Adjuvant therapy for colorectal cancer (Reprinted from Curr Probl Surg, vol 34, pg 601-676, 1997)

The cure rate for patients with colorectal cancer depends on early diagnosis, successful operation, and appropriate use of adjuvant therapy. Long-term strategies of prevention through diet or nutritional supplements and screening of not only the high-risk subsets but the entire population may ultimately affect the mortality rate for patients with this disease in Western countries. At present, however, successful operative resection has the greatest impact on the cure of patients with established disease. For patients with colon cancer, the surgical management involves local-regional control by resection of the primary tumor and the regional lymph nodes based on well-established surgical principles. The major surgical issue under investigation is the role of laparoscopic-assisted colectomy in these patients. For patients with rectal cancer, there has been a wide variation in the ability to control local-regional disease, apparently based on the surgical technique. A small subset of patients with early cancer are amenable to local excision and radiation therapy, a situation very similar to breast cancer treatment. Patients with transmural or node-positive rectal cancer appear to be best treated operatively by radical resection. This procedure maximizes tumor clearance at the lateral margins and improves the local control rate. Patients with node-positive colon cancer have a high incidence of systemic micrometastases, and randomized trials have demonstrated approximately a one-third reduction in cancer-related mortality from the use of adjuvant chemotherapy. This issue of Current Problems in Cancer reviews both regional and systemic chemotherapy and future directions in clinical trials. Although in selected specialty centers the local-regional recurrence rate after radical resection for rectal cancer is less than 10%, results from a wide variety of centers throughout the United States indicate a 20% to 25% local relapse rate in patients with transmural or node-positive rectal cancer. In addition, in patients with node-positive cancer the presence of systemic micrometastatic disease exceeds 50%. For patients with extraperitoneal rectal cancer (below the peritoneal reflection), overall local control and overall survival are maximized by the use of combined chemoradiation therapy. The questions of which chemotherapy drug combination and the sequence of operation, chemotherapy, and radiation therapy regarding overall cancer control and patient functional outcome with sphincter-preserving surgery is the basis of current clinical trials. After 2 decades of nonproductive studies of adjuvant chemotherapy for colorectal cancer, large clinical trials over the past decade conclusively demonstrate a survival benefit when patients with node-positive colon cancer receive adjuvant chemotherapy. One-year treatment with 5-fluorouracil (5FU) and levamisole reduces the cancer-related mortality by approximately one third. Recently completed trials in Europe and the United States indicate that identical benefit is obtained with a 6-month course of 5FU modulated with leucovorin. A recent multicenter trial from Germany suggests a survival benefit with murine monoclonal antibody 17-1A.A current trial is exploring the potential incremental benefit of such immunotherapy in addition to conventional adjuvant chemotherapy. Data suggest the benefit in patients with node-negative colon cancer is minimal, and adjuvant chemotherapy should be offered only to highly selected high-risk patients with node-negative cancer. Indicators of increased risk include obstruction or perforation, high grade, aneuploidy, and certain molecular markers. Adjuvant therapy is generally advised for patients with rectal cancer who have transmural extension and positive lymph nodes. Patients with upper-rectal and rectosigmoid tumors should be treated under the colon guidelines. In almost all instances, adjuvant therapy involves combined systemic chemotherapy and pelvic radiation therapy. The exact sequence and choice of agents remain uncertain. Randomized clinical trials with surgery-alone arms demonstrate a 50% reduction in local failure rates and approximately a 20% improvement in the overall survival rate with postoperative chemoradiation therapy. The most common combined modality strategy is operation followed by 2 months of chemotherapy, 6 weeks of chemoradiation, and then 2 additional months of chemotherapy. The concurrent chemoradiation should be either infusional 5FU or bolus 5FU and leucovorin. Preoperative radiation or chemoradiation, operation, and postoperative chemotherapy is the preferred sequence for locally advanced, tethered, or fixed rectal cancers. Because retrospective studies indicate that preoperative radiation appears to be well tolerated and perhaps is associated with better local control, combined with the observation that postoperative radiation therapy adversely affects late bowel function, two randomized trials comparing the preoperative with the postoperative sequences for the patients with more common resectable transmural rectal cancer are ongoing. Outcomes will be not only overall survival but also local failures and late bowel function. A small subset of patients with early rectal cancer may be treated by full-thickness local excision either transanally or through a posterior proctotomy. Patients with low-grade exophytic T1 lesions require no further therapy. The remainder of patients are at risk for mural or nodal local and distant failure and should receive postoperative chemoradiation. Patients with locally advanced rectal cancer remain a therapeutic challenge. Radical resection followed by high-dose pelvic radiation is associated with a 50% local failure pattern. High-dose preoperative chemoradiation results in a 75% resectability rate but a persistent 30% to 40% local failure rate despite negative margins. Despite the absence of randomized trials, data from the major centers with intraoperative radiation facilities indicate that the strategy of preoperative chemoradiation, radical resection, and intraoperative radiation boosting reduces the local failure rate to 10%, with approximately a 50% longterm survival. Intraoperative radiation boosting is feasible with electron beam, high-dose rate iridium-192, iodine-125 suture seeds, or iridium-192 afterloading systems. The high-dose rate iridium-192 system is probably the most realistic for widespread use, at least in major medical centers.