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Important: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Rectal cancer


Table of Contents

GENERAL INFORMATION
Adjuvant therapy
Advanced disease
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
Stage 0
Stage I
Stage II
Stage III
Stage IV
TREATMENT OPTION OVERVIEW
STAGE 0 RECTAL CANCER
STAGE I RECTAL CANCER
Stage I (old stage: Dukes' A or Modified Astler-Coller A and B1)
STAGE II RECTAL CANCER
Stage II (old staging: Dukes' B or Modified Astler-Coller B2 and B3)
STAGE III RECTAL CANCER
Stage III (old staging: Dukes' C or Modified Astler-Coller C1-C3)
STAGE IV RECTAL CANCER
RECURRENT RECTAL CANCER

GENERAL INFORMATION

(Separate summaries containing information on screening for colorectal cancer and prevention of colorectal cancer are also available in PDQ.)

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 levels of evidence summary 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).[1] EUS is an accurate method of evaluating tumor stage (up to 95% accuracy), nodal stage (up to 74% accuracy), and regional peritoneal disease (no accuracy reported). 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. Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with rectal cancer, although most have not been prospectively validated.[2] 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.[3] The radial margin of resection of rectal primaries may also predict for local recurrence.[4]

Because of the frequency of the disease, the demonstrated slow growth of primary lesions, the better survival 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.[5] 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), Lynch I Syndrome, Lynch II Syndrome, and ulcerative colitis.[6] 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.[7][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.[8,9] 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.[10] For more information on this subject, consult the PDQ summaries on screening for colorectal cancer and prevention of colorectal cancer.

Following treatment of rectal cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.[11] 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.[12,13] Postoperative monitoring may detect asymptomatic recurrences that can be resected or metachronous tumors.[14-16] 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.[17] However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear.[18]


Adjuvant therapy

Patients with stage II or 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;[11,19-21] although a Swedish trial has shown a survival advantage from preoperative radiation therapy compared to surgery alone.[22][Level of evidence: 1iiA] Two trials have confirmed that fluorouracil (5-FU) plus radiation therapy is effective and may be considered standard treatment.[19-21] 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.[23] 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 end points 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. There is no evidence that chemotherapy improves survival, although short-term palliation may be achieved in approximately 10% to 20% of patients. Several studies suggest an advantage in terms of response rate and palliation of symptoms, but not always in terms of survival when leucovorin is added to 5-FU.[24-28] Reoperation for recurrences in the pelvis may provide palliation and occasionally long-term disease control.

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. Clinical stage remains the most important prognostic indicator.

References:

  1. Snady H, Merrick MA: Improving the treatment of colorectal cancer: the role of EUS. Cancer Investigation 16(8): 572-581, 1998.

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

  3. Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1(8496): 1479-1482, 1986.

  4. de Haas-Kock DF, Baeten CG, Jager JJ, et al.: Prognostic significance of radial margins of clearance in rectal cancer. British Journal of Surgery 83(6): 781-785, 1996.

  5. Cannon-Albright LA, Skolnick MH, Bishop DT, et al.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. New England Journal of Medicine 319(9): 533-537, 1988.

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

  7. Watson P, Lin KM, Rodriguez-Bigas MA, et al.: Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83(2): 259-266, 1998.

  8. Ransohoff DF, Lang CA: Screening for colorectal cancer. New England Journal of Medicine 325(1): 37-41, 1991.

  9. Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. New England Journal of Medicine 331(25): 1669-1674, 1994.

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

  11. Martin EW, Minton JP, Carey LC: CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma. Annals of Surgery 202(1): 310-317, 1985.

  12. Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Diseases of the Colon and Rectum 36(7): 636-644, 1993.

  13. Moertel CG, Fleming TR, Macdonald JS, et al.: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. Journal of the American Medical Association 270(8): 943-947, 1993.

  14. Bruinvels DJ, Stiggelbout AM, Kievit J, et al.: Follow-up of patients with colorectal cancer: a meta-analysis. Annals of Surgery 219(2): 174-182, 1994.

  15. Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Annals of Surgery 220(2): 206-211, 1994.

  16. Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Diseases of the Colon and Rectum 39(3): 252-256, 1996.

  17. American Society of Clinical Oncology: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Journal of Clinical Oncology 14(10): 2843-2877, 1996.

  18. Rosen M, Chan L, Beart RW, et al.: Follow-up of colorectal cancer: a meta-analysis. Diseases of the Colon and Rectum 41(9): 1116-1126, 1998.

  19. 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. Proceedings of the American Society of Clinical Oncology 10: A-403, 134, 1991.

  20. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Journal of Clinical Oncology 10(4): 549-557, 1992.

  21. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  22. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. New England Journal of Medicine 336(14): 980-987, 1997.

  23. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Annals of Surgery 220(5): 676-682, 1994.

  24. Petrelli N, Herrera L, Rustum Y, et al.: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. Journal of Clinical Oncology 5(10): 1559-1565, 1987.

  25. 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. Journal of Clinical Oncology 8(3): 491-501, 1990.

  26. 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. Journal of Clinical Oncology 9(11): 1967-1972, 1991.

  27. 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. Journal of Clinical Oncology 7(10): 1427-1436, 1989.

  28. Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Journal of Clinical Oncology 7(10): 1419-1426, 1989.


CELLULAR CLASSIFICATION

adenocarcinoma (majority of 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: A separate summary on gastrointestinal carcinoid tumor is
also available in PDQ.

References:

  1. Saclarides TJ, Szeluga D, Staren ED: Neuroendocrine cancers of the colon and rectum: results of a ten-year experience. Diseases of the Colon and Rectum 37(7): 635-642, 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 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**

*Note: 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.

**Note: 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.

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 greater than 3 mm in diameter in the perirectal or pericolic fat
without histologic evidence of a residual node in the nodule is classified as
regional perirectal or pericolic lymph node metastasis. A tumor nodule 3 mm
or less in diameter is classified in the T category as a noncontiguous
extension, that is T3.[1]

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


Stage 0

Tis, N0, M0


Stage I

T1, N0, M0
T2, N0, M0


Stage II

T3, N0, M0
T4, N0, M0


Stage III

Any T, N1, M0
Any T, N2, M0


Stage IV

Any T, Any N, M1

References:

  1. Colon and rectum. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 83-90.


TREATMENT OPTION OVERVIEW

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 levels of evidence summary for more information.

Treatment of rectal cancer is surgical resection of the primary and regional lymph nodes for localized disease. The technique of rectal excision may impact the rate of local recurrence. Local failure rates in the range of 4% to 8% following rectal resection with appropriate mesorectal excision (total mesorectal excision for low/middle rectal tumors and mesorectal excision at least 5 centimeters below the tumor for high rectal tumors) have been reported.[1-5] The low incidence of local relapse following meticulous mesorectal excision has led some investigators to question the routine use of adjuvant radiation therapy. Total mesorectal excision combined with low stapled colorectal or coloanal anastomosis obviates the need, in many patients, for abdominoperineal resection and associated permanent stoma. However, the risk of anastomotic dehiscence with these sphincter-preserving procedures is considerable (>15%), necessitating routine temporary proximal diversion. 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.[6] Both preoperative and postoperative radiation therapy alone decrease local failure.[7-9] Substantial improvement in overall survival has not been demonstrated with adjuvant radiation alone, except in a single trial of preoperative radiation therapy.[9][Level of evidence: 1iiA]

A Consensus Development Conference on adjuvant therapy for patients with colon and rectal cancers was held at the National Institutes of Health (NIH), April 16-18, 1990. Updates of the National Surgical Adjuvant Breast and Bowel Project, Gastrointestinal Tumor Study Group (GITSG), and North Central Cancer Treatment Group-Mayo (CCTG-Mayo) experience were presented.[10-12] It was concluded that, based on the GITSG and NCCTG-Mayo results, combined modality treatment with chemotherapy and high-dose pelvic irradiation (45-55 Gy) is recommended for patients with stages II and III rectal cancer.

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 randomized trial has demonstrated that adjuvant 5-FU plus semustine was not more effective than a higher dose of 5-FU given alone, and that prolonged infusion of 5-FU was superior to bolus infusion of 5-FU during radiation therapy.[13] Thus, postoperative radiation and 5-FU alone may be considered standard.[13-15] 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.[16] 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 end points of disease-free and overall survival.

Several studies suggested 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.[17-21] Such treatment results in survival rates similar to those observed with more radical surgery without increasing the risk of pelvic or perineal recurrences. This therapeutic approach continues to be under evaluation. Several clinical trials are addressing this same issue.

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

References:

  1. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341(8843): 457-460, 1993.

  2. Enker WE, Thaler HT, Cranor ML, et al.: Total mesorectal excision in the operative treatment of carcinoma of the rectum. Journal of the American College of Surgeons 181(4): 335-346, 1995.

  3. Zaheer S, Pemberton JH, Farouk R, et al.: Surgical treatment of adenocarcinoma of the rectum. Annals of Surgery 227(6): 800-811, 1998.

  4. Heald RJ, Smedh RK, Kald A, et al.: Abdominoperineal excision of the rectum: an endangered operation. Diseases of the Colon and Rectum 40(7): 747-751, 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): 612-618, 1998.

  6. 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): 1278-1292, 1974.

  7. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 348(9042): 1605-1610, 1996.

  8. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet 348(9042): 1610-1614, 1996.

  9. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. New England Journal of Medicine 336(14): 980-987, 1997.

  10. Thomas PR, Lindblad AS: Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiotherapy and Oncology 13(4): 245-252, 1988.

  11. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. New England Journal of Medicine 324(11): 709-715, 1991.

  12. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 1990.

  13. 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. New England Journal of Medicine 331(8): 502-507, 1994.

  14. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Journal of Clinical Oncology 10(4): 549-557, 1992.

  15. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  16. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Annals of Surgery 220(5): 676-682, 1994.

  17. Mohiuddin M, Marks G: High dose preoperative irradiation for cancer of the rectum, 1976-1988. International Journal of Radiation Oncology, Biology, Physics 20(1): 37-43, 1991.

  18. Ng AK, Recht A, Busse PM: Sphincter preservation therapy for distal rectal carcinoma: a review. Cancer 79(4): 671-683, 1997.

  19. Mohiuddin M, Marks G, Bannon J: High-dose preoperative radiation and full thickness local excision: a new option for selected T3 distal rectal cancers. International Journal of Radiation Oncology, Biology, Physics 30(4): 845-849, 1994.

  20. Willett CG: Organ preservation in anal and rectal cancers. Current Opinion in Oncology 8(4): 329-333, 1996.

  21. Harms BA, Starling JR: Current status of sphincter preservation in rectal cancer. Oncology 4(8): 53-60, 1990.


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.

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. Electrofulguration.

4. Endocavitary irradiation.[2,3]

5. Local radiation therapy.[2]

References:

  1. Bailey HR, Huval WV, Max E, et al.: Local excision of carcinoma of the rectum for cure. Surgery 111(5): 555-561, 1992.

  2. Kodner IJ, Gilley MT, Shemesh EI, et al.: Radiation therapy as definitive treatment for selected invasive rectal cancer. Surgery 114(4): 850-857, 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. Journal of Clinical Oncology 15(10): 3241-3248, 1997.


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.

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 colo-anal 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] with or without perioperative external-beam irradiation plus fluorouracil (5-FU). There are no randomized trials comparing local excision with or without postoperative chemoradiation treatments to wide surgical resection (LAR and APR). 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 or venous invasion treated with full-thickness local excision that results in negative margins and with or without postoperative radiation therapy may have outcomes equivalent to APR or LAR.[2] 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.[3] 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.[4-6] Special equipment and experience are required to achieve results equivalent to surgery.

5. Electrofulguration, in highly selected instances, may be as effective as local excision.

References:

  1. Bailey HR, Huval WV, Max E, et al.: Local excision of carcinoma of the rectum for cure. Surgery 111(5): 555-561, 1992.

  2. Willett CG, Compton CC, Shellito PC, et al.: Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. Cancer 73(11): 2716-2720, 1994.

  3. Sitzler PJ, Seow-Choen F, Ho YH, et al.: Lymph node involvement and tumor depth in rectal cancers: an analysis of 805 patients. Diseases of the Colon and Rectum 40(12): 1472-1476, 1997.

  4. Sischy B, Graney MJ, Hinson EJ: Endocavitary irradiation for adenocarcinoma of the rectum. Ca-A Cancer Journal for Clinicians 34(6): 333-339, 1984.

  5. Kodner IJ, Gilley MT, Shemesh EI, et al.: Radiation therapy as definitive treatment for selected invasive rectal cancer. Surgery 114(4): 850-857, 1993.

  6. Maingon P, Guerif S, Darsouni R, et al.: Conservative management of rectal adenocarcinoma by radiotherapy. International Journal of Radiation Oncology, Biology, Physics 40(5): 1077-1085, 1998.


STAGE II RECTAL CANCER

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 levels of evidence summary for more information.


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

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

A randomized trial by the Gastrointestinal Tumor Study Group demonstrated an increase in both disease-free interval and overall survival when radiation therapy is combined with chemotherapy following surgical resection in patients whose rectal cancer has penetrated through the bowel wall into the perirectal fat or has metastasized to regional lymph nodes (stage III).[4] A disease-free survival advantage has been observed in patients with Astler-Coller B2 and C 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 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.[7] 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.[8] 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 end points of disease-free and overall survival.

Treatment options:

1. Wide surgical resection and low anterior resection with colorectal or colo-anal reanastomosis when feasible, followed by chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.[4,5,9-12]

2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.[9,13-15]

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.[7,16-19]

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.[20][Level of evidence: 3iiiDi];[21].

References:

  1. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 348(9042): 1605-1610, 1996.

  2. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet 348(9042): 1610-1614, 1996.

  3. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. New England Journal of Medicine 336(14): 980-987, 1997.

  4. Thomas PR, Lindblad AS: Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiotherapy and Oncology 13(4): 245-252, 1988.

  5. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. New England Journal of Medicine 324(11): 709-715, 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. New England Journal of Medicine 331(8): 502-507, 1994.

  7. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Annals of Surgery 220(5): 676-682, 1994.

  8. Dahlberg M, Glimelius B, Graf W, et al.: Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Diseases of the Colon and Rectum 41(5): 543-551, 1998.

  9. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 1990.

  10. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  11. Smalley SR, Southwest Oncology Group: Phase III Randomized Study of Adjuvant 5-FU in Patients with Stages B2/B3/C Rectal Cancer: Bolus vs Prolonged Venous Infusion (PVI) 5-FU Before and After Pelvic Irradiation, each with PVI 5-FU Radiosensitization, vs Bolus 5-FU/CF/LEV Before and After Radiotherapy (Summary Last Modified 12/1997), SWOG-9304, clinical trial, active, 03/01/1994.

  12. 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. Journal of Clinical Oncology 16(7): 2542-2547, 1998.

  13. 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. Annals of Surgery 204(4): 480-489, 1986.

  14. 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. Journal of Clinical Oncology 15(5): 2030-2039, 1997.

  15. 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. Annals of Oncology 4(Suppl 2): S21-S28, 1993.

  16. 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. International Journal of Radiation Oncology, Biology, Physics 40(3): 569-574, 1998.

  17. Mohiuddin M, Marks G, Bannon J: High-dose preoperative radiation and full thickness local excision: a new option for selected T3 distal rectal cancers. International Journal of Radiation Oncology, Biology, Physics 30(4): 845-849, 1994.

  18. 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, 10/28/1997.

  19. Valentini V, Coco C, Cellini N, et al.: Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. International Journal of Radiation Oncology, Biology, Physics 40(5): 1067-1075, 1998.

  20. Gunderson LL, Nelson H, Martenson JA, et al.: Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU. International Journal of Radiation Oncology, Biology, Physics 37(3): 601-614, 1997.

  21. 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. Annals of Surgery 228(2): 194-200, 1998.


STAGE III RECTAL CANCER

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 levels of evidence summary for more information.


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

Stage III rectal cancer denotes disease with lymph node involvement. The number of positive lymph nodes affects prognosis: patients with 1 to 3 involved nodes have superior survival to those with 4 or more involved nodes. Studies employing preoperative or postoperative radiation therapy alone have demonstrated decreased locoregional failure rates.[1-3] Significant improvement in overall survival has not been demonstrated with 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 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] 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.[10] 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.[11] However, a quality-of-life analysis 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.[12][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 end points of disease-free and overall survival.[13]

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.[4-6,14,15]

2. Wide surgical resection with abdominoperineal resection with adjuvant chemotherapy and postoperative radiation therapy, preferably through participation in a clinical trial.[6,16-18]

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

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

5. Intraoperative electron beam radiation therapy (IORT) to the sites of residual microscopic or gross residual disease following surgical extirpation can be considered at institutions where the appropriate equipment is available. When combined with external-beam radiation therapy and chemotherapy in highly selected patients, IORT has resulted in improved local control in a single institution experience.[22][Level of evidence: 3iiiDi].

6. Palliative chemoradiation.

References:

  1. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 348(9042): 1605-1610, 1996.

  2. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet 348(9042): 1610-1614, 1996.

  3. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. New England Journal of Medicine 336(14): 980-987, 1997.

  4. Thomas PR, Lindblad AS: Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiotherapy and Oncology 13(4): 245-252, 1988.

  5. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. New England Journal of Medicine 324(11): 709-715, 1991.

  6. National Institutes of Health: NIH Consensus Conference: adjuvant therapy for patients with colon and rectal cancer. Journal of the American Medical Association 264(11): 1444-1450, 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. Proceedings of the American Society of Clinical Oncology 10: A-403, 134, 1991.

  8. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Journal of Clinical Oncology 10(4): 549-557, 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. New England Journal of Medicine 331(8): 502-507, 1994.

  10. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Annals of Surgery 220(5): 676-682, 1994.

  11. Dahlberg M, Glimelius B, Graf W, et al.: Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Diseases of the Colon and Rectum 41(5): 543-551, 1998.

  12. 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. Journal of the National Cancer Institute 88(15): 1039-1045, 1996.

  13. 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®-03, clinical trial, closed, 06/30/1999.

  14. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  15. Smalley SR, Southwest Oncology Group: Phase III Randomized Study of Adjuvant 5-FU in Patients with Stages B2/B3/C Rectal Cancer: Bolus vs Prolonged Venous Infusion (PVI) 5-FU Before and After Pelvic Irradiation, each with PVI 5-FU Radiosensitization, vs Bolus 5-FU/CF/LEV Before and After Radiotherapy (Summary Last Modified 12/1997), SWOG-9304, clinical trial, active, 03/01/1994.

  16. Tepper JE, O'Connell MJ, Petroni GR, et al.: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. Journal of Clinical Oncology 15(5): 2030-2039, 1997.

  17. Wolmark N, Fisher B: An analysis of survival and treatment failure following abdominoperineal and sphincter-saving resection in Dukes' B and C rectal carcinoma: a report of the NSABP clinical trials. Annals of Surgery 204(4): 480-489, 1986.

  18. Rougier P, Nordlinger B: Large scale trial for adjuvant treatment in high risk resected colorectal cancers: rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Annals of Oncology 4(Suppl 2): S21-S28, 1993.

  19. Mohiuddin M, Regine WF, Marks GJ, et al.: High-dose preoperative radiation and the challenge of sphincter-preservation surgery for cancer of the distal 2 cm of the rectum. International Journal of Radiation Oncology, Biology, Physics 40(3): 569-574, 1998.

  20. 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, 10/28/1997.

  21. Valentini V, Coco C, Cellini N, et al.: Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. International Journal of Radiation Oncology, Biology, Physics 40(5): 1067-1075, 1998.

  22. Gunderson LL, Nelson H, Martenson JA, et al.: Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU. International Journal of Radiation Oncology, Biology, Physics 37(3): 601-614, 1997.


STAGE IV RECTAL CANCER

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 levels of evidence summary for more information.

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 30%.[1-4] Other local ablative techniques that have been used to manage liver metastases include cryosurgery, embolization, and interstitial radiation therapy.[5,6] 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. 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.[7][Level of evidence: 3iiiA] Hepatic intraarterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no improvement in survival when compared to systemic chemotherapy.[8-13] 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. Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[14,15]

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.[16] Combination chemotherapy has not been shown to be more effective than 5-FU alone. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin [17-23] or methotrexate.[24,25] Randomized clinical trials show that interferon alfa appears to add toxic effects but no clinical benefit to 5- FU therapy.[26,27] Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.[28] The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.[29] Oral regimens using prodrugs of 5-FU or inhibitors of dihydropyrimidine dehydrogenase (DPD) (GW 776C85) pharmacologically simulate continuous infusion and are under clinical evaluation. 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.[30] 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.[31]

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.[32-34]

Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy.[35,36] It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.[37] Another drug, Tomudex, is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin.[38][Level of evidence: 1iiA];[39] A number of other drugs are undergoing early evaluation for the treatment of colon cancer.[40] Oxaliplatin plus 5-FU and leucovorin has also shown activity in 5-FU refractory patients.[41]

Patients with advanced rectal cancer who have relapsed after either adjuvant therapy or treatment for advanced disease with 5-FU and leucovorin are often able to consider additional therapy. A number of approaches have been used in the treatment of such patients, including retreatment with 5-FU and treatment with CPT-11.[42] Patients retreated with bolus or infusional 5-FU following adjuvant 5-FU therapy or discontinuation of 5-FU in responding patients with metastatic disease have response rates and response durations similar to previously untreated patients.[42][Level of evidence: 2B] 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. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.[43][Levels of evidence: 1iiA,1iiC];[44][Levels of evidence: 1iiA,1iiC]

Treatment options:

1. Surgical resection/anastomosis or bypass of obstructing lesions in selected cases or resection for palliation.[45]

2. Surgical resection of isolated metastases (liver, lung, ovaries).[1,3,8,46-49]

3. Chemoradiation.[50]

4. Clinical trials evaluating new drugs and biologic therapy.

References:

  1. Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. British Journal of Surgery 77(11): 1241-1246, 1990.

  2. Steele G, 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. Journal of Clinical Oncology 9(7): 1105-1112, 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. Diseases of the Colon and Rectum 37(11): 1078-1082, 1994.

  5. Thomas DS, Nauta RJ, Rodgers JE, et al.: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Cancer 71(6): 1977-1981, 1993.

  6. Ravikumar TS: Interstitial therapies for liver tumors. Surgical Oncology Clinics of North America 5(2): 365-377, 1996.

  7. Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Annals of Surgery 228(2): 201-208, 1998.

  8. Wagman LD, Kemeny MM, Leong L, et al.: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. Journal of Clinical Oncology 8(11): 1885-1893, 1990.

  9. Kemeny N, Daly J, Reichman B, et al.: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Annals of Internal Medicine 107(4): 459-465, 1987.

  10. 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. Annals of Surgery 206(6): 685-693, 1987.

  11. Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. Journal of Clinical Oncology 10(7): 1112-1118, 1992.

  12. Meta-Analysis Group In Cancer: Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Journal of the National Cancer Institute 88(5): 252-258, 1996.

  13. 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. Journal of Clinical Oncology 11(2): 330-335, 1993.

  14. McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Annals of Thoracic Surgery 53(5): 780-786, 1992.

  15. Girard P, Ducreux M, Baldeyrou P, et al.: Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. Journal of Clinical Oncology 14(7): 2047-2053, 1996.

  16. Moertel CG: Chemotherapy for colorectal cancer. New England Journal of Medicine 330(16): 1136-1142, 1994.

  17. 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. Journal of Clinical Oncology 9(11): 1967-1972, 1991.

  18. 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. Journal of Clinical Oncology 7(10): 1427-1436, 1989.

  19. Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Journal of Clinical Oncology 7(10): 1419-1426, 1989.

  20. Erlichman C, Fine S, Wong A, et al.: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. Journal of Clinical Oncology 6(3): 469-475, 1988.

  21. 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. Journal of Clinical Oncology 8(3): 491-501, 1990.

  22. 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. Journal of Clinical Oncology 12(1): 14-20, 1994.

  23. Jager 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. Journal of Clinical Oncology 14(8): 2274-2279, 1996.

  24. The Advanced Colorectal Cancer Meta-Analysis Project: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Journal of Clinical Oncology 12(5): 960-969, 1994.

  25. 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. Journal of Clinical Oncology 14(8): 2266-2273, 1996.

  26. 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. Journal of Clinical Oncology 14(10): 2682-2687, 1996.

  27. 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. Journal of Clinical Oncology 14(10): 2674-2681, 1996.

  28. Hansen RM, Ryan L, Anderson T, et al: Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. Journal of the National Cancer Institute 88(10): 668-674, 1996.

  29. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Journal of Clinical Oncology 16(1): 301-308, 1998.

  30. 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. Journal of Clinical Oncology 13(6): 1303-1311, 1995.

  31. Meta-Analysis Group in Cancer: Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. Journal of Clinical Oncology 16(11): 3537-3541, 1998.

  32. Gamelin E, Boisdron-Celle M, Guerin-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. Journal of Clinical Oncology 17(4): 1105-1110, 1999.

  33. Morrison GB, Bastian A, Dela Rosa T, et al.: Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncology Nursing Forum 24(1): 83-88, 1997.

  34. Diasio RB: Clinical implications of dihydropyrimidine dehydrogenase inhibition. Oncology (Huntington NY) 13(7 suppl 3): 17-21, 1999.

  35. Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. Journal of Clinical Oncology 14(4): 1128-1135, 1996.

  36. Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Journal of Clinical Oncology 14(3): 709-715, 1996.

  37. 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). Proceedings of the American Society of Clinical Oncology 17: A-1, 1a, 1998.

  38. Cunningham D: Mature results from three large controlled studies with raltitrexed ('Tomudex'). British Journal of Cancer 77(Suppl 2): 15-21, 1998.

  39. 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. Journal of Clinical Oncology 16(9): 2943-2952, 1998.

  40. Von Hoff DD: Promising new agents for treatment of patients with colorectal cancer. Seminars in Oncology 25(5, suppl 11): 47-52, 1998.

  41. 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. European Journal of Cancer 33(2): 214-219, 1997.

  42. Goldberg RM: Is repeated treatment with a 5-fluorouracil-based regimen useful in colorectal cancer? Seminars in Oncology 25(5, suppl 11): 21-28, 1998.

  43. 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): 1407-1412, 1998.

  44. Cunningham D, Pyrhonen 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): 1413-1418, 1998.

  45. Wanebo HJ, Koness RJ, Vezeridis MP: Pelvic resection of recurrent rectal cancer. Annals of Surgery 220(4): 586-597, 1994.

  46. Adson MA, van Heerden JA, Wagner JS, et al.: Resection of hepatic metastases from colorectal cancer. Archives of Surgery 119(6): 647-651, 1984.

  47. Coppa GF, Eng K, Ranson JH, et al.: Hepatic resection for metastatic colon and rectal cancer. Annals of Surgery 202(2): 203-208, 1985.

  48. Taylor M, Forster J, Langer B, et al.: A study of prognostic factors for hepatic resection for colorectal metastases. American Journal of Surgery 173(6): 467-471, 1997.

  49. Jaeck D, Bachellier P, Guiguet M, et al.: Long-term survival following resection of colorectal hepatic metastases. British Journal of Surgery 84(7): 977-980, 1997.

  50. Wong CS, Cummings BJ, Brierley JD, et al.: Treatment of locally recurrent rectal carcinoma: results and prognostic factors. International Journal of Radiation Oncology, Biology, Physics 40(2): 427-435, 1998.


RECURRENT RECTAL CANCER

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 levels of evidence summary 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 non-irradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation.[2] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[3] Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[4,5]

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.[6] Combination chemotherapy has not been shown to be more effective than 5-FU alone. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin,[7-13] methotrexate,[14] or other agents.[15-19] Interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy.[20,21] Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival.[22] The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis.[23] Oral regimens using prodrugs of 5-FU or inhibitors of DPD (GW 776C85) pharmacologically simulate continuous infusion and are under clinical evaluation. 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.[24] 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.[25,26] 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.[27]

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.[28-30] It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.[31] Another drug, Tomudex, is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin.[32][Level of evidence: 1iiA];[33] A number of other drugs are undergoing early evaluation for the treatment of rectal cancer.[34] Oxaliplatin plus 5-FU and leucovorin has also shown activity in 5-FU refractory patients.[35]

Patients with advanced rectal cancer who have relapsed after either adjuvant therapy or treatment for advanced disease with 5-FU and leucovorin are often able to consider additional therapy. A number of approaches have been used in the treatment of such patients, including retreatment with 5-FU and treatment with CPT-11.[36] Patients retreated with bolus or infusional 5-FU following adjuvant 5-FU therapy or discontinuation of 5-FU in responding patients with metastatic disease have response rates and response durations similar to previously untreated patients.[36][Level of evidence: 2B] 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. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.[37][Levels of evidence: 1iiA,1iiC];[38][Levels of evidence: 1iiA,1iiC]

Treatment options:

1. Resection of locally recurrent rectal cancer may be palliative or curative in selected patients.[39]

2. Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).[40-46]

3. Resection of isolated pulmonary or ovarian metastases.

4. Palliative radiation therapy.[47]

5. Palliative chemotherapy in phase I and II clinical trials.[7-11,15,48]

6. Palliative chemoradiation.

References:

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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. Annals of Surgery 223(2): 177-185, 1996.

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

  4. McAfee MK, Allen MS, Trastek VF, et al.: Colorectal lung metastases: results of surgical excision. Annals of Thoracic Surgery 53(5): 780-786, 1992.

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  7. 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. Journal of Clinical Oncology 7(10): 1427-1436, 1989.

  8. Petrelli N, Douglass HO, Herrera L, et al.: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Journal of Clinical Oncology 7(10): 1419-1426, 1989.

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  11. 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. Journal of Clinical Oncology 9(11): 1967-1972, 1991.

  12. 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. Journal of Clinical Oncology 12(1): 14-20, 1994.

  13. Jager 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. Journal of Clinical Oncology 14(8): 2274-2279, 1996.

  14. The Advanced Colorectal Cancer Meta-Analysis Project: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Journal of Clinical Oncology 12(5): 960-969, 1994.

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  16. Kemeny N, Younes A, Seiter K, et al.: Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma: assessment of activity and toxicity. Cancer 66(12): 2470-2475, 1990.

  17. Pazdur R, Ajani JA, Patt YZ, et al.: Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. Journal of Clinical Oncology 8(12): 2027-2031, 1990.

  18. The Corfu-A Study Group: Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. Journal of Clinical Oncology 13(4): 921-928, 1995.

  19. Hill M, Norman A, Cunningham D, et al.: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. Journal of Clinical Oncology 13(6): 1297-1302, 1995.

  20. 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. Journal of Clinical Oncology 14(10): 2682-2687, 1996.

  21. 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. Journal of Clinical Oncology 14(10): 2674-2681, 1996.

  22. Hansen RM, Ryan L, Anderson T, et al: Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. Journal of the National Cancer Institute 88(10): 668-674, 1996.

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  24. 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. Journal of Clinical Oncology 13(6): 1303-1311, 1995.

  25. Levi FA, Zidani R, Vannetzel J, et al.: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (Leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute 86(21): 1608-1617, 1994.

  26. Bertheault-Cvitkovic F, Jami A, Ithzaki M, et al.: Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. Journal of Clinical Oncology 14(11): 2950-2958, 1996.

  27. Meta-Analysis Group in Cancer: Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. Journal of Clinical Oncology 16(11): 3537-3541, 1998.

  28. Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. Journal of Clinical Oncology 14(4): 1128-1135, 1996.

  29. Conti JA, Kemeny NE, Saltz LB, et al.: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Journal of Clinical Oncology 14(3): 709-715, 1996.

  30. Rougier P, Bugat R, Douillard JY, et al.: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. Journal of Clinical Oncology 15(1): 251-260, 1997.

  31. 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). Proceedings of the American Society of Clinical Oncology 17: A-1, 1a, 1998.

  32. Cunningham D: Mature results from three large controlled studies with raltitrexed ('Tomudex'). British Journal of Cancer 77(Suppl 2): 15-21, 1998.

  33. 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. Journal of Clinical Oncology 16(9): 2943-2952, 1998.

  34. Von Hoff DD: Promising new agents for treatment of patients with colorectal cancer. Seminars in Oncology 25(5, suppl 11): 47-52, 1998.

  35. 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. European Journal of Cancer 33(2): 214-219, 1997.

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  38. Cunningham D, Pyrhonen 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): 1413-1418, 1998.

  39. Wanebo HJ, Koness RJ, Vezeridis MP: Pelvic resection of recurrent rectal cancer. Annals of Surgery 220(4): 586-597, 1994.

  40. Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. British Journal of Surgery 77(11): 1241-1246, 1990.

  41. Adson MA, van Heerden JA, Wagner JS, et al.: Resection of hepatic metastases from colorectal cancer. Archives of Surgery 119(6): 647-651, 1984.

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  43. Gayowski TJ, Iwatsuki S, Madariaga JR, et al.: Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 116(4): 703-711, 1994.

  44. Fernandez-Trigo V, Shamsa F, Sugarbaker PH, et al.: Repeat liver resections from colorectal metastasis. Surgery 117(3): 296-304, 1995.

  45. Taylor M, Forster J, Langer B, et al.: A study of prognostic factors for hepatic resection for colorectal metastases. American Journal of Surgery 173(6): 467-471, 1997.

  46. Jaeck D, Bachellier P, Guiguet M, et al.: Long-term survival following resection of colorectal hepatic metastases. British Journal of Surgery 84(7): 977-980, 1997.

  47. Wong CS, Cummings BJ, Brierley JD, et al.: Treatment of locally recurrent rectal carcinoma: results and prognostic factors. International Journal of Radiation Oncology, Biology, Physics 40(2): 427-435, 1998.

  48. Grem JL, Jordan E, Robson ME, et al.: Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. Journal of Clinical Oncology 11(9): 1737-1745, 1993.

Date Last Modified: 11/1999



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