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.)

Treatment of rectal cancer is surgical resection of the primary tumor and regional lymph nodes for localized disease. The technique of rectal excision may impact the rate of local recurrence. Local failure rates in the range of 4% to 8% following rectal resection with appropriate mesorectal excision (total mesorectal excision for low/middle rectal tumors and mesorectal excision at least 5 centimeters below the tumor for high rectal tumors) have been reported.[1-5] The low incidence of local relapse following meticulous mesorectal excision has led some investigators to question the routine use of adjuvant radiation therapy. Total mesorectal excision combined with low stapled colorectal or coloanal anastomosis obviates the need, in many patients, for abdominoperineal resection and associated permanent stoma. The risk of anastomotic dehiscence with these sphincter-preserving procedures, however, is considerable (>15%), frequently requiring temporary proximal diversion. The role of sentinel lymph node mapping in regional nodal staging for rectal cancer is under clinical evaluation.[6] Because of an increased tendency for first failure in locoregional sites only, the impact of perioperative irradiation is greater in rectal cancer than in colon cancer.[7] Both preoperative and postoperative radiation therapy alone decrease local failure.[8-11] Substantial improvement in overall survival has not been demonstrated with preoperative or postoperative radiation therapy alone, except in a single European trial.[10][Level of evidence: 1iiA]

Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy to radiation, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation and 5-FU-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomized clinical trials (the Gastrointestinal Tumor Study Group (GITSG) Protocol 7175 (GITSG-7175), the Mayo/North Central Cancer Treatment Group (NCCTG-794751) NCCTG Protocol 79-47-51, and the National Surgical Adjuvant Breast and Bowel Project (NSABP R-01).[12-14][Level of evidence: 1iiA] These studies demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection. Following the publication of these trials, the National Cancer Institute (NCI) concluded at a Consensus Development Conference in 1990 that postoperative combined modality treatment is recommended for patients with stage II and stage III rectal carcinoma.[15]

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems. The chemotherapy associated with the first successful combined modality treatments was fluorouracil (5-FU) and semustine. Semustine is not commercially available, and previous studies have linked this drug to 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 radiotherapy and 5-FU.[16][Level of evidence: 1iiA] The Intergroup 86-47-51 trial (NCCTG-864751) has demonstrated a 10% improved overall survival 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).[17][Level of evidence: 1iiA] The final results of Intergroup trial 0114 show no survival or local control benefit to the addition of leucovorin, levamisole, or both, to 5-FU administered postoperatively for stage II and stage III rectal cancers at a median follow-up of 7.4 years.[18][Level of evidence: 1iiA] Intergroup 0144 is a three-arm randomized trial (SWOG-9304) designed to determine whether continuous-infusion 5-FU throughout the entire standard adjuvant 6 cycle chemotherapy course is more effective than continuous 5-FU only during pelvic radiation.[Level of evidence: 1iiA] This trial is now closed and results are pending.

While the above data demonstrate a benefit of postoperative radiation and 5-FU chemotherapy for stage II and stage III rectal cancer, a follow-up study to the R-01 study, the NSABP R-02 (NSABP R-02), addressed whether the addition of radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[19][Level of evidence: 1iiA] The addition of radiation while significantly reducing local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02), demonstrated no significant benefit in survival. The interpretation of the interaction of radiotherapy with prognostic factors, however, was challenging. Radiation appeared to improve survival in patients younger than 60 years, as well as in patients who received abdominoperineal resection. This trial has initiated discussion in the oncologic community as to the proper role of postoperative radiation therapy. Omission of radiotherapy seems premature, since locoregional recurrence remains a clinically relevant problem. Using current surgical techniques, including total mesorectal excision (TME), it may be possible to identify subsets of patients whose chance of pelvic failure is low enough to omit postoperative radiation. A Dutch trial (CKVO-9504) randomizing patients with resectable rectal cancers (stages I–IV) to a short course of radiation (5 Gy × 5) followed by TME compared to TME alone demonstrated no difference in overall survival at 2 years (82% for both arms).[20][Level of evidence: 1iiA] Local recurrence rates were significantly reduced in the radiation therapy plus TME arm (2.4%) as compared to the TME only arm (8.2%, P < .001). At present, acceptable postoperative therapy for patients with stage II or stage III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation, followed by four cycles of maintenance chemotherapy with bolus 5-FU with or without modulation with leucovorin.

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.[21] 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.[22,23]

Although combined chemoradiotherapy is standard in the United States, European centers typically use preoperative radiation therapy alone. Several studies suggest that in selected patients with low rectal tumors, high-dose preoperative radiation therapy may permit resection of the primary tumor with a high rate of preservation of sphincter function.[24-28] Such treatment results in survival rates similar to those observed with more radical surgery without increasing the risk of pelvic or perineal recurrences. In a randomized trial evaluating the optimal timing of surgery following radiation therapy, a longer interval of surgery (6 to 8 weeks) following radiation therapy of 39 Gy in 13 fractions produced significantly better tumor response rates (53% vs. 72%, P = .007) and pathologic downstaging (10% vs. 26%, P = .005) when compared to the shorter interval of surgery (2 weeks) following radiation therapy.[29][Level of evidence: 1iiDiv] A trend toward more sphincter-preserving surgery was noted for the longer-interval arm (76%) compared to the shorter-interval arm (68%, P = .27). An ongoing trial (EORTC-22921) is addressing whether chemotherapy adds to the benefits of preoperative radiation.

Because of the suggestion of enhanced sphincter preservation with preoperative radiation with or without chemotherapy for clinically resectable T3 rectal cancers, ongoing randomized trials comparing preoperative and postoperative adjuvant combined modality therapy should further clarify the impact of either approach on bowel function as well as on the endpoints of local control and overall survival. An interval analysis of the first 116 patients enrolled on the randomized trial (NSABP R-03) of preoperative versus postoperative chemoradiation revealed a similar incidence of postoperative complications in both arms.[30] This trial closed in 1999 and preliminary results are expected. A similar trial from Germany is ongoing. Preliminary results in 417 patients indicate lower rates of acute toxicity and higher rates of sphincter preserving surgery and complete resection with negative margins in patients receiving preoperative chemoradiation versus postoperative chemoradiation.[31]

References

1. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341 (8843): 457-60, 1993.  [PUBMED Abstract]
   
   
2. Enker WE, Thaler HT, Cranor ML, et al.: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181 (4): 335-46, 1995.  [PUBMED Abstract]
   
   
3. Zaheer S, Pemberton JH, Farouk R, et al.: Surgical treatment of adenocarcinoma of the rectum. Ann Surg 227 (6): 800-11, 1998.  [PUBMED Abstract]
   
   
4. Heald RJ, Smedh RK, Kald A, et al.: Abdominoperineal excision of the rectum--an endangered operation. Norman Nigro Lectureship. Dis Colon Rectum 40 (7): 747-51, 1997.  [PUBMED Abstract]
   
   
5. Lopez-Kostner F, Lavery IC, Hool GR, et al.: Total mesorectal excision is not necessary for cancers of the upper rectum. Surgery 124 (4): 612-7; discussion 617-8, 1998.  [PUBMED Abstract]
   
   
6. Esser S, Reilly WT, Riley LB, et al.: The role of sentinel lymph node mapping in staging of colon and rectal cancer. Dis Colon Rectum 44 (6): 850-4; discussion 854-6, 2001.  [PUBMED Abstract]
   
   
7. Gunderson LL, Sosin H: Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum. Clinicopathologic correlation and implications for adjuvant therapy. Cancer 34 (4): 1278-92, 1974.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. Martling A, Holm T, Johansson H, et al.: The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: long-term follow-up of a population-based study. Cancer 92 (4): 896-902, 2001.  [PUBMED Abstract]
    
    
11. Dahlberg M, Glimelius B, Påhlman L: Improved survival and reduction in local failure rates after preoperative radiotherapy: evidence for the generalizability of the results of Swedish Rectal Cancer Trial. Ann Surg 229 (4): 493-7, 1999.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    
14. Fisher B, Wolmark N, Rockette H, et al.: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 80 (1): 21-9, 1988.  [PUBMED Abstract]
    
    
15. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. Wolmark N, Wieand HS, Hyams DM, et al.: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92 (5): 388-96, 2000.  [PUBMED Abstract]
    
    
20. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al.: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345 (9): 638-46, 2001.  [PUBMED Abstract]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. Mohiuddin M, Marks G: High dose preoperative irradiation for cancer of the rectum, 1976-1988. Int J Radiat Oncol Biol Phys 20 (1): 37-43, 1991.  [PUBMED Abstract]
    
    
25. Ng AK, Recht A, Busse PM: Sphincter preservation therapy for distal rectal carcinoma: a review. Cancer 79 (4): 671-83, 1997.  [PUBMED Abstract]
    
    
26. 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]
    
    
27. Willett CG: Organ preservation in anal and rectal cancers. Curr Opin Oncol 8 (4): 329-33, 1996.  [PUBMED Abstract]
    
    
28. Harms BA, Starling JR: Current status of sphincter preservation in rectal cancer. Oncology (Huntingt) 4 (8): 53-60; discussion 65-6, 1990.  [PUBMED Abstract]
    
    
29. Francois Y, Nemoz CJ, Baulieux J, et al.: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 17 (8): 2396, 1999.  [PUBMED Abstract]
    
    
30. Hyams DM, Mamounas EP, Petrelli N, et al.: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 40 (2): 131-9, 1997.  [PUBMED Abstract]
    
    
31. Sauer R, Fietkau R, Martus P, et al.: Adjuvant and neoadjuvant radiochemotherapy for advanced rectal cancer--first results of the German multicenter phase III trial. Int J Radiat Oncol Biol Phys 48(suppl 119): #17, 2000. 
    
    

Back to Top

< Previous Section  |  Next Section >