Stage III Rectal Cancer
- Preoperative chemoradiation with fluorouracil (5-FU) for patients with clinically staged T3 or T4 rectal adenocarcinoma.
- Total mesorectal excision (TME) with either low anterior resection (LAR) or abdominoperineal resection (APR).
- Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.
- Four to six months of 5-FU-based chemotherapy postoperatively.
- Short-course preoperative radiation therapy followed by surgery and chemotherapy.
- A clinical trial.
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 course of radiation therapy) compared with bolus 5-FU (500 mg/m2/day for 3 consecutive days during the first and fifth weeks of radiation).[Level of evidence: 1iiA] The final results of Intergroup trial 0114 (CLB-9081) showed 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, 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 and included the following:[Level of evidence: 1iiA]
- 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/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; LV 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.
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 disease-free survival (DFS), OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; 3-year LRF, 4.6% to 8%).[Level of evidence: 1iiA]
The German Rectal Cancer Study Group (CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society]) randomly assigned 823 patients with ultrasound-staged T3 or T4 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 therapy and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxicity 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 toxicity 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 therapy (P = .004).
These results have now been updated with a median follow-up of 11 years. The 10-year 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 ultrasound 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 chemoradiation therapy 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 the 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.
Short-course Preoperative Radiation Therapy
Short-course radiation therapy before surgery has been a standard approach in parts of Europe and Australia. The use of short-course radiation therapy was evaluated in a randomized study in the Swedish Rectal Trial (NCT00337545).[Level of evidence: 1iiA] In the trial, 1,168 patients younger than 80 years with stage I to III resectable rectal adenocarcinoma were randomly assigned to receive preoperative radiation therapy (25 Gy in five fractions) or taken directly to surgery. Patients did not receive adjuvant chemotherapy. The 5-year OS rate was 58% in the radiation group and 48% in the surgery group (P = .005). The rate of local control was 11% in the radiation group and 27% in the surgery group (P < .001). Subsequently, the following two studies compared short-course preoperative radiation therapy with the standard long-course radiation therapy administered with 5-FU:
- In the Polish Rectal Trial, 312 patients with clinical stage T3 or T4 rectal cancer were randomly assigned to preoperative radiation therapy (25 Gy in five fractions) followed by TME within 7 days, 6 months of adjuvant 5-FU/LV or preoperative chemoradiation (50.4 Gy in 28 fractions with concurrent bolus 5-FU/LV), TME in 4 to 6 weeks after completion of radiation, and 4 months of adjuvant 5-FU/LV. The primary endpoint of the study was to detect a difference of at least 15% in sphincter preservation with a power of 80%. The rates of sphincter preservation were 61.2% in the short-course group and 58% in the chemoradiation group (P = .570). The actuarial 4-year survival rate was 67.2% in the short-course group and 66.2% in the chemoradiation group (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.69–1.48; P = .960). The HR for local recurrence in the short-course group compared with the chemoradiation group was 0.65 (95% CI, 0.32–1.28; P = .210). There was no difference in late toxicity.
- In the Trans-Tasmanian Radiation Oncology Group (TROG) trial (TROG 01.04 [NCT00145769]), 326 patients with ultrasound- or magnetic resonance imaging (MRI)-staged T3 N0–2 M0 rectal adenocarcinoma within 12 cm from the anal verge were randomly assigned to short-course radiation therapy (25 Gy in five fractions) followed by surgery 3 to 7 days later or long-course chemoradiation (50.4 Gy in 28 fractions with concurrent continuous infusional 5-FU) followed by surgery in 4 to 6 weeks. All patients received adjuvant chemotherapy (5-FU/LV) after surgery. The trial was designed to have 80% power to detect a 10% difference in local recurrence at 3 years with a two-sided test at the 5% level of significance. Cumulative incidence of local recurrence at 3 years was 7.5% for the short-course group and 4.4% for the long-course group (P = .24). OS at 5 years was 74% for the short-course group and 70% for the long-course group (HR, 1.12; 95% CI, 0.76–1.67; P = .62).
The Medical Research Council of the United Kingdom and the National Cancer Institute of Canada built on the short-course experience and undertook a randomized study (MRC-CR07 and NCIC-CTG C016) that compared short-course preoperative radiation therapy with selective postoperative chemoradiation. In the trial, 1,350 patients from 80 centers, who had resectable rectal adenocarcinoma less than 15 cm from the anal verge, were randomly assigned. Of note, pelvic MRI or ultrasound was not mandated. Patients randomly assigned to short-course radiation therapy received 25 Gy in five fractions, followed by TME, and further followed by adjuvant chemotherapy according to the local center policy about nodal and margin status. Patients randomly assigned to selective postoperative chemoradiation received immediate surgery followed by postoperative chemoradiation (45 Gy in 25 fractions with concurrent 5-FU) if their circumferential resection margin was 1 mm or less. Adjuvant chemotherapy for the group receiving selective chemoradiaton was again given based on local standards regarding nodal and margin status. The risk of local recurrence at 3 years was 4.4% in the preoperative short-course group and 10.6% for the selective chemoradiation group (HR, 0.39; 95% CI, 0.27–0.58; P < .0001). OS did not differ between the groups.
Taken together, these studies demonstrate that short-course radiation therapy and long-course preoperative chemoradiation are both reasonable treatment strategies in patients with stage II or III rectal adenocarcinoma.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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.References
- O'Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994. [PUBMED Abstract]
- Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002. [PUBMED Abstract]
- Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006. [PUBMED Abstract]
- Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004. [PUBMED Abstract]
- Roh MS, Colangelo LH, O'Connell MJ, et al.: Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27 (31): 5124-30, 2009. [PUBMED Abstract]
- Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997. [PUBMED Abstract]
- Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al.: Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93 (10): 1215-23, 2006. [PUBMED Abstract]
- Ngan SY, Burmeister B, Fisher RJ, et al.: Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 30 (31): 3827-33, 2012. [PUBMED Abstract]
- Sebag-Montefiore D, Stephens RJ, Steele R, et al.: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373 (9666): 811-20, 2009. [PUBMED Abstract]