Rectal Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of rectal cancer.

Rectal Cancer

General Information

Note: Separate PDQ summaries on Screening for Colorectal Cancer, Prevention of Colorectal Cancer, and Genetics of Colorectal Cancer are also available. Information about colon cancer in children is available in the PDQ summary on Unusual Cancers of Childhood Treatment.

Note: Estimated new cases and deaths from rectal cancer in the United States in 2006: ^1,

• New cases: 41,930.
• Deaths (colon and rectal cancers combined): 55,170.

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.)

Cancer of the rectum is a highly treatable and often curable disease when localized. Surgery is the primary treatment and results in cure in approximately 45% of all patients. The prognosis of rectal cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Preoperative staging procedures include digital rectal examination, computed tomographic scan or magnetic resonance imaging scan of the abdomen and pelvis, endoscopic evaluation with biopsy, and endoscopic ultrasound (EUS).² EUS is an accurate method of evaluating tumor stage (up to 95% accuracy) and the status of the perirectal nodes (up to 74% accuracy). Accurate staging can influence therapy by helping to determine which patients may be candidates for local excision rather than more extensive surgery and which patients may be candidates for preoperative chemotherapy and radiation therapy to maximize the likelihood of resection with clear margins. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.^3,4,5 This recommendation takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.^6,7,8,9 Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with rectal cancer, though most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.^10,11,12 Microsatellite instability, also associated with hereditary nonpolyposis rectal cancer, has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer.¹³ Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.¹⁴ A major limitation of surgery is the inability to obtain wide radial margins because of the presence of the bony pelvis. In those patients with disease penetration through the bowel wall and/or spread into lymph nodes at the time of diagnosis, local recurrence following surgery is a major problem and often ultimately results in death.¹⁵ The radial margin of resection of rectal primaries may also predict for local recurrence.^16,

Because of the frequency of the disease, the demonstrated slow growth of primary lesions, the better survival of patients with early-stage lesions, and the relative simplicity and accuracy of screening tests, screening for rectal cancer should be a part of routine care for all adults over the age of 50 years, especially those with first-degree relatives with colorectal cancer.¹⁷ There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC) or Lynch Syndrome Variants I and II, and those with a personal history of ulcerative colitis or Crohn's colitis.^18,19 (Refer to the PDQ summary on Genetics of Colorectal Cancer for more information.) Together they account for 10% to 15% of colorectal cancers. Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and the possibility of selection factors make this observation difficult to interpret.^20,[Level of evidence: 3iiiA] More common conditions with an increased risk include: a personal history of colorectal cancer or adenomas, first degree family history of colorectal cancer or adenomas, and a personal history of ovarian, endometrial, or breast cancer.^21,22 These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.²³ (Refer to the PDQ summaries on Screening for Colorectal Cancer and Prevention of Colorectal Cancer for more information.)

Following treatment of rectal cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.^24,25,26,27 However, the impact of such monitoring on overall mortality of patients with recurrent rectal cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program.^{28,29,30,31,32} Carcinoembryonic antigen (CEA) is a serum glycoprotein frequently used in the management of patients with rectal cancer. A review of the use of this tumor marker suggests: that CEA is not useful as a screening test; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended.³³ However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor.^30,31,32 New surveillance methods including CEA immunoscintigraphy and positron tomography are under clinical evaluation.^34,

Although a large number of studies have evaluated various clinical, pathological, and molecular parameters with prognosis, as yet, none have had a major impact on prognosis or therapy.³⁵ Clinical stage remains the most important prognostic indicator.

Gastrointestinal stromal tumors can occur in the rectum. (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.)

Adjuvant therapy

Patients with stage II or stage III rectal cancer are at high risk for local and systemic relapse. Adjuvant therapy should address both problems. Most trials of preoperative or postoperative radiation therapy alone have shown a decrease in the local recurrence rate but no definite effect on survival;^{24,36,37,38,39,} although a Swedish trial has shown a survival advantage from preoperative radiation therapy compared to surgery alone.^40,[Level of evidence: 1iiA] Two trials have confirmed that fluorouracil (5-FU) plus radiation therapy is effective and may be considered standard treatment.^36,37,38 In these trials, combined modality adjuvant treatment with radiation therapy and chemotherapy following surgery also resulted in local failure rates lower than with either radiation therapy or chemotherapy alone. 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.⁴¹ 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 with oral contrast, and the incorporation of three-dimensional or comparative treatment planning.^42,43 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.

Advanced disease

Radiation therapy in rectal cancer is palliative in most situations but may have greater impact when used perioperatively. Palliation may be achieved in approximately 10% to 20% of patients with 5-FU. Several studies suggest an advantage when leucovorin is added to 5-FU in terms of response rate and palliation of symptoms but not always in terms of survival.^{44,45,46,47,48,49,50} Irinotecan (CPT-11) has been approved by the US Food and Drug Administration for the treatment of patients whose tumors are refractory to 5-FU.^51,52,53,54 Participation in clinical trials is appropriate. A number of other drugs are undergoing evaluation for the treatment of colon cancer.⁵⁵ Oxaliplatin, alone or combined with 5-FU and leucovorin, has also shown activity in 5-FU refractory patients.^56,57,58,59,

¹ American Cancer Society.: Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society, 2006. Also available online. Last accessed March 8, 2007.

² Snady H, Merrick MA: Improving the treatment of colorectal cancer: the role of EUS. Cancer Invest 16 (8): 572-81, 1998.

³ Colon and rectum. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 113-124.

⁴ Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.

⁵ Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.

⁶ Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.

⁷ Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.

⁸ Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.

⁹ Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.

¹⁰ McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999.

¹¹ Jen J, Kim H, Piantadosi S, et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331 (4): 213-21, 1994.

¹² Lanza G, Matteuzzi M, Gafá R, et al.: Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 79 (4): 390-5, 1998.

¹³ Gryfe R, Kim H, Hsieh ET, et al.: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342 (2): 69-77, 2000.

¹⁴ Dignam JJ, Colangelo L, Tian W, et al.: Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst 91 (22): 1933-40, 1999.

¹⁵ Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1 (8496): 1479-82, 1986.

¹⁶ de Haas-Kock DF, Baeten CG, Jager JJ, et al.: Prognostic significance of radial margins of clearance in rectal cancer. Br J Surg 83 (6): 781-5, 1996.

¹⁷ Cannon-Albright LA, Skolnick MH, Bishop DT, et al.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 319 (9): 533-7, 1988.

¹⁸ Thorson AG, Knezetic JA, Lynch HT: A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). Dis Colon Rectum 42 (1): 1-9, 1999.

¹⁹ Smith RA, von Eschenbach AC, Wender R, et al.: American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection. CA Cancer J Clin 51 (1): 38-75; quiz 77-80, 2001 Jan-Feb.

²⁰ Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83 (2): 259-66, 1998.

²¹ Ransohoff DF, Lang CA: Screening for colorectal cancer. N Engl J Med 325 (1): 37-41, 1991.

²² Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994.

²³ Winawer SJ: Screening for colorectal cancer. Cancer: Principles and Practice of Oncology Updates 2(1): 1-16, 1987.

²⁴ Martin EW Jr, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Ann Surg 202 (3): 310-7, 1985.

²⁵ Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer. A meta-analysis. Ann Surg 219 (2): 174-82, 1994.

²⁶ Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Ann Surg 220 (2): 206-11, 1994.

²⁷ Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996.

²⁸ Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Dis Colon Rectum 36 (7): 636-43; discussion 643-4, 1993.

²⁹ Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270 (8): 943-7, 1993.

³⁰ Rosen M, Chan L, Beart RW Jr, et al.: Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 41 (9): 1116-26, 1998.

³¹ Desch CE, Benson AB 3rd, Smith TJ, et al.: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17 (4): 1312, 1999.

³² Benson AB 3rd, Desch CE, Flynn PJ, et al.: 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 18 (20): 3586-8, 2000.

³³ Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14 (10): 2843-77, 1996.

³⁴ Lechner P, Lind P, Goldenberg DM: Can postoperative surveillance with serial CEA immunoscintigraphy detect resectable rectal cancer recurrence and potentially improve tumor-free survival? J Am Coll Surg 191 (5): 511-8, 2000.

³⁵ Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999.

³⁶ 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.

³⁷ 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.

³⁸ Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.

³⁹ Kachnic LA, Willett CG: Radiation therapy in the management of rectal cancer. Curr Opin Oncol 13 (4): 300-6, 2001.

⁴⁰ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997.

⁴¹ 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.

⁴² 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.

⁴³ 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.

⁴⁴ Petrelli N, Douglass HO Jr, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 7 (10): 1419-26, 1989.

⁴⁵ Erlichman C, Fine S, Wong A, et al.: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6 (3): 469-75, 1988.

⁴⁶ Doroshow JH, Multhauf P, Leong L, et al.: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8 (3): 491-501, 1990.

⁴⁷ Poon MA, O'Connell MJ, Wieand HS, et al.: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9 (11): 1967-72, 1991.

⁴⁸ Valone FH, Friedman MA, Wittlinger PS, et al.: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group. J Clin Oncol 7 (10): 1427-36, 1989.

⁴⁹ Borner MM, Castiglione M, Bacchi M, et al.: The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 9 (5): 535-41, 1998.

⁵⁰ Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 10 (6): 896-903, 1992.

⁵¹ Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.

⁵² Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14 (3): 709-15, 1996.

⁵³ Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352 (9138): 1407-12, 1998.

⁵⁴ Cunningham D, Pyrhönen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352 (9138): 1413-8, 1998.

⁵⁵ Von Hoff DD: Promising new agents for treatment of patients with colorectal cancer. Semin Oncol 25 (5 Suppl 11): 47-52, 1998.

⁵⁶ de Gramont A, Vignoud J, Tournigand C, et al.: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33 (2): 214-9, 1997.

⁵⁷ Bleiberg H, de Gramont A: Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer. Semin Oncol 25 (2 Suppl 5): 32-9, 1998.

⁵⁸ Cvitkovic E, Bekradda M: Oxaliplatin: a new therapeutic option in colorectal cancer. Semin Oncol 26 (6): 647-62, 1999.

⁵⁹ Giacchetti S, Perpoint B, Zidani R, et al.: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18 (1): 136-47, 2000.

Cellular Classification

Histologic types of rectal cancer include:

• Adenocarcinoma (most rectal cases).
  • Mucinous (colloid) adenocarcinoma.
  • Signet ring adenocarcinoma.
• Scirrhous tumors.
• Neuroendocrine:¹ Tumors with neuroendocrine differentiation typically have a poorer prognosis than pure adenocarcinoma variants.
• Carcinoid tumors. (Refer to the PDQ summary on Gastrointestinal Carcinoid Tumor Treatment for more information.)

¹ Saclarides TJ, Szeluga D, Staren ED: Neuroendocrine cancers of the colon and rectum. Results of a ten-year experience. Dis Colon Rectum 37 (7): 635-42, 1994.

Stage Information

Treatment decisions should be made with reference to the TNM classification,¹ rather than the older Dukes’ or the Modified Astler-Coller (MAC) classification schema.

The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.^1,2,3 This recommendation takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.^4,5,6,7,

The AJCC has designated staging by TNM classification.^1,

TNM definitions

Primary tumor (T)
• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ: intraepithelial or invasion of the lamina propria*
• T1: Tumor invades submucosa
• T2: Tumor invades muscularis propria
• T3: Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized pericolic or perirectal tissues
• T4: Tumor directly invades other organs or structures, and/or perforates the visceral peritoneum**,***

*Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

**Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.

***Tumor that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion.

Regional lymph nodes (N)
• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in 1 to 3 regional lymph nodes
• N2: Metastasis in 4 or more regional lymph nodes

A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that is represents venous invasion.

Distant metastasis (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC stage groupings

Stage 0
• Tis, N0, M0

Stage I
• T1, N0, M0
• T2, N0, M0

Stage IIA
• T3, N0, M0

Stage IIB
• T4, N0, M0

Stage IIIA
• T1, N1, M0
• T2, N1, M0

Stage IIIB
• T3, N1, M0
• T4, N1, M0

Stage IIIC
• Any T, N2, M0

Stage IV
• Any T, any N, M1

¹ Colon and rectum. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 113-124.

² Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.

³ Nelson H, Petrelli N, Carlin A, et al.: Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 93 (8): 583-96, 2001.

⁴ Swanson RS, Compton CC, Stewart AK, et al.: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10 (1): 65-71, 2003 Jan-Feb.

⁵ Le Voyer TE, Sigurdson ER, Hanlon AL, et al.: Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 21 (15): 2912-9, 2003.

⁶ Prandi M, Lionetto R, Bini A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 235 (4): 458-63, 2002.

⁷ Tepper JE, O'Connell MJ, Niedzwiecki D, et al.: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19 (1): 157-63, 2001.

Treatment Option Overview

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.^1,2,3,4,5 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.^8,9,10,11 Substantial improvement in overall survival has not been demonstrated with pre- 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, the Mayo/North Central Cancer Treatment Group (NCCTG) Protocol 79-47-51, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01).^12,13,14,[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 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 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.^19,[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, addressed whether the addition of radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.^20,[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 95-04) randomizing patients with resectable rectal cancers (stages I-IV) to a short course of radiation (500 cGy x 5) followed by TME compared to TME alone demonstrated no difference in overall survival at 2 years (82% for both arms).^21,[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 4 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.²² 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.^23,24

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.^{25,26,27,28,29} 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.^30,[Level of evidence: 1iiDiii] 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 is addressing whether chemotherapy adds to the benefits of preoperative radiation.^31,

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 NSABP R-03 randomized trial of pre- versus postoperative chemoradiation revealed a similar incidence of postoperative complications in both arms.³² This trial closed in 1999 and preliminary results are expected. A similar trial from Germany (COA/ARO/AIO 94) 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.^33,

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

¹ MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341 (8843): 457-60, 1993.

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.

³ Zaheer S, Pemberton JH, Farouk R, et al.: Surgical treatment of adenocarcinoma of the rectum. Ann Surg 227 (6): 800-11, 1998.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

¹⁵ NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.

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.

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.

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.

¹⁹ Smalley SR, Southwest Oncology Group: Phase III Randomized Study of Three Different Regimens Containing Fluorouracil in Patients With Stage II or III Rectal Cancer, SWOG-9304, Clinical trial, Closed.

²⁰ 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.

²¹ 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.

²² 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.

²³ 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.

²⁴ 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.

²⁵ 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.

²⁶ Ng AK, Recht A, Busse PM: Sphincter preservation therapy for distal rectal carcinoma: a review. Cancer 79 (4): 671-83, 1997.

²⁷ 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.

²⁸ Willett CG: Organ preservation in anal and rectal cancers. Curr Opin Oncol 8 (4): 329-33, 1996.

²⁹ Harms BA, Starling JR: Current status of sphincter preservation in rectal cancer. Oncology (Huntingt) 4 (8): 53-60; discussion 65-6, 1990.

³⁰ 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.

³¹ Bosset J, European Organization for Research and Treatment of Cancer: Phase III Randomized Study of Preoperative Radiotherapy With or Without Fluorouracil (5-FU) Combined With Leucovorin Calcium (CF) and/or Postoperative 5-FU/CF in Patients With Resectable Adenocarcinoma of the Rectum, EORTC-22921, Clinical trial, Closed.

³² 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.

³³ 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.

Stage 0 Rectal Cancer

Stage 0 rectal cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, surgical and other procedures may be limited.

Standard treatment options:

1. Local excision or simple polypectomy.^1,
2. Full thickness rectal resection by the transanal or transcoccygeal route for large lesions not amenable to local excision.
3. Endocavitary irradiation.^2,3,4,
4. Local radiation therapy.^2,

¹ Bailey HR, Huval WV, Max E, et al.: Local excision of carcinoma of the rectum for cure. Surgery 111 (5): 555-61, 1992.

² Kodner IJ, Gilley MT, Shemesh EI, et al.: Radiation therapy as definitive treatment for selected invasive rectal cancer. Surgery 114 (4): 850-6; discussion 856-7, 1993.

³ Mendenhall WM, Rout WR, Vauthey JN, et al.: Conservative treatment of rectal adenocarcinoma with endocavitary irradiation or wide local excision and postoperative irradiation. J Clin Oncol 15 (10): 3241-8, 1997.

⁴ Aumock A, Birnbaum EH, Fleshman JW, et al.: Treatment of rectal adenocarcinoma with endocavitary and external beam radiotherapy: results for 199 patients with localized tumors. Int J Radiat Oncol Biol Phys 51 (2): 363-70, 2001.

Stage I Rectal Cancer

Stage I (old stage: Dukes’ A or Modified Astler-Coller A and B1)

Because of its localized nature, stage I has a high cure rate.

Standard treatment options:

1. Wide surgical resection and anastomosis when an adequate low anterior resection (LAR) can be performed with sufficient distal rectum to allow a conventional anastomosis or coloanal anastomosis.
2. Wide surgical resection with abdominoperineal resection (APR) for lesions too distal to permit low anterior resection (LAR).
3. Local transanal or other resection ^1,2 with or without perioperative external beam radiation plus fluorouracil (5-FU). No randomized trials are available to compare local excision with or without postoperative chemoradiation treatments to wide surgical resection (LAR and APR). One prospective multicenter phase II study and several larger retrospective series suggest that well-staged patients with small (<4 centimeters) tumors with good histologic prognostic features (well- to moderately-differentiated adenocarcinomas), mobile, and no lymphatic, venous, or perineural invasion, treated with full-thickness local excision that results in negative margins may have outcomes equivalent to APR or LAR with the selective post-operative use chemoradiation therapy.^3,4,5 Endoscopic ultrasound studies have been helpful in defining these patients. Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement of 20% or more and require additional therapy, such as radiation and chemotherapy, or more standard surgical resection.⁶ Patients with poor histologic features should consider LAR or APR and postoperative treatment as dictated by full surgical staging. The selection of patients for local excision may also be improved by newer imaging techniques, such as endorectal magnetic resonance imaging and endorectal ultrasound.
4. Endocavitary, with or without external beam, radiation in selected patients with tumors less than 3 centimeters in size, with well-differentiated tumors, and without deep ulceration, tumor fixation, or palpable lymph nodes.^7,8,9,10 Special equipment and experience are required to achieve results equivalent to surgery.

¹ Bailey HR, Huval WV, Max E, et al.: Local excision of carcinoma of the rectum for cure. Surgery 111 (5): 555-61, 1992.

² Benson R, Wong CS, Cummings BJ, et al.: Local excision and postoperative radiotherapy for distal rectal cancer. Int J Radiat Oncol Biol Phys 50 (5): 1309-16, 2001.

³ Willett CG, Compton CC, Shellito PC, et al.: Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. Cancer 73 (11): 2716-20, 1994.

⁴ Russell AH, Harris J, Rosenberg PJ, et al.: Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02. Int J Radiat Oncol Biol Phys 46 (2): 313-22, 2000.

⁵ Steele GD Jr, Herndon JE, Bleday R, et al.: Sphincter-sparing treatment for distal rectal adenocarcinoma. Ann Surg Oncol 6 (5): 433-41, 1999 Jul-Aug.

⁶ Sitzler PJ, Seow-Choen F, Ho YH, et al.: Lymph node involvement and tumor depth in rectal cancers: an analysis of 805 patients. Dis Colon Rectum 40 (12): 1472-6, 1997.

⁷ Sischy B, Graney MJ, Hinson EJ: Endocavitary irradiation for adenocarcinoma of the rectum. CA Cancer J Clin 34 (6): 333-9, 1984 Nov-Dec.

⁸ Kodner IJ, Gilley MT, Shemesh EI, et al.: Radiation therapy as definitive treatment for selected invasive rectal cancer. Surgery 114 (4): 850-6; discussion 856-7, 1993.

⁹ Maingon P, Guerif S, Darsouni R, et al.: Conservative management of rectal adenocarcinoma by radiotherapy. Int J Radiat Oncol Biol Phys 40 (5): 1077-85, 1998.

¹⁰ Aumock A, Birnbaum EH, Fleshman JW, et al.: Treatment of rectal adenocarcinoma with endocavitary and external beam radiotherapy: results for 199 patients with localized tumors. Int J Radiat Oncol Biol Phys 51 (2): 363-70, 2001.

Stage II Rectal Cancer

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)

The uterus, vagina, parametria, ovaries, or prostate are sometimes involved. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates.^1,2,3 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.^{4,5,13,14,15,16,}
2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.^13,17,18,19,
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.^{9,20,21,22,23,}
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.^24,[Level of evidence: 3iiiDi];^25,.

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.

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.

³ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997.

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.

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.

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.

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.

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.

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.

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.

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.

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.

¹³ NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.

¹⁴ Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.

¹⁵ Smalley SR, Southwest Oncology Group: Phase III Randomized Study of Three Different Regimens Containing Fluorouracil in Patients With Stage II or III Rectal Cancer, SWOG-9304, Clinical trial, Closed.

¹⁶ 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.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² Minsky BD, Radiation Therapy Oncology Group: Phase III Intergroup Randomized Study of Preoperative vs Postoperative Combined 5-FU/CF and Radiotherapy for Resectable Rectal Adenocarcinoma (Summary Last Modified 01/98), RTOG-9401, Clinical trial, Completed.

²³ 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.

²⁴ 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.

²⁵ 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.

Stage III Rectal Cancer

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.^1,2,3 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.^4,5,6,17,18,
2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.^6,19,20,21,
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.^22,23,24,
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.^25,[Level of evidence: 3iiiDi].
6. Palliative chemoradiation.

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.

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.

³ Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997.

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.

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.

⁶ NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.

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.

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.

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.

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.

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.

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.

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.

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.

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.

¹⁷ Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.

¹⁸ Smalley SR, Southwest Oncology Group: Phase III Randomized Study of Three Different Regimens Containing Fluorouracil in Patients With Stage II or III Rectal Cancer, SWOG-9304, Clinical trial, Closed.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² 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.

²³ Minsky BD, Radiation Therapy Oncology Group: Phase III Intergroup Randomized Study of Preoperative vs Postoperative Combined 5-FU/CF and Radiotherapy for Resectable Rectal Adenocarcinoma (Summary Last Modified 01/98), RTOG-9401, Clinical trial, Completed.

²⁴ 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.

²⁵ 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.

Stage IV Rectal Cancer

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 IV (old staging: Modified Astler-Coller D)

Stage IV rectal cancer denotes distant metastatic disease. Local regional approaches to treating liver metastases include hepatic resection and/or intraarterial administration of chemotherapy with implantable infusion ports or pumps. For patients with limited (3 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40%.^{1,2,3,4,5,6 7,}Other local ablative techniques that have been used to manage liver metastases include cryosurgery, embolization, and interstitial radiation therapy.^8,9 For those patients with hepatic metastases deemed unresectable (due to such factors as location, distribution, and excess number), cryosurgical ablation has been associated with long term tumor control.¹⁰ Prognostic variables that predict a favorable outcome for cryotherapy are similar to those for hepatic resection, and include low preoperative carcinoembryonic antigen level, absence of extrahepatic disease, negative margins, and lymph node negative primary.^11,[Level of evidence: 3iiiA] Patients with limited pulmonary metastases, and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.^7,12,13 The role of additional systemic therapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine plus systemic fluorouracil (5-FU) plus leucovorin was shown to result in improved 2-year disease-free and overall survival (86% versus 72%, P=.03), but did not show a significant statistical difference in medial survival, compared to systemic 5-FU therapy alone.^14,[Level of evidence: 1iiA] Further follow-up is required to confirm these findings and to determine whether more effective combination chemotherapy alone may provide similar results compared to hepatic intra-arterial therapy plus systemic treatment.

Hepatic intraarterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no improvement in survival when compared to systemic chemotherapy.^{15,16,17,18,19,20} Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CALGB-9481) of hepatic arterial infusion versus systemic chemotherapy. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

In stage IV and recurrent rectal cancer, chemotherapy has been used for palliation with 5-FU-based treatment and is considered to be standard therapy.^21,22,23 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin ^{24,25,26,27,28,29,30} or methotrexate.^31,32 Randomized clinical trials show that interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy.^33,34 Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.³⁵ The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.³⁶ Oral regimens using prodrugs of 5-FU or inhibitors of dihydropyrimidine dehydrogenase (DPD) pharmacologically simulate continuous infusion and are under clinical evaluation.³⁷ The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and toxic effects profile of the chosen regimen, as well as cost and quality-of-life issues.^38,39 In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous infusion or bolus administration.^40,

DPD is the rate-limiting enzyme in the degradation pathway for 5-FU. While genetic polymorphism commonly results in considerable individual variability in levels of this enzyme, between 0.5% and 3% of the population are severely DPD deficient. Severe mucositis, neutropenia, diarrhea, and cerebellar dysfunction can result in toxic deaths among patients who are DPD deficient. Standard testing for DPD deficiency is not widely available, but one study found that patients with a pretreatment ratio of dihydrouracil to uracil of 1.8 or less were at risk of increased 5-FU toxic effects.^41,42,43,

Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic rectal cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.^44,45 It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.^46,

CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU.^47,48,[Level of evidence: 1iiA,1iiC]

Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT-11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival.⁴⁹ The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival.^49,[Level of evidence: 1iiA] The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time-to-tumor progression was significantly prolonged with the combination (7.0 vs. 4.3 months, P = .004). Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm (P = .042).

The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid (either the AIO [Arbeitsgemeinschaft Internische Onkologie] or the deGramont regimen).⁵⁰ Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm (P = .032).^50,[Level of evidence: 1iiA] A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting.⁵¹ The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen (P = .003). This represents a survival hazard ratio of 0.79.

Another drug, raltitrexed (Tomudex), is a specific thymidylate synthase inhibitor that has demonstrated activity similar to that of bolus 5-FU and leucovorin.^52,[Level of evidence: 1iiA];⁵³ A number of other drugs are undergoing evaluation for the treatment of rectal cancer.^54,

Oxaliplatin, alone or combined with 5-FU and leucovorin, has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease.^55,56,57 One multicenter trial reported a response rate of 21%, a median progression-free survival of 5 months, and a median survival of 11 months.⁵⁸ Overall survival from the start of first-line chemotherapy was 19 months. In this trial, oxaliplatin was given first, followed by 48-hour infusion of 5-FU, with short leucovorin infusion.

The data and safety monitoring committees of the cooperative groups conducting studies comparing the value of 5-FU/leucovorin/CPT-11 to 5-FU/leucovorin in the adjuvant setting, and comparing the value to 5-FU/leucovorin/oxaliplatin or oxaliplatin/CPT-11 in the advanced disease setting, have suspended accrual to these trials because of an unexpectedly high death rate on the 5-FU/leucovorin/CPT-11 arms.⁵⁹ This 3-drug regimen appears to be more toxic than initially reported. The majority of deaths in both studies were observed in the first 60 days, usually during the first chemotherapy cycle. This may imply increased sensitivity in a minority of patients, possibly based on genetic differences in key steps in the metabolic activation/deactivation of irinotecan, 5-FU, or both agents. Additional analyses may provide guidance in dose adjustment for the initial cycle and/or in patient selection. For the present, the use of this regimen should be accompanied by careful attention to early signs of diarrhea, dehydration, neutropenia, or other toxic effects, especially during the first chemotherapy cycle.

Standard treatment options:

1. Surgical resection/anastomosis or bypass of obstructing lesions in selected cases or resection for palliation.^60,
2. Surgical resection of isolated metastases (liver, lung, ovaries).^{1,3,15,61,62,63,64,}
3. Chemoradiation for local palliation.^65,66,
4. Chemotherapy alone for distant disease after resection of local disease.
5. Clinical trials evaluating new drugs and biologic therapy.

¹ Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 77 (11): 1241-6, 1990.

² Steele G Jr, Bleday R, Mayer RJ, et al.: A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 9 (7): 1105-12, 1991.

³ Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110 (1): 13-29, 1991.

⁴ Pedersen IK, Burcharth F, Roikjaer O, et al.: Resection of liver metastases from colorectal cancer. Indications and results. Dis Colon Rectum 37 (11): 1078-82, 1994.

⁵ Harmon KE, Ryan JA Jr, Biehl TR, et al.: Benefits and safety of hepatic resection for colorectal metastases. Am J Surg 177 (5): 402-4, 1999.

⁶ Fong Y, Cohen AM, Fortner JG, et al.: Liver resection for colorectal metastases. J Clin Oncol 15 (3): 938-46, 1997.

⁷ Headrick JR, Miller DL, Nagorney DM, et al.: Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 71 (3): 975-9; discussion 979-80, 2001.

⁸ Thomas DS, Nauta RJ, Rodgers JE, et al.: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Results of a phase I-II trial. Cancer 71 (6): 1977-81, 1993.

⁹ Ravikumar TS: Interstitial therapies for liver tumors. Surg Oncol Clin N Am 5 (2): 365-77, 1996.

¹⁰ Ravikumar TS, Kaleya R, Kishinevsky A: Surgical ablative therapy of liver tumors. Cancer: Principles and Practice of Oncology Updates 14 (3): 1-12, 2000.

¹¹ Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228 (2): 201-8, 1998.

¹² McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 53 (5): 780-5; discussion 785-6, 1992.

¹³ Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 14 (7): 2047-53, 1996.

¹⁴ Kemeny N, Huang Y, Cohen AM, et al.: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341 (27): 2039-48, 1999.

¹⁵ Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8 (11): 1885-93, 1990.

¹⁶ Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 107 (4): 459-65, 1987.

¹⁷ Chang AE, Schneider PD, Sugarbaker PH, et al.: A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206 (6): 685-93, 1987.

¹⁸ Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 10 (7): 1112-8, 1992.

¹⁹ Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst 88 (5): 252-8, 1996.

²⁰ Kemeny N, Cohen A, Seiter K, et al.: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer. J Clin Oncol 11 (2): 330-5, 1993.

²¹ Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330 (16): 1136-42, 1994.

²² Schmoll HJ, Büchele T, Grothey A, et al.: Where do we stand with 5-fluorouracil? Semin Oncol 26 (6): 589-605, 1999.

²³ Grothey A, Schmoll HJ: New chemotherapy approaches in colorectal cancer. Curr Opin Oncol 13 (4): 275-86, 2001.

²⁴ Poon MA, O'Connell MJ, Wieand HS, et al.: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9 (11): 1967-72, 1991.

²⁵ Valone FH, Friedman MA, Wittlinger PS, et al.: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group. J Clin Oncol 7 (10): 1427-36, 1989.

²⁶ Petrelli N, Douglass HO Jr, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 7 (10): 1419-26, 1989.

²⁷ Erlichman C, Fine S, Wong A, et al.: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6 (3): 469-75, 1988.

²⁸ Doroshow JH, Multhauf P, Leong L, et al.: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8 (3): 491-501, 1990.

²⁹ Buroker TR, O'Connell MJ, Wieand HS, et al.: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12 (1): 14-20, 1994.

³⁰ Jäger E, Heike M, Bernhard H, et al.: Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial.Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol 14 (8): 2274-9, 1996.

³¹ Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 12 (5): 960-9, 1994.

³² Blijham G, Wagener T, Wils J, et al.: Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study. J Clin Oncol 14 (8): 2266-73, 1996.

³³ Kosmidis PA, Tsavaris N, Skarlos D, et al.: Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. J Clin Oncol 14 (10): 2682-7, 1996.

³⁴ Greco FA, Figlin R, York M, et al.: Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 14 (10): 2674-81, 1996.

³⁵ Hansen RM, Ryan L, Anderson T, et al.: Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst 88 (10): 668-74, 1996.

³⁶ Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol 16 (1): 301-8, 1998.

³⁷ Hoff PM, Royce M, Medgyesy D, et al.: Oral fluoropoyrimidines. Semin Oncol 26 (6): 640-6, 1999.

³⁸ Leichman CG, Fleming TR, Muggia FM, et al.: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13 (6): 1303-11, 1995.

³⁹ Twelves C, Boyer M, Findlay M, et al.: Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer 37 (5): 597-604, 2001.

⁴⁰ Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. Meta-Analysis Group In Cancer. J Clin Oncol 16 (11): 3537-41, 1998.

⁴¹ Gamelin E, Boisdron-Celle M, Guérin-Meyer V, et al.: Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 17 (4): 1105, 1999.

⁴² Morrison GB, Bastian A, Dela Rosa T, et al.: Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncol Nurs Forum 24 (1): 83-8, 1997 Jan-Feb.

⁴³ Diasio RB: Clinical implications of dihydropyrimidine dehydrogenase inhibition. Oncology (Huntingt) 13 (7 Suppl 3): 17-21, 1999.

⁴⁴ Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.

⁴⁵ Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14 (3): 709-15, 1996.

⁴⁶ Cunningham D, Pyrhonen S, James RD, et al.: A phase III multicenter randomized study of CPT-11 versus supportive care (SC) alone in patients (Pts) with 5FU-resistant metastatic colorectal cancer (MCRC). [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-1, 1a, 1998.

⁴⁷ Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352 (9138): 1407-12, 1998.

⁴⁸ Cunningham D, Pyrhönen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352 (9138): 1413-8, 1998.

⁴⁹ Saltz LB, Cox JV, Blanke C, et al.: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343 (13): 905-14, 2000.

⁵⁰ Douillard JY, Cunningham D, Roth AD, et al.: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355 (9209): 1041-7, 2000.

⁵¹ Saltz LB, Douillard J, Pirotta N, et al.: Combined analysis of two phase III randomized trials comparing irinotecan (C), fluorouracil (F), leucovorin (L) vs F alone as first-line therapy of previously untreated metastatic colorectal cancer (MCRC). [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-938, 242a, 2000.

⁵² Cunningham D: Mature results from three large controlled studies with raltitrexed ('Tomudex'). Br J Cancer 77 (Suppl 2): 15-21, 1998.

⁵³ Cocconi G, Cunningham D, Van Cutsem E, et al.: Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16 (9): 2943-52, 1998.

⁵⁴ Von Hoff DD: Promising new agents for treatment of patients with colorectal cancer. Semin Oncol 25 (5 Suppl 11): 47-52, 1998.

⁵⁵ de Gramont A, Vignoud J, Tournigand C, et al.: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33 (2): 214-9, 1997.

⁵⁶ Bleiberg H, de Gramont A: Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer. Semin Oncol 25 (2 Suppl 5): 32-9, 1998.

⁵⁷ Cvitkovic E, Bekradda M: Oxaliplatin: a new therapeutic option in colorectal cancer. Semin Oncol 26 (6): 647-62, 1999.

⁵⁸ André T, Bensmaine MA, Louvet C, et al.: Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 17 (11): 3560-8, 1999.

⁵⁹ Sargent DJ, Niedzwiecki D, O'Connell MJ, et al.: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345 (2): 144-5; discussion 146, 2001.

⁶⁰ Wanebo HJ, Koness RJ, Vezeridis MP, et al.: Pelvic resection of recurrent rectal cancer. Ann Surg 220 (4): 586-95; discussion 595-7, 1994.

⁶¹ Adson MA, van Heerden JA, Adson MH, et al.: Resection of hepatic metastases from colorectal cancer. Arch Surg 119 (6): 647-51, 1984.

⁶² Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. An evaluation of preoperative and postoperative factors. Ann Surg 202 (2): 203-8, 1985.

⁶³ Taylor M, Forster J, Langer B, et al.: A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 173 (6): 467-71, 1997.

⁶⁴ Jaeck D, Bachellier P, Guiguet M, et al.: Long-term survival following resection of colorectal hepatic metastases. Association Française de Chirurgie. Br J Surg 84 (7): 977-80, 1997.

⁶⁵ Wong CS, Cummings BJ, Brierley JD, et al.: Treatment of locally recurrent rectal carcinoma--results and prognostic factors. Int J Radiat Oncol Biol Phys 40 (2): 427-35, 1998.

⁶⁶ Crane CH, Janjan NA, Abbruzzese JL, et al.: Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer. Int J Radiat Oncol Biol Phys 49 (1): 107-16, 2001.

Recurrent Rectal Cancer

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.)

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following initial attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival.¹ The use of induction chemoradiation for previously nonirradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation.^2,3 Intraoperative radiation therapy in patients who received previous external beam radiation may improve local control in patients with locally recurrent disease with acceptable morbidity.⁴ The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.⁵ Patients with limited pulmonary metastases and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.^6,7,8,

In stage IV and recurrent rectal cancer, chemotherapy has been used for palliation with fluorouracil (5-FU)-based treatment and is considered to be standard therapy.^9,10 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin,^{11,12,13,14,15,16,17} methotrexate,¹⁸ or other agents.^{19,20,21,22,23} Interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy.^24,25 Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.²⁶ The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.²⁷ Oral regimens using prodrugs of 5-FU or inhibitors of DPD pharmacologically simulate continuous infusion and are under clinical evaluation.²⁸ The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and toxic effects profile of the chosen regimen, as well as cost and quality-of-life issues.^29,30 Innovative ways of altering toxic effects patterns, and potentially improving clinical benefit, include chronomodulated therapy, in which drug doses are varied throughout the day to allow for greater dose intensity without increased toxic effects.^31,32 In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous infusion or bolus administration.^33,

Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic rectal cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.^34,35 Irinotecan is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.³⁶

CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU.^37,38,[Level of evidence: 1iiA,1iiC]

Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT-11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival.³⁹ The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival.^39,[Level of evidence: 1iiA] The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time-to-tumor progression was significantly prolonged with the combination (7.0 vs. 4.3 months, P = .004). Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm (P = .042).

The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid (either the AIO [Arbeitsgemeinschaft Internische Onkologie] or the deGramont regimen).⁴⁰ Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm (P = .032).^40,[Level of evidence: 1iiA] A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting.⁴¹ The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen (P = .003). This represents a survival hazard ratio of 0.79.

Another drug, raltitrexed (Tomudex), is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin.^42,[Level of evidence: 1iiA];⁴³ A number of other drugs are undergoing evaluation for the treatment of rectal cancer.^44,

Oxaliplatin, alone or combined with 5-FU and leucovorin, has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease.^45,46,47 One multicenter trial reported a response rate of 21%, a median progression-free survival of 5 months, and a median survival of 11 months.⁴⁸ Overall survival from the start of first-line chemotherapy was 19 months. In this trial, oxaliplatin was given first, followed by 48-hour infusion of 5-FU, with short leucovorin infusion.

The data and safety monitoring committees of the cooperative groups conducting studies comparing the value of 5-FU/leucovorin/CPT-11 to 5-FU/leucovorin in the adjuvant setting, and comparing the value to 5-FU/leucovorin/oxaliplatin or oxaliplatin/CPT-11 in the advanced disease setting have suspended accrual to these trials because of an unexpectedly high death rate on the 5-FU/leucovorin/CPT-11 arms.⁴⁹ This 3 drug regimen appears to be more toxic than initially reported. The majority of deaths in both studies were observed in the first 60 days, usually during the first chemotherapy cycle. This may imply increased sensitivity in a minority of patients, possibly based on genetic differences in key steps in the metabolic activation/deactivation of irinotecan, 5-FU, or both agents. Additional analyses may provide guidance in dose adjustment for the initial cycle and/or in patient selection. For the present, the use of this regimen should be accompanied by careful attention to early signs of diarrhea, dehydration, neutropenia, or other toxic effects, especially during the first chemotherapy cycle.

Standard treatment options:

1. Resection of locally recurrent rectal cancer may be palliative or curative in selected patients.^50,
2. Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).^{37,51,52,53,54,55,56,}
3. Resection of isolated pulmonary or ovarian metastases.
4. Palliative radiation therapy.^4,38,
5. Palliative chemotherapy.^{11,12,13,14,15,19,57,}
6. Palliative chemoradiation.
7. Palliative endoscopic-placed stents to relieve obstruction.^58,

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² Lowy AM, Rich TA, Skibber JM, et al.: Preoperative infusional chemoradiation, selective intraoperative radiation, and resection for locally advanced pelvic recurrence of colorectal adenocarcinoma. Ann Surg 223 (2): 177-85, 1996.

³ Valentini V, Morganti AG, De Franco A, et al.: Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome. Cancer 86 (12): 2612-24, 1999.

⁴ Haddock MG, Gunderson LL, Nelson H, et al.: Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys 49 (5): 1267-74, 2001.

⁵ Rodriguez-Bigas MA, Herrera L, Petrelli NJ: Surgery for recurrent rectal adenocarcinoma in the presence of hydronephrosis. Am J Surg 164 (1): 18-21, 1992.

⁶ McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 53 (5): 780-5; discussion 785-6, 1992.

⁷ Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 14 (7): 2047-53, 1996.

⁸ Headrick JR, Miller DL, Nagorney DM, et al.: Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 71 (3): 975-9; discussion 979-80, 2001.

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²⁸ Hoff PM, Royce M, Medgyesy D, et al.: Oral fluoropoyrimidines. Semin Oncol 26 (6): 640-6, 1999.

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