The initial management strategy in patients who present with distant metastases from colorectal cancer is controversial. Commonly, patients are treated initially with surgery followed by systemic therapy, and symptomatic patients should be considered for surgical palliation prior to being offered chemotherapy. However, nonsurgical options for asymptomatic patients have gained popularity as the chemotherapy regimens become more effective. Initial chemoradiation has been used with some success instead of nontherapeutic colostomy in rectal cancer patients when systemic options were more limited. Durable symptomatic palliation was achieved in 80% of patients and colostomy was avoided in 90%. The clinical activity and survival improvements for colorectal cancer patients who have been seen with the new chemotherapeutic regimens introduced in recent years makes the use of front-line chemotherapy very appealing in patients with synchronous metastatic and asymptomatic intact primary disease. However, surgery and radiotherapy should be considered for symptomatic patients.

LOCAL RECURRENCE  
In contrast to rectal cancer, colon cancer is frequently resected with wide negative margins and local recurrences are less of a problem. In a retrospective analysis, patients with T4 N0 or T4 N1 colon cancer were first shown to have an approximately 30 to 50% local failure rate and a 10% isolated local failure rate. Subsequently, postoperative radiation was used and higher local disease control and disease-free survival rates were seen in these patients. The indications for postoperative chemoradiation (50.4 Gy to the tumor bed) are invasion of surrounding organs and tumor perforation of the visceral peritoneum (T4 disease).

This therapy is typically given with concurrent continuous infusion of 5-FU and integrated with the adjuvant chemotherapy. The results of the only randomized trial evaluating the role of postoperative chemoradiation in patients with colon cancer who had either T3 N1 or T3 N2 or tumor adherence to or invasion of surrounding structures have been published. Patients were randomized to receive bolus 5-FU and levamisole for one year with or without radiotherapy. There was no detectable difference in overall survival between the two arms, but the authors acknowledge that clinically significant differences in survival could not be excluded because the study was terminated early owing to poor accrual.

Local recurrence after surgery alone for operable rectal cancer has been reported to be between 25 and 50% for stage II and III rectal adenocarcinoma. These high recurrence rates are probably the result of incomplete dissection of the mesorectum. However, with total mesorectal excision, the risk of local recurrence is significantly lower. In the Dutch total mesorectal excision trial, a randomized prospective trial, local recurrence was 8.2% after total mesorectal excision (TME) alone for resectable rectal cancer.

The major risk factors for pelvic tumor recurrence include nodal involvement and tumor penetration beyond the bowel wall (T3 and T4 disease). Extension of tumor into the perirectal fat or adjacent viscera increases the rate of local recurrence to approximately 25 to 50% with surgery alone. The extent of tumor penetration beyond the bowel wall is also a significant factor predicting for recurrence risk. Willet and colleagues examined a group of patients with T3 N0 rectal cancer who underwent resection alone. Surgical specimens were assessed for maximum depth of tumor invasion into perirectal fat, lymphatic or venous involvement, and tumor grade. Local tumor control correlated with increasing extent of tumor penetration beyond the rectal wall. Tumor penetration more than 2 mm led to a > 20% local recurrence rate. In 25 patients with tumors with favorable histological features (well-differentiated or moderately well-differentiated carcinomas invading less than 2 mm into perirectal fat, without lymphatic or venous vessel involvement), the 10-year actuarial rates of local control and recurrence-free survival were 95% and 87%, respectively. The anatomic location of the tumor also correlates with the risk of tumor recurrence. Tumors that are lower in the pelvis are more difficult to resect with wide negative margins because of physical anatomic restrictions. Several clinical experiences bear this out, including the Dutch TME Trial. Although the factors are probably interrelated, the width of radial margins of resection has also been correlated with the risk of pelvic tumor recurrence in patients who undergo surgery alone. In the Dutch TME Trial, patients who were randomized to total mesorectal excision alone whose resected tumors had at least a 1 cm negative radial margin had 5-year pelvic tumor recurrence risk of less than 5%. A margin of ≤ 2 mm was associated with a local recurrence risk of 16% (p

< .0001). The radial margin of excision can also serve as an indicator of the quality of the surgery. In the Dutch trial, in a sample of 656 patients who underwent total mesorectal excision alone, 18.3% (n = 120) had a positive circumferential margin after curative resection. Patients undergoing abdominoperineal resection (APR) had a higher incidence (28.8%) than those undergoing low anterior resection (LAR) (13.5%). Distant metastases occurred in 37.6% of patients with positive circumferential margins, whereas it was 12.7% in patients with > 1 cm margin. Systematic macroscopic evaluation of the mesorectum was performed in 180 specimens of patients undergoing TME. Almost 24% of the patients had an incomplete mesorectal excision as defined by the pathologist. Even though the follow-up was short, there was a statistically significant difference in survival in patients with a macroscopically incomplete TME. However, there was no statistically significant difference in local recurrence.

In the INT-0114, lower body mass index and female sex correlated with sphincter preservation. Obese men, but not obese women, had significantly worse sphincter preservation and pelvic control. These outcomes are possibly related to the mechanical difficulties associated with adiposity and with operating in the comparatively narrow male pelvis. In summary, the major risk factors for tumor recurrence in patients with resected rectal cancer treated with resection alone include tumor penetration of the muscularis propria (and the extent of penetration), nodal involvement, the number of negative nodes in node-negative patients, and the width of the radial margin. The ability to achieve negative margins and optimize pelvic tumor control is also related to adiposity in male patients. Other favorable factors for local control that are probably not independent include tumor grade and lymphovascular space invasion. Thus a highly selected subgroup of patients with T3 N0 tumors and T1-2 N1 tumors, may have a low risk of tumor recurrence with no further therapy. This concept would be an interesting one to study on a prospective trial.

Miguel A. Rodriguez-Bigas, MD, Paulo Hoff, MD, Christopher H. Crane, MD

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