologic confirmation of adenocarcinoma, to evaluate the extent of tumor, and to detect synchronous primary cancers, which occur in 3% to 5% of patients. Baseline blood counts with liver function tests and carcinoembryonic antigen levels should be obtained. Abdominal and pelvic computed tomography (CT) scan and chest x-ray/chest CT scan allow for evaluation of the extent of locoregional disease as well as the presence or absence of distant metastases. Positron-emission tomography, magnetic resonance imaging, and ultrasound may be useful in evaluating patients with oligometastatic disease who may be appropriate candidates for resection of distant metastases with curative intent. Figure 1 shows a diagnostic algorithm for the management of patients with potentially resectable colon cancer.
Prognostic factors influencing survival in colon cancer patients include depth of tumor invasion into and beyond the bowel wall, the number of involved regional nodes, and the presence or absence of distant metastases. These factors are included in the tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer (AJCC), which can be used as a clinical (preoperative) or postoperative staging system (Tables 1 and 2).
Surgery remains the primary treatment for patients with colon cancer. Approximately 75% of patients are candidates for resection at presentation. Surgical technique is based on large bowel anatomy and patterns of disease spread. Adenocarcinomas generally grow by direct extension into the bowel wall and submucosal lymphatics. Resection of sufficient lengths of bowel proximally and distally to the primary cancer avoids cutting across intramural lymphatics. Resection generally includes removal of the mesentery, where the major lymphatic drainage is located. The boundaries for resection of large bowel cancers are relatively uniform and include named blood vessels along with their associated draining lymphatics (Figure 2).
In patients with disease limited to the bowel wall without involved nodes, resection provides excellent cure rates (5-year survival rate of 97% for T1, N0; 85%-90% for T2, N0). When disease extends beyond the colonic wall (T3-4, N0) or involves locoregional lymph nodes (T0-2, N1-2), 5-year survival with surgery falls to approximately 65% to 75%. Adjuvant treatment is often indicated in these patients. For higher-risk patients with extension beyond the colonic wall and nodal involvement (T3-4, N1-2), 5-year survival ranges from 35% to 50% and adjuvant treatment is strongly recommended.
For more than a decade, fluorouracil (5-FU)-based chemotherapy has been considered standard adjuvant therapy for stage III colorectal cancer. Three major clinical trials defined the use of 5-FU/leucovorin chemotherapy as the standard of care for these patients. The first of these trials was National Surgical Adjuvant Breast and Bowel Project (NSABP) C-03, which randomized 1,081 patients with resected Dukes B and C colon cancer to either a regimen known as MOF (methyl-lomustine [CCNU, CeeNU], vincristine [Oncovin], 5-FU) or 5-FU/leucovorin. This trial showed a significant increase in 3-year disease-free survival (73% vs 64%) and overall survival (84% vs 77%) for the 5-FU/leucovorin group.
The IMPACT report pooled data from 1,526 patients with resected Dukes B or C colon cancer who were treated on one of three randomized clinical trials from Canada, Italy, and France. Patients were randomized to 5-FU and leucovorin given as a daily bolus on days 1 to 5 of a monthly cycle for 6 months, or observation. The 3-year overall survival rate was superior for the treated group (83% vs 78%), translating to a 22% reduction in mortality. The North Central Cancer Treatment Group (NCCTG) randomized 317 patients with resected high-risk stage II or III disease to bolus 5-FU and leucovorin delivered as the Mayo Clinic regimen (bolus 5-FU, 425 mg/m2, and leucovorin, 20 mg/m2, given on days 1 to 5 of a 28-day cycle) or observation.[6,7] Treated patients showed a statistically significant improvement in overall survival.
Recently, newer chemotherapy agents demonstrating benefit in patients with metastatic disease have been tested in the adjuvant setting. The benefit of oxaliplatin (Eloxatin) in the metastatic setting was shown by Goldberg et al in the Intergroup 9741 study. This trial randomized 795 patients with metastatic colorectal cancer to IFL (irinotecan [Camptosar], 5-FU, leucovorin), FOLFOX4 (a regimen of infusional 5-FU/leucovorin with oxaliplatin chemotherapy), or IROX (irinotecan, oxaliplatin). Compared to patients receiving IFL or IROX, patients receiving FOLFOX experienced an improved median survival (19.5 vs 15 vs 17.4 months; P < .05 for oxaliplatin vs non-oxaliplatin-containing regimens).
In the adjuvant setting, the MOSAIC study demonstrated the benefit of oxaliplatin. This trial randomized 2,246 patients with resected stage II/III colon cancer to FOLFOX4 or the same infusional 5-FU/leucovorin regimen alone. The 3-year disease-free survival in the FOLFOX4 group was significantly improved with the addition of oxaliplatin (78.2% vs 72.9%).
The beneficial role for oxaliplatin in the adjuvant setting was further confirmed with the results of NSABP C-07. This trial randomized 2,407 patients with resected stage II/III colon cancer to bolus 5-FU and leucovorin (5-FU, 500 mg/m2, and leucovorin, 500 mg/m2, given weekly for 6 out of 8 weeks for three cycles) or the same bolus 5-FU/leucovorin regimen plus oxaliplatin at 85 mg/m2 on weeks 1, 3, and 5 of each cycle. The addition to oxaliplatin resulted in a significant improvement in 3-year disease-free survival (76.5% vs 71.6%), similar to the MOSAIC study.
Irinotecan, a topoisomerase I inhibitor, has also been shown to improve survival when combined with 5-FU and leucovorin in the metastatic setting. Saltz et al reported a randomized trial comparing IFL, 5-FU/leucovorin, and irinotecan alone. Patients receiving IFL had an improved median survival and response rate compared to 5-FU/leucovorin alone (14.8 vs 12.6 months, 39% vs 21%, respectively, P < .05).
As with oxaliplatin, adjuvant trials have been reported using irinotecan in combination with 5-FU and leucovorin. However, these trials have not confirmed benefit. The first reported phase III trial of this combination was CALGB 89803, which randomized 1,264 patients with resected stage III disease to bolus irinotecan, 5-FU, and leucovorin or 5-FU/leucovorin alone. No significant difference in disease-free or overall survival was observed. In addition, patients receiving irinotecan had a significantly higher mortality rate during treatment (2.8% vs 1.0%), prompting premature closure of the trial.
The PETACC 3 study examined the use of irinotecan with an infusional 5-FU/leucovorin regimen. These investigators randomized 3,278 patients with resected stage II or stage III colon cancer to one of two infusional 5-FU/leucovorin regimens with irinotecan. Patients with stage III disease showed no statistically significant improvement in 3-year disease-free survival with the addition of irinotecan. Pooled data including stage II patients showed a significant (although marginal) benefit for disease-free survival (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.76-0.99).
Dr. Czito receives research funding from Roche, Sanofi-Aventis, and Genentech. Dr. Bendell is a consultant for Genentech.
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