Rectal Cancer Treatment (Professional) (cont.)
IN THIS ARTICLE
Stage II Rectal Cancer
Prior to the standard use of preoperative chemoradiation for stage II and III rectal cancer, several studies established the benefits of adjuvant combined-modality therapy for surgical stage II and III disease. Intergroup protocol 86-47-51 (MAYO-864751) demonstrated a 10% improvement in overall survival (OS) with the use of continuous-infusion 5-FU (225 mg/m2 /day throughout the entire course of radiation therapy) compared with bolus 5-FU (500 mg/m2 /day for three consecutive days during the first and fifth weeks of radiation).[Level of evidence: 1iiA] The final results of (CLB-9081) showed no survival or local-control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for patients with stage II and III rectal cancers at a median follow-up of 7.4 years.[Level of evidence: 1iiA]
Another study, (INT-0144 [NCT00002551]), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation and included the following:
Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3), versus 4% of patients in the continuous-infusion arm. No DFS, OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[Level of evidence: 1iiA]
The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3 orT4 or node-positive rectal cancer to either preoperative chemoradiation or postoperative chemoradiation (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy). All patients received a TME and an additional four cycles of 5-FU-based chemotherapy. The 5-year OS rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group as compared with 40% of the patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[Level of evidence: 1iA] There was no difference in the number of patients receiving an APR in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).
These results have now been updated with a median follow-up of 11 years. The 10-year overall survival (OS) is equivalent in both arms (10-year OS, 59.6% vs. 59.9%, P = .85). However, a local control benefit persists among patients treated with preoperative chemoradiation compared with postoperative chemoradiation (10-year cumulative of local relapse, respectively: 7.1% vs. 10.1%, P = .048). There were no significant differences detected for 10-year cumulative incidence of distant metastases or DFS. Among the patients assigned to the postoperative chemoradiation treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.
The NSABP R-03 similarly compared preoperative versus postoperative chemoradiotherapy for patients with clinically staged T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of 5-FU/LV with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients. With a median follow-up of 8.4 years, preoperative chemoradiation was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients, P = .011). Similar to the German Rectal Study, there was no significant difference seen in OS between treatment arms (74.5% vs. 65.6%, P =. 065 for preoperative vs. postoperative chemoradiation.)[Level of evidence: 1iiA]
Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.
Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with no further therapy after surgery have a very low risk of local and systemic recurrence. In addition, a pooled analysis of 3,791 patients enrolled in clinical trials demonstrated that, for patients with T3, N0 disease, the 5-year OS rate with surgery plus chemotherapy (84%) compared favorably with the survival rates of patients treated with surgery plus radiation and bolus chemotherapy (76%) or surgery plus radiation and protracted-infusion chemotherapy (80%). However, a multi-institutional retrospective analysis demonstrated that 22% of patients thought to have clinically node-negative T3 disease by ultrasound or magnetic resonance imaging were found, at the time of resection, to have positive mesorectal lymph nodes even after chemoradiation.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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