Resection of the primary colonic or rectal cancer is the treatment of choice for almost all patients who have resectable lesions and can tolerate general anesthesia. Multiple studies demonstrate that minimally invasive, laparoscopically assisted colectomy results in similar outcomes and rates of recurrence to open colectomy. Regional lymph node dissection should be performed to determine staging, which guides decisions about adjuvant therapy. Even patients with extensive metastatic disease may benefit from resection of the colonic tumor to reduce the likelihood of intestinal obstruction or serious bleeding.

For rectal carcinoma, the operative approach depends on the level of the tumor above the anal verge, the size and depth of penetration, and the patient’s overall condition. Clinical staging by endorectal ultrasound or MRI with endorectal coil is important in guiding the clinical approach. In carefully selected patients with small, mobile (< 4 cm), well-differentiated T1 or T2 rectal tumors that are less than 8 cm from the anal verge and that appear on endosonography to be localized to the rectal wall, transanal excision may be performed. This approach avoids laparotomy and spares the rectum and anal sphincter, preserving normal bowel continence. All other patients will require either a low anterior resection with a colorectal anastomosis or an abdominoperineal resection with a colostomy, depending on how far above the anal verge the tumor is located and the extent of local tumor spread.

Careful dissection of the entire mesorectum at the time of surgery has been shown to reduce local recurrence to 8%. With improvements in surgical stapling techniques, it is possible to perform low anterior resection provided there is a margin of at least 2 cm of normal tissue below the tumor. Although low resections obviate a colostomy, they are associated with increased immediate postsurgical complications (leak, dehiscence, stricture) and defecatory complaints (increased stool frequency, defecatory problems, and incontinence). With unresectable rectal cancer, the patient may be palliated with a diverting colostomy, laser fulguration, or placement of an expandable wire stent.

A. Adjuvant Therapy for Colon Cancer

Adjuvant chemotherapy and radiotherapy have been demonstrated to improve overall and tumor-free survival in selected patients with colon cancer.

1. Stage I - Because of the excellent 5-year survival rate (90-100%), no adjuvant therapy is recommended.

2. Stage II (node-negative disease) - The expected 5-year survival rate is 80%. A benefit from adjuvant chemotherapy has not been demonstrated in most controlled trials for stage II colon cancer (see discussion for stage III disease). However, otherwise healthy patients with stage II disease that is at higher risk for recurrence (perforation, T4, poor differentiation on histology) may benefit from adjuvant chemotherapy.

3. Stage III (node-positive disease) - With surgical resection alone, the expected 5-year survival rate is 30-50%. Postoperative adjuvant chemotherapy significantly increases disease-free survival as well as overall survival and is recommended for all patients. In stage III colorectal cancer, patients treated for 6 months with intravenous 5-fluorouracil (5-FU) (bolus or continuous infusion) and leucovorin (folinic acid) who have one to three involved nodes have a 5-year survival of 65%, and those with more than three involved nodes have a 5-year survival of up to 40%. Therefore, until recently, adjuvant therapy with 5-FU and leucovorin was most widely used for stage III disease. An important recent advance was the development of an oral 5-FU analog, capecitabine, which obviates the need for intravenous infusions. Monotherapy with capecitabine yields a similar rate of disease-free survival with a lower rate of serious side effects compared with intravenous 5-FU and leucovorin. A further important advance has been the FDA approval of oxaliplatin for combination adjuvant therapy. Large, well-designed studies of adjuvant therapy for stage II and III colon cancer reported a higher rate of disease-free survival at 3-4 years for patients treated with a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) (76%) than with fluorouracil and leucovorin (FL) alone (69%). The addition of oxaliplatin was associated with an increased incidence of neutropenia and sensory neuropathy, which generally is reversible. Based on these studies, FOLFOX currently is the preferred adjuvant therapy for most patients with Stage III disease. Current studies are evaluating oral capecitabine in combination with oxaliplatin. The role of combination adjuvant therapy of FOLFOX plus a biologic agent (bevacixumab, cetuximab, or panituxumab) also is under investigation.

4. Stage IV (metastatic disease) - Approximately 20% of patients have metastatic disease at the time of initial diagnosis, and another 30% eventually develop metastasis. The long-term survival of these patients is only 5%, and the median survival is only 6 months in the absence of other treatment. Resection of isolated (one to three) liver or lung metastases may result in long-term (over 5 years) survival in 35-55% of cases. For those with unresectable hepatic metastases, local ablative techniques (cryosurgery, radiofrequency or microwave coagulation, embolization, hepatic intra-arterial chemotherapy) may provide long-term tumor control. Approximately 20% of patients with metastatic disease respond to chemotherapy regimens containing intravenous 5-FU and folinic acid (leucovorin) or the oral 6-FU analog capecitabine, prolonging median survival to about 11 months. However, the addition of either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI; IFL) to 5-FU and folinic acid provides further improvement in tumor response rate (40%) and median survival (15-20 months). Currently, FOLFOX and FOLFIRI are the preferred first-line treatment regimens for most patients with metastatic colorectal cancer. Patients progressing with one regimen may respond to the alternative regimen, prolonging mean survival to > 20 months. The role of oral capecitabine (instead of intravenous 5-FU) in combination with oxaliplatin or irinotecan is under investigation. The most recent advance in the treatment of metastatic colon cancer is the development of the biologic agents, cetuximab, panitumumab, and bevacizumab. The role of these agents is rapidly evolving. Cetuximab and panitumumab are monoclonal antibodies to EGFR; bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF). Combination therapy with bevacizumab and FOLFOX or FOLFIRI prolong mean survival 2-5 months compared with either regimen alone. Therefore, many oncologists are now using one of these combinations for initial therapy of metastatic disease. Bevacizumab may cause serious thromboembolic events (including stroke and myocardial infarction) in 5% of patients. Cetuximab and panitumumab have modest efficacy when used as single agents for second-line therapy in patients whose disease has progressed on chemotherapeutic regiments containing 5-FU, irinotecan, or oxaliplatin. The role of these agents in combination with FOLFOX and FOLFIRI is under investigation. Similarly, the role of combination therapy of bevacizumab plus cetuximab or panitumumab with or without other agents requires further study.

B. Adjuvant Therapy for Rectal Cancer

Compared with colon cancer, rectal cancer has lower long-term survival rates and significantly higher rates of local tumor recurrence (25%) due to the difficulty of achieving adequate surgical resection margins. Combination therapy with fluorouracil and radiation has been shown to improve the disease-free survival rate and to decrease pelvic recurrence and is recommended for all patients with stage II and stage III rectal cancers. It has long been controversial whether chemoradiation should be administered preoperatively (“neoadjuvant”) or postoperatively (“adjuvant”). Neoadjuvant therapy may decrease the size of the tumor before surgery (tumor downstaging), allowing more patients to undergo curative resection with sphincter preservation rather than abdominoperineal resection. When initial imaging studies suggest stage I disease, surgery may be performed first, followed by postoperative chemoradiation in patients found at surgery to have more advanced (stage II or III) disease. A recent, large, randomized controlled trial reported that preoperative therapy led to better patient treatment compliance, reduced local recurrence and toxicity, and a higher number of sphincter-preserving resections. Therefore, preoperative chemoradiation increasingly is recommended for patients with distal rectal cancers that are determined to be stage II or III by endorectal ultrasound or MRI.

Rebecca A. Barnetson and Malcolm G. Dunlop
Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K.

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