Rectal Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Treatment Option Overview
National Surgical Adjuvant Breast and Bowel Project (NSABP)
The NSABP R-03 trial similarly compared preoperative with postoperative chemoradiation therapy for patients with clinical T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of fluorouracil and leucovorin 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]
Postoperative Chemoradiation Therapy
Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy with radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomized clinical trials from the Gastrointestinal Tumor Study Group (GITSG-7175), the Mayo/North Central Cancer Treatment Group (NCCTG-794751), and the National Surgical Adjuvant Breast and Bowel Project (NSABP-R-01).[10,11,12][Level of evidence: 1iiA] These studies demonstrated an increase in both disease-free survival (DFS) interval and OS when radiation therapy was combined with chemotherapy after surgical resection. Following publication of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference in 1990 concluded that postoperative combined-modality treatment is recommended for patients with stage II and III rectal carcinoma.
Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems. The agents associated with the first successful combined-modality treatments were 5-FU and semustine. Semustine is not commercially available, and previous studies have associated this drug with the potential for increased risks of renal toxic effects and leukemia.
A follow-up randomized trial from GITSG demonstrated that semustine does not produce an additive survival benefit to radiation therapy and 5-FU.[Level of evidence: 1iiA] The Intergroup 86-47-51 trial (NCCTG-864751 [MAYO-864751]) showed a 10% improvement in OS with the use of continuous-infusion 5-FU (225 mg/m2 /day) throughout the course of radiation therapy when compared with bolus 5-FU (500 mg/m2 times three injections in the first and fifth weeks of radiation).[Level of evidence: 1iiA]
Subsequently, several studies attempted to determine the optimal way to deliver adjuvant 5-FU. The final results of Intergroup 0114 (INT-0114 [CLB-9081]) demonstrated no survival or local control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[Level of evidence: 1iiA] Another study, Intergroup 0144 (SWOG-9304 [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.
- Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m2 /day) and after (450 mg/m2 /day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m2 /day) during radiation therapy.
- Arm 2 received continuous infusion 5-FU before (300 mg/m2 /day for 42 days), after (300 mg/m2 / day for 56 days), and during (225 mg/m2 /day) radiation therapy.
- Arm 3 received bolus 5-FU plus LV (5-FU/LV) in two 5-day cycles before (5-FU 425 mg/m2 /day; LV 20 mg/m2 /day) and after (5-FU 380 mg/m2 /day; LV 20 mg/m2 /day) radiation therapy, and bolus 5-FU/LV (5-FU 400 mg/m2 /day; leucovorin 20 mg/m2 /day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.