Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage II (old staging: Dukes B or Modified Astler-Coller B2 and B3) rectal cancer

Treatment options:

1. Preoperative chemoradiation with fluorouracil (5-FU) for patients with clinically staged T3/T4 rectal adenocarcinoma.
2. Total mesorectal excision (TME) with either low anterior resection (LAR) or abdominoperineal resection (APR).
3. Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.
4. Four to six months of 5-FU-based chemotherapy postoperatively.
5. 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 (NCCTG-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).[1][Level of evidence: 1iiA] The final results of INT-0114 showed no survival or local-control benefit with the addition of leucovorin, 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.[2][Level of evidence: 1iiA]

Another study, Intergroup 0144 (SWOG-9304), 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:[3]

• 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 leucovorin in two 5-day cycles before (5-FU 425 mg/m²/day; leucovorin 20 mg/m²/day) and after (5-FU 380 mg/m²/day; leucovorin 20 mg/m²/day) radiation therapy, and bolus 5-FU plus leucovorin (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.

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%).[3][Level of evidence: 1iiA]

The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3/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).[4] 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).[4][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).

Of the patients assigned to the postoperative chemoradiation arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal ultrasound to have T3/T4 or node-positive disease. A similar number of patients may have been overtreated in the preoperative treatment group. Nevertheless, on the basis of this study, preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3/T4 or node-positive disease.

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.[5] 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 to the survival rates of patients treated with surgery plus radiation and bolus chemotherapy (76%) or surgery plus radiation and protracted-infusion chemotherapy (80%).[6] However, a multi-institutional retrospective analysis demonstrated that 22% of patients thought to have clinically node-negative T3 disease by ultrasound or MRI were found, at the time of resection, to have positive mesorectal lymph nodes even after chemoradiation.[7]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. Willett CG, Badizadegan K, Ancukiewicz M, et al.: Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum 42 (2): 167-73, 1999.  [PUBMED Abstract]
   
   
6. Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.  [PUBMED Abstract]
   
   
7. Guillem JG, Díaz-González JA, Minsky BD, et al.: cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26 (3): 368-73, 2008.  [PUBMED Abstract]
   
   

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