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 III (old staging: Dukes C or Modified Astler-Coller C1-C3)

Stage III rectal cancer denotes disease with lymph node involvement. The number of positive lymph nodes affects prognosis: patients with 1 to 3 involved nodes have superior survival to those with 4 or more involved nodes. 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 pre- or postoperative radiation therapy alone except in a single trial.[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 similar survival advantage has been observed in patients with stage III rectal cancer treated with chemotherapy and radiation therapy compared to those treated with radiation alone.[5,6] These trials were reviewed at the National Institutes of Health Consensus Development Conference, and an advantage for combined-modality therapy with radiation and chemotherapy was confirmed.[6] The chemotherapy associated with these initial studies of successful combined-modality therapy was fluorouracil (5-FU) plus semustine. Subsequent trials confirmed that semustine can be omitted from the combined-modality therapy, and 5-FU alone with radiation therapy should be considered standard treatment.[7,8] An Intergroup trial has demonstrated 10% improved survival with the use of continuous-infusion 5-FU throughout the course of radiation therapy when compared with bolus 5-FU. This, or another modulation of 5-FU with leucovorin, should be considered standard.[9] Clinical trials addressing the use of oral 5-FU prodrugs are ongoing.[10]The radiation should be delivered to high-dose levels (45-55 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.[11] Late effects of radiation have also been observed in patients receiving preoperative radiation alone. 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] 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.[13,14] A quality-of-life analysis, however, suggests that the increased early and late toxic effects associated with combined modality therapy are balanced by the decreased morbidity for delayed recurrence and increased survival.[15][Level of evidence: 1iiA,1iiB,1iiC] 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.[16]

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).[4-6,17]



2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.[6,18-20]



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).[21,22]



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 has resulted in improved local control in a single institution experience.[23][Level of evidence: 3iiiDii].



6. Palliative chemoradiation.

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

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. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.  [PUBMED Abstract]
   
   
7. O'Connell M, Wieand H, Krook J, et al.: Lack of value for methyl-CCNU (MeCCNU) as a component of effective rectal cancer surgical adjuvant therapy: interim analysis of intergroup protocol 86-47-51. [Abstract] Proceedings of the American Society of Clinical Oncology 10: A-403, 134, 1991. 
   
   
8. Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Gastrointestinal Tumor Study Group. J Clin Oncol 10 (4): 549-57, 1992.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
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. 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]
    
    
14. 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]
    
    
15. Gelber RD, Goldhirsch A, Cole BF, et al.: A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer. J Natl Cancer Inst 88 (15): 1039-45, 1996.  [PUBMED Abstract]
    
    
16. Wolmark N, National Surgical Adjuvant Breast and Bowel Project: Phase III Randomized Study of Preoperative vs Postoperative 5-FU/CF/Radiotherapy in Patients with Operable Adenocarcinoma of the Rectum (Summary Last Modified 09/1999), NSABP-R-03, Clinical trial, Closed.  [PDQ Clinical Trial]
    
    
17. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.  [PUBMED Abstract]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    

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