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 ¹ for more information.)

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

The uterus, vagina, parametria, ovaries, or prostate are sometimes involved. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates.[1-3] Significant improvement in overall survival has not been demonstrated with radiation therapy alone except in a single trial of preoperative radiation therapy.[3][Level of evidence: 1iiA]

A randomized trial by the Gastrointestinal Tumor Study Group demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection in patients whose rectal cancer has penetrated through the bowel wall into the perirectal fat (stage II) or has metastasized to regional lymph nodes (stage III).[4] A disease-free survival advantage has been observed in patients with stage II and stage III rectal cancer treated with chemotherapy and radiation therapy compared to those treated with radiation therapy alone.[5] An Intergroup trial has demonstrated a 10% improved survival with the use of continuous-infusion fluorouracil (5-FU) throughout the course of radiation therapy when compared with bolus 5-FU. This method of 5-FU administration should be considered standard.[6] The final results of Intergroup trial 0114 showed no survival benefit with the addition of leucovorin, levamisole, or both, to 5-FU administered postoperatively at a median follow-up of 7.4 years.[7] Clinical trials further addressing 5-FU modulation are underway, including the use of oral 5-FU prodrugs.[8] The radiation should be delivered to high-dose levels (45 Gy to 55 Gy) either preoperatively or postoperatively, with meticulous attention to technique. An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction compared to those who undergo surgical resection alone.[9] Improved radiation planning and techniques can be used to minimize treatment-related complications. These techniques include the use of multiple pelvic fields, prone positioning, customized bowel immobilization molds (belly boards), bladder distention, visualization of the small bowel through oral contrast, and the incorporation of three-dimensional or comparative treatment planning.[10,11] Late effects of radiation have also been observed in patients receiving preoperative radiation alone with high doses per fraction. Results from the Swedish Rectal Cancer trial suggest an increase in long-term bowel dysfunction in patients treated with short-course, high-dose preoperative radiation therapy when compared to patients treated with surgery alone.[12] Ongoing clinical trials comparing preoperative and postoperative adjuvant chemoradiotherapy should further clarify the impact of either approach on bowel function and other important quality-of-life issues (e.g., sphincter preservation) in addition to the more conventional endpoints of disease-free and overall survival.

Standard treatment options:

1. Wide surgical resection and low anterior resection with colorectal or coloanal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial (SWOG-9304 ²).[4,5,13-15]



2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.[13,16-18]



3. Partial or total pelvic exenteration in the uncommon situation where bladder, uterus, vagina, or prostate are invaded, with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.



4. Preoperative radiation therapy with or without chemotherapy followed by surgery with an attempt to preserve sphincter function with subsequent adjuvant chemotherapy, preferably through participation in a clinical trial (RTOG-9401 ³).[9,19-21]



5. Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT with or without 5-FU has resulted in improved local control in single institution experiences.[22][Level of evidence: 3iiiDii];[23].

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II rectal cancer ⁴. 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 ⁵.

References

1. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party. Lancet 348 (9042): 1605-10, 1996.  [PUBMED Abstract]
   
   
2. Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Medical Research Council Rectal Cancer Working Party. Lancet 348 (9042): 1610-4, 1996.  [PUBMED Abstract]
   
   
3. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997.  [PUBMED Abstract]
   
   
4. Thomas PR, Lindblad AS: Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol 13 (4): 245-52, 1988.  [PUBMED Abstract]
   
   
5. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324 (11): 709-15, 1991.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. 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]
   
   
8. Min JS, Kim NK, Park JK, et al.: A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. Ann Surg Oncol 7 (9): 674-9, 2000.  [PUBMED Abstract]
   
   
9. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 220 (5): 676-82, 1994.  [PUBMED Abstract]
   
   
10. Koelbl O, Richter S, Flentje M: Influence of patient positioning on dose-volume histogram and normal tissue complication probability for small bowel and bladder in patients receiving pelvic irradiation: a prospective study using a 3D planning system and a radiobiological model. Int J Radiat Oncol Biol Phys 45 (5): 1193-8, 1999.  [PUBMED Abstract]
    
    
11. Gunderson LL, Russell AH, Llewellyn HJ, et al.: Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 11 (7): 1379-93, 1985.  [PUBMED Abstract]
    
    
12. Dahlberg M, Glimelius B, Graf W, et al.: Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Dis Colon Rectum 41 (5): 543-9; discussion 549-51, 1998.  [PUBMED Abstract]
    
    
13. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.  [PUBMED Abstract]
    
    
14. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.  [PUBMED Abstract]
    
    
15. Minsky BD, Coia L, Haller DG, et al.: Radiation therapy for rectosigmoid and rectal cancer: results of the 1992-1994 Patterns of Care process survey. J Clin Oncol 16 (7): 2542-7, 1998.  [PUBMED Abstract]
    
    
16. Tepper JE, O'Connell MJ, Petroni GR, et al.: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol 15 (5): 2030-9, 1997.  [PUBMED Abstract]
    
    
17. Wolmark N, Fisher B: An analysis of survival and treatment failure following abdominoperineal and sphincter-saving resection in Dukes' B and C rectal carcinoma. A report of the NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project. Ann Surg 204 (4): 480-9, 1986.  [PUBMED Abstract]
    
    
18. Rougier P, Nordlinger B: Large scale trial for adjuvant treatment in high risk resected colorectal cancers. Rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Ann Oncol 4 (Suppl 2): 21-8, 1993.  [PUBMED Abstract]
    
    
19. Mohiuddin M, Regine WF, Marks GJ, et al.: High-dose preoperative radiation and the challenge of sphincter-preservation surgery for cancer of the distal 2 cm of the rectum. Int J Radiat Oncol Biol Phys 40 (3): 569-74, 1998.  [PUBMED Abstract]
    
    
20. Mohiuddin M, Marks G, Bannon J: High-dose preoperative radiation and full thickness local excision: a new option for selected T3 distal rectal cancers. Int J Radiat Oncol Biol Phys 30 (4): 845-9, 1994.  [PUBMED Abstract]
    
    
21. Valentini V, Coco C, Cellini N, et al.: Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys 40 (5): 1067-75, 1998.  [PUBMED Abstract]
    
    
22. Gunderson LL, Nelson H, Martenson JA, et al.: Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU. Int J Radiat Oncol Biol Phys 37 (3): 601-14, 1997.  [PUBMED Abstract]
    
    
23. Nakfoor BM, Willett CG, Shellito PC, et al.: The impact of 5-fluorouracil and intraoperative electron beam radiation therapy on the outcome of patients with locally advanced primary rectal and rectosigmoid cancer. Ann Surg 228 (2): 194-200, 1998.  [PUBMED Abstract]
    
    

Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.