Purpose of This PDQ Summary
General Information About Rectal Cancer

Related Summaries Statistics Epidemiology Anatomy Risk Factors         Genetic risk factors         Other risk factors Clinical Presentation and Symptoms Clinical Evaluation and Staging Treatment Prognostic Factors Follow-up

Cellular Classification and Pathology of Rectal Cancer

Epithelial Tumors Nonepithelial Tumors

Stage Information for Rectal Cancer

TNM Definitions AJCC Stage Groupings

Treatment Option Overview

Preoperative Chemoradiation Therapy Postoperative Chemoradiation Therapy         Chemotherapy         Addition of Radiation Therapy The Role of Oxaliplatin for Localized Disease Treatment Toxicity

Stage 0 Rectal Cancer

Current Clinical Trials

Stage I Rectal Cancer

Current Clinical Trials

Stage II Rectal Cancer

Current Clinical Trials

Stage III Rectal Cancer

Current Clinical Trials

Stage IV and Recurrent Rectal Cancer

Metastatic Rectal Cancer         First-line Multiagent Chemotherapy         Second-line and Third-line Chemotherapy         Liver Metastases         Current Clinical Trials Locally Recurrent Rectal Cancer Current Clinical Trials

Get More Information From NCI
Changes to This Summary (12/12/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of rectal cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

Back to Top

General Information About 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.)

Other PDQ summaries containing information related to rectal cancer include:

• Unusual Cancers of Childhood Treatment (colorectal cancer in children).
• Genetics of Colorectal Cancer.
• Colorectal Cancer Prevention.
• Colorectal Cancer Screening.

Note: Estimated new cases and deaths from rectal cancer in the United States in 2008:[1]

• New cases: 40,740.



• Deaths (colon and rectal cancers combined): 49,960.

  It is difficult to separate epidemiological considerations of rectal cancer from those of colon cancer because epidemiological studies often consider colon and rectal cancer (i.e., colorectal cancer) together.

Worldwide, colorectal cancer is the third most common form of cancer. In 2000, colorectal cancer accounted for 9.4% of the world's new cancers, with 945,000 cases diagnosed, and 7.9% of the world's cancer deaths, with 492,000 deaths.[2] Colorectal cancer affects men and women almost equally. Among all racial groups in the United States, African Americans have the highest sporadic colorectal cancer incidence and mortality rates.[3,4]

Adenocarcinomas account for the vast majority of rectal tumors in the United States.[5] Rare tumors, including carcinoid tumors, lymphomas, and neuroendocrine tumors, account for less than 3% of colorectal tumors.[5]

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

The rectum is located within the pelvis, extending from the transitional mucosa of the anal dentate line to the sigmoid colon at the peritoneal reflection; by rigid sigmoidoscopy, the rectum measures between 10 cm and 15 cm from the anal verge.[6] The location of a rectal tumor is usually indicated by the distance between the anal verge, dentate line, or anorectal ring and the lower edge of the tumor, with measurements differing depending on the use of a rigid or flexible endoscope or digital examination.[7] The distance of the tumor from the anal sphincter musculature has implications for the ability to perform sphincter-sparing surgery. The bony constraints of the pelvis limit surgical access to the rectum, which results in a lesser likelihood of attaining widely negative margins and a higher risk of local recurrence.[6]

Individuals with certain known single-gene disorders are at an increased risk of developing rectal cancer. Single-gene disorders related to known syndromes account for about 10% to 15% of colorectal cancers. (Refer to the PDQ summary on Genetics of Colorectal Cancer for more information.) The hereditary colorectal cancer syndromes and some genes that are involved include:[7-9]

Nonpolyposis disorders

• Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome: mismatch repair (MMR) genes.

Polyposis disorders

• Familial adenomatous polyposis (FAP): APC gene.
• Turcot syndrome: APC gene; MMR genes.
• Attenuated familial adenomatous polyposis (AFAP): APC gene.
• Hyperplastic polyposis syndrome: BRAF and KRAS2 genes.

Hamartomatous disorders

• Peutz-Jeghers syndrome: STK11/LKB1 gene.
• Juvenile polyposis syndrome: SMAD4/DPC4 and BMPR1A genes.
• Cowden syndrome: PTEN gene.
• Ruvalcaba–Myhre–Smith syndrome: PTEN gene.
• Hereditary mixed polyposis syndrome.

HNPCC, the result of defects in MMR genes (involving hMSH2, hMLH1, hPMS1, hPMS2, or hMSH6) represents the most common form of hereditary colorectal cancer, accounting for approximately 3% to 5% of all colorectal malignancies.[8] The majority of genetically defined cases involve hMSH2 on chromosome 2p, and hMLH1 on chromosome 3p. In affected families, 15% to 60% of family members are found to have mutations in hMSH2 or hMLH1; the mutation prevalence depends on features of the family history.[10] Ashkenazi Jews also have an increased risk for colorectal cancer related to a mutation in the APC gene (I1307K), which occurs in 6% to 7% of the Ashkenazi Jewish population.[11]

More common conditions with an increased risk include:

• Personal history of colorectal cancer or colorectal adenomas.
• First-degree family history of colorectal cancer or colorectal adenomas.[12]
• Personal history of ovarian, endometrial, or breast cancer.[13,14]

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.[15] (Refer to the PDQ summaries on Colorectal Cancer Screening and Colorectal Cancer Prevention for more information.)

Similar to colon cancer, symptoms of rectal cancer may include:[16]

• Gastrointestinal bleeding.
• Change in bowel habits.
• Abdominal pain.
• Intestinal obstruction.
• Weight loss.
• Change in appetite.
• Weakness.

Excepting obstructive symptoms, the symptoms of rectal cancer neither necessarily correlate with the stage of disease nor signify a particular diagnosis.[17] Physical examination may reveal a palpable mass and bright blood in the rectum. With metastatic disease, adenopathy, hepatomegaly, or pulmonary signs may be present.[7] Laboratory examination may reveal iron-deficiency anemia and electrolyte and liver function abnormalities.

Accurate staging provides crucial information about the location and size of the primary tumor in the rectum, and, if present, the size, number, and location of any metastases. Accurate initial staging can influence therapy by helping to determine the type of surgical intervention and the choice of neoadjuvant therapy to maximize the likelihood of resection with clear margins. In primary rectal cancer, pelvic imaging helps determine the depth of tumor invasion, the distance from the sphincter complex, the potential for achieving negative circumferential (radial) margins, and the involvement of locoregional lymph nodes or adjacent organs.[18] The initial clinical evaluation and staging procedures may include:[7,18-23]

• Digital-rectal examination and/or rectovaginal exam and rigid proctoscopy to determine if sphincter-saving surgery is possible.[7,18,19]



• Complete colonoscopy to rule out cancers elsewhere in the bowel.[7]



• Pan-body computed tomography (CT) scan to rule out metastatic disease.[7]



• Magnetic resonance imaging (MRI) of the abdomen and pelvis to determine the depth of penetration and the potential for achieving negative circumferential (radial) margins, as well as to identify locoregional nodal metastases and distant metastatic disease.[18]



• Endorectal ultrasound (ERUS) with a rigid probe or a flexible scope for stenotic lesions to determine the depth of penetration and identify locoregional nodal metastases.[19,21]



• Positron emission tomography (PET) to image distant metastatic disease.[18]



• Measurement of the serum carcinoembryonic antigen (CEA) level for prognostic assessment and the determination of response to therapy.[22,23]

In the tumor (T) staging of rectal carcinoma, several studies indicate that the accuracy of EUS ranges from 80% to 95% compared with 65% to 75% for CT and 75% to 85% for MRI. The accuracy in determining metastatic nodal involvement by EUS is approximately 70% to 75% compared with 55% to 65% for CT and 60% to 70% for MRI.[19] In a meta-analysis of 84 studies, none of the three imaging modalities, including EUS, CT, and MRI, were found to be significantly superior to the others in staging nodal status.[24] ERUS using a rigid probe may be similarly accurate in T and regional lymph node (N) staging when compared to EUS using a flexible scope; however, a technically difficult ERUS may give an inconclusive or inaccurate result for both T stage and N stage. In this case, further assessment by MRI or flexible EUS may be considered.[21,25]

In patients with rectal cancer, the circumferential resection margin (CRM) is an important pathological staging parameter. Measured in millimeters, it is defined as the retroperitoneal or peritoneal adventitial soft-tissue margin closest to the deepest penetration of tumor.[26]

Although based on retrospective data, the American Joint Committee on Cancer and a National Cancer Institute-sponsored panel have recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by the tumor.[26-28][Level of evidence: 3iiiA] 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 have demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with therapeutic outcome.[29-32] Staging studies may be required if recurrence or progression of disease is suspected; MRI may be particularly helpful in determining sacral involvement in local recurrence.[18]

Due to the increased risk of local recurrence and a poorer overall prognosis, the management of rectal cancer varies somewhat from that of colon cancer. Differences include surgical technique, the use of radiation therapy, and the method of chemotherapy administration. In addition to determining the intent of rectal cancer surgery (i.e., curative or palliative), it is important to consider therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary, and sexual functions.[25,33] The approach to the management of rectal cancer should be multimodal and should involve a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.

The surgical approach to treatment varies according to the location, stage, and presence or absence of high-risk features (i.e., positive margins, lymphovascular invasion, perineural invasion, and poorly differentiated histology) and may include:[25,33,34]

• Polypectomy for select T1 cancers.



• Transanal local excision (LE) and transanal endoscopic microsurgery (TEM) for select clinically staged T1/T2 N0 rectal cancers.



• Total mesorectal excision (TME) with autonomic nerve preservation (ANP) techniques via low anterior resection (LAR).



• TME via abdominoperineal resection (APR) for patients who are not candidates for sphincter-preserving operations, leaving patients with a permanent end-colostomy.

Polypectomy alone for cure may be used in certain instances in which polyps with invasive cancer can be completely resected with clear margins and have favorable histologic features.[35,36] For patients with advanced cancers of the mid- to upper rectum, LAR followed by the creation of a colorectal anastomosis may be the treatment of choice. However, in general, for locally advanced rectal cancers for which radical resection is indicated, TME with ANP techniques via LAR is preferable to APR.[25,33]

Although postoperative therapy for patients with stage II or III rectal cancer remains an acceptable option, neoadjuvant therapy for rectal cancer, using preoperative chemoradiation, is now the preferred option for patients with stage II and III disease.[37][Level of evidence: 1iA] Benefits of neoadjuvant chemoradiation include tumor regression, downstaging and improvement in resectability, and a higher rate of sphincter preservation and local control.[37] Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[38-45] However, preoperative radiation therapy is associated with increased complications compared to surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[46-49] (See Treatment Option Overview section for more information.)

The prognosis of patients with rectal cancer is related to several factors, including:[7,25,26,29-32,50-52]

• Presence or absence of nodal involvement and the number of positive lymph nodes.[7,29-32]



• Adherence to or invasion of adjacent organs.[26]



• Presence or absence of distant metastases.[7,26]



• Presence or absence of high-risk pathologic features, including positive surgical margins, lymphovascular invasion, perineural invasion, and poorly differentiated histology.[7,50,51]



• Perforation or obstruction of the bowel.[7,52]



• CRM or depth of penetration of the tumor through the bowel wall.[7,25,53]

However, only disease stage (tumor, nodal, and distant) has been validated in multi-institutional prospective studies.

A large number of studies have evaluated various other clinical, pathologic, and molecular parameters; as yet, none has been validated in multi-institutional prospective trials.[54-60] For example, MSI-H, also associated with hereditary nonpolyposis rectal cancer, was shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients with colorectal cancer who were 50 years old or younger at the time of diagnosis.[61] In addition, gene expression profiling has been reported to be useful in predicting the response of rectal adenocarcinomas to preoperative chemoradiation therapy and in determining the prognosis of stage II and III rectal cancer after neoadjuvant fluorouracil-based chemoradiation therapy.[62,63] Racial and ethnic differences in overall survival (OS) after adjuvant therapy for rectal cancer have been observed, with shorter OS for blacks compared to whites; factors contributing to this disparity may include tumor position, type of surgical procedure, and various comorbid conditions.[64]

The primary goals of postoperative surveillance programs for rectal cancer are:[65]

1. To assess the efficacy of initial therapy.
2. To detect new or metachronous malignancies.
3. To detect potentially curable recurrent or metastatic cancers.

Routine, periodic studies following patients treated for rectal cancer may lead to earlier identification and management of recurrent disease.[65-69] A statistically significant survival benefit has been demonstrated for more intensive follow-up protocols in two clinical trials. A meta-analysis that combined these two trials with four others was reported to show a statistically significant improvement in survival for patients who were intensively followed.[65,70,71] Guidelines for surveillance after initial treatment with curative intent for colorectal cancer vary between leading U.S. and European societies, and optimal surveillance strategies remain uncertain.[72,73] Large, well-designed, prospective, multi-institutional, randomized studies may be required to establish an evidence-based consensus for follow-up evaluation.

Measurement of CEA, a serum glycoprotein, is frequently used in the management and follow-up of patients with rectal cancer. A review of the use of this tumor marker for rectal cancer suggests the following:[65]

• Serum CEA testing is not a valuable screening tool for rectal cancer because of its low sensitivity and low specificity.



• Postoperative CEA testing should be restricted to patients who are potential candidates for further intervention, as follows:
  1. Patients with stage II or III rectal cancer (every 2 to 3 months for at least 2 years after diagnosis).
  2. Patients with rectal cancer who would be candidates for resection of liver metastases.

In one retrospective study of the Dutch TME trial for the treatment of rectal cancer, investigators found that the preoperative serum CEA level was normal in the majority of patients with rectal cancer, and yet, serum CEA levels rose by at least 50% in patients with recurrence; the authors concluded that serial, postoperative CEA testing cannot be discarded based on a normal preoperative serum CEA level in patients with rectal cancer.[74,75]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 
   
   
2. Parkin DM: Global cancer statistics in the year 2000. Lancet Oncol 2 (9): 533-43, 2001.  [PUBMED Abstract]
   
   
3. Albano JD, Ward E, Jemal A, et al.: Cancer mortality in the United States by education level and race. J Natl Cancer Inst 99 (18): 1384-94, 2007.  [PUBMED Abstract]
   
   
4. Kauh J, Brawley OW, Berger M: Racial disparities in colorectal cancer. Curr Probl Cancer 31 (3): 123-33, 2007 May-Jun.  [PUBMED Abstract]
   
   
5. Kang H, O'Connell JB, Leonardi MJ, et al.: Rare tumors of the colon and rectum: a national review. Int J Colorectal Dis 22 (2): 183-9, 2007.  [PUBMED Abstract]
   
   
6. Wolpin BM, Meyerhardt JA, Mamon HJ, et al.: Adjuvant treatment of colorectal cancer. CA Cancer J Clin 57 (3): 168-85, 2007 May-Jun.  [PUBMED Abstract]
   
   
7. DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008. 
   
   
8. Strate LL, Syngal S: Hereditary colorectal cancer syndromes. Cancer Causes Control 16 (3): 201-13, 2005.  [PUBMED Abstract]
   
   
9. Young J, Jenkins M, Parry S, et al.: Serrated pathway colorectal cancer in the population: genetic consideration. Gut 56 (10): 1453-9, 2007.  [PUBMED Abstract]
   
   
10. Syngal S, Fox EA, Li C, et al.: Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 282 (3): 247-53, 1999.  [PUBMED Abstract]
    
    
11. Locker GY, Kaul K, Weinberg DS, et al.: The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features. Cancer Genet Cytogenet 169 (1): 33-8, 2006.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Weinberg DS, Newschaffer CJ, Topham A: Risk for colorectal cancer after gynecologic cancer. Ann Intern Med 131 (3): 189-93, 1999.  [PUBMED Abstract]
    
    
14. Burstein HJ, Winer EP: Primary care for survivors of breast cancer. N Engl J Med 343 (15): 1086-94, 2000.  [PUBMED Abstract]
    
    
15. Winawer SJ: Screening for colorectal cancer. Cancer: Principles and Practice of Oncology Updates 2(1): 1-16, 1987. 
    
    
16. Stein W, Farina A, Gaffney K, et al.: Characteristics of colon cancer at time of presentation. Fam Pract Res J 13 (4): 355-63, 1993.  [PUBMED Abstract]
    
    
17. Majumdar SR, Fletcher RH, Evans AT: How does colorectal cancer present? Symptoms, duration, and clues to location. Am J Gastroenterol 94 (10): 3039-45, 1999.  [PUBMED Abstract]
    
    
18. Schmidt CR, Gollub MJ, Weiser MR: Contemporary imaging for colorectal cancer. Surg Oncol Clin N Am 16 (2): 369-88, 2007.  [PUBMED Abstract]
    
    
19. Siddiqui AA, Fayiga Y, Huerta S: The role of endoscopic ultrasound in the evaluation of rectal cancer. Int Semin Surg Oncol 3: 36, 2006.  [PUBMED Abstract]
    
    
20. Søreide K: Molecular testing for microsatellite instability and DNA mismatch repair defects in hereditary and sporadic colorectal cancers--ready for prime time? Tumour Biol 28 (5): 290-300, 2007.  [PUBMED Abstract]
    
    
21. Zammit M, Jenkins JT, Urie A, et al.: A technically difficult endorectal ultrasound is more likely to be inaccurate. Colorectal Dis 7 (5): 486-91, 2005.  [PUBMED Abstract]
    
    
22. Goldstein MJ, Mitchell EP: Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 23 (4): 338-51, 2005.  [PUBMED Abstract]
    
    
23. Das P, Skibber JM, Rodriguez-Bigas MA, et al.: Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer 109 (9): 1750-5, 2007.  [PUBMED Abstract]
    
    
24. Lahaye MJ, Engelen SM, Nelemans PJ, et al.: Imaging for predicting the risk factors--the circumferential resection margin and nodal disease--of local recurrence in rectal cancer: a meta-analysis. Semin Ultrasound CT MR 26 (4): 259-68, 2005.  [PUBMED Abstract]
    
    
25. Balch GC, De Meo A, Guillem JG: Modern management of rectal cancer: a 2006 update. World J Gastroenterol 12 (20): 3186-95, 2006.  [PUBMED Abstract]
    
    
26. Compton CC, Greene FL: The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54 (6): 295-308, 2004 Nov-Dec.  [PUBMED Abstract]
    
    
27. Colon and rectum. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 113-124. 
    
    
28. 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.  [PUBMED Abstract]
    
    
29. 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.  [PUBMED Abstract]
    
    
30. 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.  [PUBMED Abstract]
    
    
31. 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.  [PUBMED Abstract]
    
    
32. 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.  [PUBMED Abstract]
    
    
33. Baxter NN, Garcia-Aguilar J: Organ preservation for rectal cancer. J Clin Oncol 25 (8): 1014-20, 2007.  [PUBMED Abstract]
    
    
34. Guillem JG, Cohen AM: Current issues in colorectal cancer surgery. Semin Oncol 26 (5): 505-13, 1999.  [PUBMED Abstract]
    
    
35. Cooper HS, Deppisch LM, Gourley WK, et al.: Endoscopically removed malignant colorectal polyps: clinicopathologic correlations. Gastroenterology 108 (6): 1657-65, 1995.  [PUBMED Abstract]
    
    
36. Seitz U, Bohnacker S, Seewald S, et al.: Is endoscopic polypectomy an adequate therapy for malignant colorectal adenomas? Presentation of 114 patients and review of the literature. Dis Colon Rectum 47 (11): 1789-96; discussion 1796-7, 2004.  [PUBMED Abstract]
    
    
37. Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004.  [PUBMED Abstract]
    
    
38. Janjan NA, Khoo VS, Abbruzzese J, et al.: Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 44 (5): 1027-38, 1999.  [PUBMED Abstract]
    
    
39. Crane CH, Skibber JM, Birnbaum EH, et al.: The addition of continuous infusion 5-FU to preoperative radiation therapy increases tumor response, leading to increased sphincter preservation in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 57 (1): 84-9, 2003.  [PUBMED Abstract]
    
    
40. Grann A, Minsky BD, Cohen AM, et al.: Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum 40 (5): 515-22, 1997.  [PUBMED Abstract]
    
    
41. Rich TA, Skibber JM, Ajani JA, et al.: Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 32 (4): 1025-9, 1995.  [PUBMED Abstract]
    
    
42. Chari RS, Tyler DS, Anscher MS, et al.: Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 221 (6): 778-86; discussion 786-7, 1995.  [PUBMED Abstract]
    
    
43. Hyams DM, Mamounas EP, Petrelli N, et al.: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 40 (2): 131-9, 1997.  [PUBMED Abstract]
    
    
44. Bosset JF, Magnin V, Maingon P, et al.: Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II trial. Int J Radiat Oncol Biol Phys 46 (2): 323-7, 2000.  [PUBMED Abstract]
    
    
45. Hiotis SP, Weber SM, Cohen AM, et al.: Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg 194 (2): 131-5; discussion 135-6, 2002.  [PUBMED Abstract]
    
    
46. Lai LL, Fuller CD, Kachnic LA, et al.: Can pelvic radiotherapy be omitted in select patients with rectal cancer? Semin Oncol 33 (6 Suppl 11): S70-4, 2006.  [PUBMED Abstract]
    
    
47. Peeters KC, van de Velde CJ, Leer JW, et al.: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study. J Clin Oncol 23 (25): 6199-206, 2005.  [PUBMED Abstract]
    
    
48. Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.  [PUBMED Abstract]
    
    
49. Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.  [PUBMED Abstract]
    
    
50. Weiser MR, Landmann RG, Wong WD, et al.: Surgical salvage of recurrent rectal cancer after transanal excision. Dis Colon Rectum 48 (6): 1169-75, 2005.  [PUBMED Abstract]
    
    
51. Fujita S, Nakanisi Y, Taniguchi H, et al.: Cancer invasion to Auerbach's plexus is an important prognostic factor in patients with pT3-pT4 colorectal cancer. Dis Colon Rectum 50 (11): 1860-6, 2007.  [PUBMED Abstract]
    
    
52. Griffin MR, Bergstralh EJ, Coffey RJ, et al.: Predictors of survival after curative resection of carcinoma of the colon and rectum. Cancer 60 (9): 2318-24, 1987.  [PUBMED Abstract]
    
    
53. Wieder HA, Rosenberg R, Lordick F, et al.: Rectal cancer: MR imaging before neoadjuvant chemotherapy and radiation therapy for prediction of tumor-free circumferential resection margins and long-term survival. Radiology 243 (3): 744-51, 2007.  [PUBMED Abstract]
    
    
54. McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999.  [PUBMED Abstract]
    
    
55. 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.  [PUBMED Abstract]
    
    
56. 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.  [PUBMED Abstract]
    
    
57. Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999.  [PUBMED Abstract]
    
    
58. Nishio H, Hamady ZZ, Malik HZ, et al.: Outcome following repeat liver resection for colorectal liver metastases. Eur J Surg Oncol 33 (6): 729-34, 2007.  [PUBMED Abstract]
    
    
59. Edler D, Hallström M, Johnston PG, et al.: Thymidylate synthase expression: an independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer. Clin Cancer Res 6 (4): 1378-84, 2000.  [PUBMED Abstract]
    
    
60. Popat S, Chen Z, Zhao D, et al.: A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer. Ann Oncol 17 (12): 1810-7, 2006.  [PUBMED Abstract]
    
    
61. 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.  [PUBMED Abstract]
    
    
62. Liersch T, Langer C, Ghadimi BM, et al.: Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol 24 (25): 4062-8, 2006.  [PUBMED Abstract]
    
    
63. Ghadimi BM, Grade M, Difilippantonio MJ, et al.: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23 (9): 1826-38, 2005.  [PUBMED Abstract]
    
    
64. Dignam JJ, Ye Y, Colangelo L, et al.: Prognosis after rectal cancer in blacks and whites participating in adjuvant therapy randomized trials. J Clin Oncol 21 (3): 413-20, 2003.  [PUBMED Abstract]
    
    
65. Abir F, Alva S, Longo WE, et al.: The postoperative surveillance of patients with colon cancer and rectal cancer. Am J Surg 192 (1): 100-8, 2006.  [PUBMED Abstract]
    
    
66. 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.  [PUBMED Abstract]
    
    
67. 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.  [PUBMED Abstract]
    
    
68. Lautenbach E, Forde KA, Neugut AI: Benefits of colonoscopic surveillance after curative resection of colorectal cancer. Ann Surg 220 (2): 206-11, 1994.  [PUBMED Abstract]
    
    
69. Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996.  [PUBMED Abstract]
    
    
70. Pietra N, Sarli L, Costi R, et al.: Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 41 (9): 1127-33, 1998.  [PUBMED Abstract]
    
    
71. Secco GB, Fardelli R, Gianquinto D, et al.: Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial. Eur J Surg Oncol 28 (4): 418-23, 2002.  [PUBMED Abstract]
    
    
72. Pfister DG, Benson AB 3rd, Somerfield MR: Clinical practice. Surveillance strategies after curative treatment of colorectal cancer. N Engl J Med 350 (23): 2375-82, 2004.  [PUBMED Abstract]
    
    
73. Li Destri G, Di Cataldo A, Puleo S: Colorectal cancer follow-up: useful or useless? Surg Oncol 15 (1): 1-12, 2006.  [PUBMED Abstract]
    
    
74. Kapiteijn E, Kranenbarg EK, Steup WH, et al.: Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch ColoRectal Cancer Group. Eur J Surg 165 (5): 410-20, 1999.  [PUBMED Abstract]
    
    
75. Grossmann I, de Bock GH, Meershoek-Klein Kranenbarg WM, et al.: Carcinoembryonic antigen (CEA) measurement during follow-up for rectal carcinoma is useful even if normal levels exist before surgery. A retrospective study of CEA values in the TME trial. Eur J Surg Oncol 33 (2): 183-7, 2007.  [PUBMED Abstract]
    
    

Back to Top

Cellular Classification and Pathology of Rectal Cancer

The World Health Organization (WHO) classification of tumors of the colon and rectum include:[1]

Adenoma

• Tubular.
• Villous.
• Tubulovillous.
• Serrated.

Intraepithelial neoplasia (dysplasia) associated with chronic inflammatory diseases

• Low-grade glandular intraepithelial neoplasia.
• High-grade glandular intraepithelial neoplasia.

Carcinoma

• Adenocarcinoma.
• Mucinous adenocarcinoma.
• Signet-ring cell carcinoma.
• Small cell carcinoma.
• Adenosquamous carcinoma.
• Medullary carcinoma.
• Undifferentiated carcinoma.

Carcinoid (well-differentiated neuroendocrine neoplasm)

• Enterochromaffin (EC)-cell, serotonin-producing neoplasm.
• L-cell, glucagon-like peptide and pancreatic polypeptide/peptide YY (PYY)-producing tumor.
• Others.

Mixed carcinoma-adenocarcinoma

• Others.

• Lipoma.
• Leiomyoma.
• Gastrointestinal stromal tumor.
• Leiomyosarcoma.
• Angiosarcoma.
• Kaposi sarcoma.
• Melanoma.
• Others.

Malignant lymphomas

• Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type.
• Mantle cell lymphoma.
• Diffuse large B-cell lymphoma.
• Burkitt lymphoma.
• Burkitt-like/atypical Burkitt lymphoma.

Adenocarcinomas account for the vast majority of rectal cancers. Other histologic types of colorectal cancer account for an estimated 2% to 5% of colorectal tumors.[2]

References

1. Hamilton SR, Aaltonen LA: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2000. 
   
   
2. Kang H, O'Connell JB, Leonardi MJ, et al.: Rare tumors of the colon and rectum: a national review. Int J Colorectal Dis 22 (2): 183-9, 2007.  [PUBMED Abstract]
   
   

Back to Top

Stage Information for Rectal Cancer

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

The American Joint Committee on Cancer (AJCC) 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 the tumor.[1-3] 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, such as Intergroup trial INT-0089, have demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.[4-7]

The staging system does not apply to the following histologies:

• Sarcoma. (See the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.)



• Lymphoma. (See the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)



• Carcinoid tumors. (See the PDQ summary on Gastrointestinal Carcinoid Tumors Treatment for more information.)



• Melanoma. (See the PDQ summary on Melanoma Treatment for more information.)

The AJCC has designated staging by TNM classification.[1]

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.]

*** [Note: 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 one to three regional lymph nodes
• N2: Metastasis in four or more regional lymph nodes

 [Note: 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 it represents venous invasion.]

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 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

A major pooled analysis evaluating the impact of T and N stage and treatment on survival and relapse in patients with adjuvant rectal cancer has been published.[8] In addition, a new tumor-metastasis staging strategy for node-positive rectal cancer has been proposed.[9]

References

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
8. Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.  [PUBMED Abstract]
   
   
9. Greene FL, Stewart AK, Norton HJ: New tumor-node-metastasis staging strategy for node-positive (stage III) rectal cancer: an analysis. J Clin Oncol 22 (10): 1778-84, 2004.  [PUBMED Abstract]
   
   

Back to Top

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.)

The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all but T1 tumors, a mesorectal excision is the treatment of choice. Very selected patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% following rectal resection with appropriate mesorectal excision (total mesorectal excision [TME] for low/middle rectal tumors and mesorectal excision at least 5 cm 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. Because of an increased tendency for first failure in locoregional sites only, the impact of perioperative radiation therapy is greater in rectal cancer than in colon cancer.[6]

Although postoperative therapy for patients with stage II or III rectal cancer remains an acceptable option, neoadjuvant therapy for rectal cancer, using preoperative chemoradiation, is now the preferred option for patients with stage II and III disease.[7][Level of evidence: 1iA] Benefits of neoadjuvant chemoradiation include tumor regression, downstaging and improvement in resectability, and a higher rate of sphincter preservation and local control.[7] Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[8-15] However, preoperative radiation therapy is associated with increased complications compared to surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[16-19]

Multiple phase II studies of preoperative chemoradiation suggested that administering radiation therapy prior to surgery improved the toxicity profile of chemoradiation and enhanced the possibility of sphincter-sparing surgery. The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3/T4 or node-positive rectal cancer to either preoperative chemoradiation therapy or postoperative chemoradiation therapy (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m² daily for 5 days during the first and fifth weeks of radiation therapy).[7] All patients received a TME and an additional four cycles of 5-FU–based chemotherapy postoperatively. The overall 5-year survival rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative treatment group (P = .006). Grade 3 or grade 4 acute toxic effects occurred in 27% of the patients in the preoperative treatment group as compared with 40% of the patients in the postoperative treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[7][Level of evidence: 1iA] There was no difference in the number of patients receiving an abdominoperineal resection in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).

Among the patients assigned to the postoperative chemoradiation therapy arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3/T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group. Nevertheless, on the basis of this study, preoperative chemoradiation therapy has become the standard treatment for patients with clinically staged T3/T4 or N1 disease. Postoperative chemotherapy with 4 to 6 months of fluoropyrimidine-based therapy has become a standard treatment, as evidenced by the control arm in current cooperative group studies.

Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy with radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and fluorouracil (5-FU)-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomized clinical trials from the Gastrointestinal Tumor Study Group (GITSG-7175), the Mayo/North Central Cancer Treatment Group (NCCTG-794751), and the National Surgical Adjuvant Breast and Bowel Project (NSABP R-01).[20-22][Level of evidence: 1iiA] These studies demonstrated an increase in both disease-free survival (DFS) interval and OS when radiation therapy was combined with chemotherapy after surgical resection. Following publication of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference in 1990 concluded that postoperative combined-modality treatment is recommended for patients with stage II and III rectal carcinoma.[23]

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems. The agents associated with the first successful combined-modality treatments were 5-FU and semustine. Semustine is not commercially available, and previous studies have associated this drug with the potential for 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 radiation therapy and 5-FU.[24][Level of evidence: 1iiA] The Intergroup 86-47-51 trial (NCCTG-864751) showed a 10% improvement in OS 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).[25][Level of evidence: 1iiA]

Subsequently, several studies attempted to determine the optimal way to deliver adjuvant 5-FU. The final results of Intergroup 0114 (INT-0114) demonstrated no survival or local control benefit with the addition of leucovorin, levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[18][Level of evidence: 1iiA] Another study, Intergroup 0144 (SWOG-9304), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation.[26]

• Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m²/day) and after (450 mg/m²/day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m²/day) during radiation therapy.
• Arm 2 received continuous infusion 5-FU before (300 mg/m²/day for 42 days), after (300 mg/m²/ day for 56 days), and during (225 mg/m²/day) radiation therapy.
• Arm 3 received bolus 5-FU plus leucovorin in two 5-day cycles before (5-FU 425 mg/m²/day; leucovorin 20 mg/m²/day) and after (5-FU 380 mg/m²/day; leucovorin 20 mg/m²/day) radiation therapy, and bolus 5-FU plus leucovorin (5-FU 400 mg/m²/day; leucovorin 20 mg/m²/day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3) versus 4% of patients in the continuous-infusion arm. No DFS, OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[26][Level of evidence: 1iiA]

Although the above data demonstrate a benefit with postoperative radiation therapy and 5-FU chemotherapy for patients with stage II and III rectal cancer, a follow-up study to the NSABP R-01 trial, the NSABP R-02 study, addressed whether the addition of radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[27][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 terms of survival. The interpretation of the interaction of radiation therapy with prognostic factors, however, was challenging. Radiation appeared to improve survival among patients younger than 60 years, as well as among 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 radiation therapy seems premature, since locoregional recurrence remains a clinically relevant problem.

Using current surgical techniques, including TME, it may be possible to identify subsets of patients whose chance of pelvic failure is low enough to omit postoperative radiation. A trial conducted by the Dutch Colorectal Cancer Group (CKVO-9504) randomly assigned patients with resectable rectal cancers (stages I–IV) to a short course of radiation (5 Gy × 5 days) followed by TME compared to TME alone and demonstrated no difference in OS at 2 years (82% for both arms).[28][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 III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation and four cycles of adjuvant 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.[29] 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.[30,31]

Oxaliplatin has significant activity when combined with 5-FU-leucovorin in patients with metastatic colorectal cancer. In the randomized Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, the toxic effects and efficacy of FOLFOX4 (a 2-hour infusion of 200 mg/m² leucovorin, followed by a bolus of 400 mg/m² 5-FU, and then a 22-hour infusion of 600 mg/m² 5-FU on 2 consecutive days every 14 days for 12 cycles, plus a 2-hour infusion of 85 mg/m² oxaliplatin on day 1, given simultaneously with the leucovorin) were compared with the same 5-FU-leucovorin regimen without oxaliplatin when administered for 6 months.[32] Each arm of the trial included 1,123 patients. Preliminary results of the study, with 37 months of follow-up, demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX4. There was no difference in OS.[33][Level of evidence: 1iiDii] Patients treated with FOLFOX4 experienced more frequent toxic effects, consisting mainly of neutropenia (41% >grade 3) and reversible peripheral sensory neuropathy (12.4% >grade 3). These results are still preliminary, and additional information with regard to OS is anticipated. Nevertheless, these data suggest that FOLFOX4 may be a therapeutic option for patients with resected stage III colon cancer.[33]

The results of NSABP C-07 confirm and extend the results of the MOSAIC trial.[34] In NSABP C-07, 2,492 patients with stage II or III colon cancer were randomly assigned to receive either FLOX (2-hour intravenous infusion of 85 mg/m² oxaliplatin on days 1, 15, and 29 of each 8-week treatment cycle, followed by a 2-hour intravenous infusion of 500 mg/m² leucovorin plus bolus 500 mg/m² 5-FU 1 hour after the start of the leucovorin infusion on days 1, 8, 15, 22, 29, and 36, followed by a 2-week rest period, for a total of three cycles [24 weeks]) or the same chemotherapy without oxaliplatin (Roswell Park regimen). The 3- and 4-year DFS rates were 71.8% and 67% for the Roswell Park regimen and 76.1% and 73.2% for FLOX, respectively. The hazard ratio was 0.80 (95% confidence interval [CI], 0.69–0.93), a 20% risk reduction in favor of FLOX (P <.004).

Many academic oncologists recommend that FOLFOX be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data in rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. The Eastern Cooperative Oncology Group trial ECOG-5202 is randomly assigning patients with stage II or III rectal cancer who have received preoperative or postoperative chemoradiation therapy to 6 months of FOLFOX with or without bevacizumab.

The other large and ongoing study in the United States, NSABP-R-04, is evaluating the role of capecitabine and oxaliplatin administered concurrently with radiation therapy. NSABP-R-04 is randomly assigning patients in a 2 × 2 factorial design to one of the following four treatment groups for clinically staged T3 or T4 or node-positive rectal cancer:

1. Intravenous continuous infusion (IVCI) 5-FU with radiation therapy.
2. Capecitabine with radiation therapy.
3. IVCI 5-FU plus weekly oxaliplatin with radiation therapy.
4. Capecitabine plus weekly oxaliplatin with radiation therapy.

The primary objective of this study is locoregional disease control.

The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment. Of greater concern is the potential for late morbidity following rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter.[35] Patients treated with adjuvant radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than those who undergo surgical resection alone.[17,36-41]

A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with adjuvant therapy.[35] Improved radiation planning and techniques may minimize these acute and late treatment-related complications. These techniques include:[42-44]

• The use of high-energy radiation machines.



• The use of multiple pelvic fields.



• Prone patient positioning.



• Customized patient molds (belly boards) to exclude as much small bowel as possible from the fields and immobilize patients during treatment.



• Bladder distention during radiation therapy to exclude as much small bowel as possible from the fields.



• Visualization of the small bowel through oral contrast during treatment planning so that when possible, the small bowel can be excluded from the radiation field.



• The use of three dimensional or other advanced radiation planning techniques.

In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy x 5 daily treatments) followed by surgery one week later, as compared to the long-course chemoradiation approach in the United States. One reason for this difference is the concern in the U.S. for heightened late effects with high radiation doses per fraction. A Polish study randomized 316 patients between preoperative long course chemoradiation (50.4 Gy in 28 daily fractions with 5-FU and folinic acid) and short-course preoperative radiation therapy (25 Gy in 5 fractions).[41] Although the primary endpoint was sphincter preservation, late toxicity was not statistically significantly different between the two treatment approaches (7% long course vs. 10% short course). Of note, data on anal sphincter and sexual function were not reported, and toxicity was physician determined, not patient reported. Ongoing clinical trials comparing preoperative and postoperative adjuvant chemoradiation therapy 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 DFS and OS.

References

1. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341 (8843): 457-60, 1993.  [PUBMED Abstract]
   
   
2. Enker WE, Thaler HT, Cranor ML, et al.: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181 (4): 335-46, 1995.  [PUBMED Abstract]
   
   
3. Zaheer S, Pemberton JH, Farouk R, et al.: Surgical treatment of adenocarcinoma of the rectum. Ann Surg 227 (6): 800-11, 1998.  [PUBMED Abstract]
   
   
4. Heald RJ, Smedh RK, Kald A, et al.: Abdominoperineal excision of the rectum--an endangered operation. Norman Nigro Lectureship. Dis Colon Rectum 40 (7): 747-51, 1997.  [PUBMED Abstract]
   
   
5. Lopez-Kostner F, Lavery IC, Hool GR, et al.: Total mesorectal excision is not necessary for cancers of the upper rectum. Surgery 124 (4): 612-7; discussion 617-8, 1998.  [PUBMED Abstract]
   
   
6. Gunderson LL, Sosin H: Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum. Clinicopathologic correlation and implications for adjuvant therapy. Cancer 34 (4): 1278-92, 1974.  [PUBMED Abstract]
   
   
7. Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004.  [PUBMED Abstract]
   
   
8. Janjan NA, Khoo VS, Abbruzzese J, et al.: Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 44 (5): 1027-38, 1999.  [PUBMED Abstract]
   
   
9. Crane CH, Skibber JM, Birnbaum EH, et al.: The addition of continuous infusion 5-FU to preoperative radiation therapy increases tumor response, leading to increased sphincter preservation in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 57 (1): 84-9, 2003.  [PUBMED Abstract]
   
   
10. Grann A, Minsky BD, Cohen AM, et al.: Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum 40 (5): 515-22, 1997.  [PUBMED Abstract]
    
    
11. Rich TA, Skibber JM, Ajani JA, et al.: Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 32 (4): 1025-9, 1995.  [PUBMED Abstract]
    
    
12. Chari RS, Tyler DS, Anscher MS, et al.: Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 221 (6): 778-86; discussion 786-7, 1995.  [PUBMED Abstract]
    
    
13. Hyams DM, Mamounas EP, Petrelli N, et al.: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 40 (2): 131-9, 1997.  [PUBMED Abstract]
    
    
14. Bosset JF, Magnin V, Maingon P, et al.: Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II trial. Int J Radiat Oncol Biol Phys 46 (2): 323-7, 2000.  [PUBMED Abstract]
    
    
15. Hiotis SP, Weber SM, Cohen AM, et al.: Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg 194 (2): 131-5; discussion 135-6, 2002.  [PUBMED Abstract]
    
    
16. Lai LL, Fuller CD, Kachnic LA, et al.: Can pelvic radiotherapy be omitted in select patients with rectal cancer? Semin Oncol 33 (6 Suppl 11): S70-4, 2006.  [PUBMED Abstract]
    
    
17. Peeters KC, van de Velde CJ, Leer JW, et al.: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study. J Clin Oncol 23 (25): 6199-206, 2005.  [PUBMED Abstract]
    
    
18. Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.  [PUBMED Abstract]
    
    
19. Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.  [PUBMED Abstract]
    
    
20. Thomas PR, Lindblad AS: Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol 13 (4): 245-52, 1988.  [PUBMED Abstract]
    
    
21. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324 (11): 709-15, 1991.  [PUBMED Abstract]
    
    
22. Fisher B, Wolmark N, Rockette H, et al.: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 80 (1): 21-9, 1988.  [PUBMED Abstract]
    
    
23. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990.  [PUBMED Abstract]
    
    
24. Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Gastrointestinal Tumor Study Group. J Clin Oncol 10 (4): 549-57, 1992.  [PUBMED Abstract]
    
    
25. O'Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994.  [PUBMED Abstract]
    
    
26. Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006.  [PUBMED Abstract]
    
    
27. Wolmark N, Wieand HS, Hyams DM, et al.: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92 (5): 388-96, 2000.  [PUBMED Abstract]
    
    
28. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al.: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345 (9): 638-46, 2001.  [PUBMED Abstract]
    
    
29. Kollmorgen CF, Meagher AP, Wolff BG, et al.: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 220 (5): 676-82, 1994.  [PUBMED Abstract]
    
    
30. Koelbl O, Richter S, Flentje M: Influence of patient positioning on dose-volume histogram and normal tissue complication probability for small bowel and bladder in patients receiving pelvic irradiation: a prospective study using a 3D planning system and a radiobiological model. Int J Radiat Oncol Biol Phys 45 (5): 1193-8, 1999.  [PUBMED Abstract]
    
    
31. Gunderson LL, Russell AH, Llewellyn HJ, et al.: Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 11 (7): 1379-93, 1985.  [PUBMED Abstract]
    
    
32. André T, Boni C, Mounedji-Boudiaf L, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350 (23): 2343-51, 2004.  [PUBMED Abstract]
    
    
33. De Gramont A, Banzi M, Navarro M, et al.: Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1015, 2003. 
    
    
34. de Gramont A, Boni C, Navarro M, et al.: Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. [Abstract] J Clin Oncol 23 (Suppl 16): A-3501, 246s, 2005. 
    
    
35. Wong RK, Tandan V, De Silva S, et al.: Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev (2): CD002102, 2007.  [PUBMED Abstract]
    
    
36. Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Medical Research Council Rectal Cancer Working Party. Lancet 348 (9042): 1610-4, 1996.  [PUBMED Abstract]
    
    
37. Initial report from a Swedish multicentre study examining the role of preoperative irradiation in the treatment of patients with resectable rectal carcinoma. Swedish Rectal Cancer Trial. Br J Surg 80 (10): 1333-6, 1993.  [PUBMED Abstract]
    
    
38. Dahlberg M, Glimelius B, Graf W, et al.: Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Dis Colon Rectum 41 (5): 543-9; discussion 549-51, 1998.  [PUBMED Abstract]
    
    
39. Birgisson H, Påhlman L, Gunnarsson U, et al.: Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23 (34): 8697-705, 2005.  [PUBMED Abstract]
    
    
40. Marijnen CA, van de Velde CJ, Putter H, et al.: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 23 (9): 1847-58, 2005.  [PUBMED Abstract]
    
    
41. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al.: Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93 (10): 1215-23, 2006.  [PUBMED Abstract]
    
    
42. Martling A, Holm T, Johansson H, et al.: The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: long-term follow-up of a population-based study. Cancer 92 (4): 896-902, 2001.  [PUBMED Abstract]
    
    
43. Dahlberg M, Glimelius B, Påhlman L: Improved survival and reduction in local failure rates after preoperative radiotherapy: evidence for the generalizability of the results of Swedish Rectal Cancer Trial. Ann Surg 229 (4): 493-7, 1999.  [PUBMED Abstract]
    
    
44. Guerrero Urbano MT, Henrys AJ, Adams EJ, et al.: Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels. Int J Radiat Oncol Biol Phys 65 (3): 907-16, 2006.  [PUBMED Abstract]
    
    

Back to Top

Stage 0 Rectal Cancer

Stage 0 rectal cancer is the most superficial of all rectal 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 radiation therapy.[2-4]
4. Local radiation therapy.[2]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage 0 rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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

Back to Top

Stage I Rectal Cancer

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

Stage I tumors extend beneath the mucosa into the submucosa (T1) or into, but not through, the bowel muscle wall (T2). Because of its localized nature at presentation, 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 LAR.
3. Local transanal or other resection [1,2] with or without perioperative external beam radiation therapy (EBRT) plus fluorouracil (5-FU).

There are three potential options for surgical resection in stage I rectal cancer: local excision, LAR, and APR. Local excision should be restricted to tumors confined to the rectal wall and that do not, on rectal ultrasound or magnetic resonance imaging, involve the full thickness of the rectum (i.e., not a T3 tumor). The ideal candidate for local excision has a T1 tumor with well-to-moderate differentiation that occupies less than one-third of the circumference of the bowel wall. Local excision should only be applied to very select patients with T2 tumors, as there is a higher risk of local and systemic failure.

For patients with T1 and T2 tumors, no randomized trials are available to compare local excision with or without postoperative chemoradiation to wide surgical resection (LAR and APR). Investigators with the Cancer and Leukemia Group B (CALGB) enrolled patients with T1 and T2 rectal adenocarcinomas that were within 10 cm of the dentate line and not more than 4 cm in diameter, and involving not more than 40% of the rectal circumference, onto a prospective protocol, CLB-8984. Patients with T1 tumors received no additional treatment following surgery, whereas patients with T2 tumors were treated with external beam radiation therapy (54 Gy of 30 fractions, 5 days/week) and 5-FU (500 mg/m² on days 1 through 2 and days 29 through 31 of radiation). At 48 months median follow-up, the 6-year failure-free survival and overall survival (OS) rates for patients with T1 tumors were 83% and 87%, respectively. For patients with T2 tumors, the 6-year failure-free survival and OS rates were 71% and 85%, respectively.[3]

Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement about 20% of the time, and additional therapy should be considered, such as radiation and chemotherapy, or more standard surgical resection.[4] Patients with poor histologic features or positive margins after local excision should consider LAR or APR and postoperative treatment as dictated by full surgical staging.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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

Back to Top

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) rectal cancer

Treatment options:

1. Preoperative chemoradiation with fluorouracil (5-FU) for patients with clinically staged T3/T4 rectal adenocarcinoma.
2. Total mesorectal excision (TME) with either low anterior resection (LAR) or abdominoperineal resection (APR).
3. Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.
4. Four to six months of 5-FU-based chemotherapy postoperatively.
5. A clinical trial.

Prior to the standard use of preoperative chemoradiation for stage II and III rectal cancer, several studies established the benefits of adjuvant combined-modality therapy for surgical stage II and III disease. Intergroup protocol 86-47-51 (NCCTG-864751) demonstrated a 10% improvement in overall survival (OS) with the use of continuous-infusion 5-FU (225 mg/m²/day throughout the entire course of radiation therapy) compared with bolus 5-FU (500 mg/m²/day for three consecutive days during the first and fifth weeks of radiation).[1][Level of evidence: 1iiA] The final results of INT-0114 showed no survival or local-control benefit with the addition of leucovorin, levamisole, or both to 5-FU administered postoperatively for patients with stage II and III rectal cancers at a median follow-up of 7.4 years.[2][Level of evidence: 1iiA]

Another study, Intergroup 0144 (SWOG-9304), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation:[3]

• Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m²/day) and after (450 mg/m²/day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m²/day) during radiation therapy.
• Arm 2 received continuous infusion 5-FU before (300 mg/m²/day for 42 days), after (300 mg/m²/day for 56 days), and during (225 mg/m²/day) radiation therapy.
• Arm 3 received bolus 5-FU plus leucovorin in two 5-day cycles before (5-FU 425 mg/m²/day; leucovorin 20 mg/m²/day) and after (5-FU 380 mg/m²/day; leucovorin 20 mg/m²/day) radiation therapy, and bolus 5-FU plus leucovorin (5-FU 400 mg/m²/day; leucovorin 20 mg/m²/day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3), versus 4% of patients in the continuous-infusion arm. No DFS, OS or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[3][Level of evidence: 1iiA]

The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3/T4 or node-positive rectal cancer to either preoperative chemoradiation or postoperative chemoradiation (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m² daily for 5 days during the first and fifth weeks of radiation therapy).[4] All patients received a TME and an additional four cycles of 5-FU-based chemotherapy. The 5-year OS rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group as compared with 40% of the patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[4][Level of evidence: 1iA] There was no difference in the number of patients receiving an APR in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).

Of the patients assigned to the postoperative chemoradiation arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal ultrasound to have T3/T4 or node-positive disease. A similar number of patients may have been overtreated in the preoperative treatment group. Nevertheless, on the basis of this study, preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3/T4 or node-positive disease.

Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with no further therapy after surgery have a very low risk of local and systemic recurrence.[5] In addition, a pooled analysis of 3,791 patients enrolled in clinical trials demonstrated that, for patients with T3, N0 disease, the 5-year OS rate with surgery plus chemotherapy (84%) compared favorably to the survival rates of patients treated with surgery plus radiation and bolus chemotherapy (76%) or surgery plus radiation and protracted-infusion chemotherapy (80%).[6] However, a multi-institutional retrospective analysis demonstrated that 22% of patients thought to have clinically node-negative T3 disease by ultrasound or MRI were found, at the time of resection, to have positive mesorectal lymph nodes even after chemoradiation.[7]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. O'Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994.  [PUBMED Abstract]
   
   
2. Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.  [PUBMED Abstract]
   
   
3. Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006.  [PUBMED Abstract]
   
   
4. Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004.  [PUBMED Abstract]
   
   
5. Willett CG, Badizadegan K, Ancukiewicz M, et al.: Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum 42 (2): 167-73, 1999.  [PUBMED Abstract]
   
   
6. Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.  [PUBMED Abstract]
   
   
7. Guillem JG, Díaz-González JA, Minsky BD, et al.: cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26 (3): 368-73, 2008.  [PUBMED Abstract]
   
   

Back to Top

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) rectal cancer

Treatment options:

1. Preoperative chemoradiation with fluorouracil (5-FU) for patients with clinically staged T3/T4 rectal adenocarcinoma.
2. Total mesorectal excision (TME) with either low anterior resection (LAR) or abdominoperineal resection (APR).
3. Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.
4. Four to six months of 5-FU-based chemotherapy postoperatively.
5. A clinical trial.

Prior to the standard use of preoperative chemoradiation for stage II and III rectal cancer, several studies established the benefits of adjuvant combined-modality therapy for surgical stage II and III disease. Intergroup protocol 86-47-51 (NCCTG-864751) demonstrated a 10% improvement in overall survival (OS) with the use of continuous-infusion 5-FU (225 mg/m²/day throughout the course of radiation therapy) compared with bolus 5-FU (500 mg/m²/day for three consecutive days during the first and fifth weeks of radiation).[1][Level of evidence: 1iiA] The final results of Intergroup trial 0114 (INT-0114) showed no survival or local-control benefit with the addition of leucovorin, levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[2][Level of evidence: 1iiA]

Another study, Intergroup 0144 (SWOG-9304), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation.[3][Level of evidence: 1iiA]

• Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m²/day) and after (450 mg/m²/day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m²/day) during radiation therapy.
• Arm 2 received continuous infusion 5-FU before (300 mg/m²/day for 42 days), after (300 mg/m²/day for 56 days), and during (225 mg/m²/day) radiation therapy.
• Arm 3 received bolus 5-FU plus leucovorin in two 5-day cycles before (5-FU 425 mg/m²/day; leucovorin 20 mg/m²/day) and after (5-FU 380 mg/m²/day; leucovorin 20 mg/m²/day) radiation therapy, and bolus 5-FU plus leucovorin (5-FU 400 mg/m²/day; leucovorin 20 mg/m²/day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3) versus 4% of patients in the continuous-infusion arm. No DFS, OS or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; 3-year LRF, 4.6% to 8%).[3][Level of evidence: 1iiA]

The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3/T4 or node-positive rectal cancer to either preoperative chemoradiation or postoperative chemoradiation (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m² daily for 5 days during the first and fifth weeks of radiation therapy).[4] All patients received a TME and an additional four cycles of 5-FU-based chemotherapy. The 5-year OS rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation therapy and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group as compared with 40% of the patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[4][Level of evidence: 1iA] There was no difference in the number of patients receiving an abdominoperineal resection in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation therapy (P = .004).

Of the patients assigned to the postoperative chemoradiation arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3/T4 or node-positive disease. A similar number of patients may have been overtreated in the preoperative treatment group. Nevertheless, on the basis of this study, preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3/T4 or node-positive disease.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. O'Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994.  [PUBMED Abstract]
   
   
2. Tepper JE, O'Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.  [PUBMED Abstract]
   
   
3. Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006.  [PUBMED Abstract]
   
   
4. Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004.  [PUBMED Abstract]
   
   

Back to Top

Stage IV and 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.)

Stage IV (old staging: Modified Astler-Coller D) and recurrent rectal cancer

Treatment options for local control:

1. Resection of locally recurrent rectal cancer may be curative in selected patients.[1]
2. Palliative surgical resection with either low-anterior resection (LAR) or abdominoperineal resection (APR).[1]
3. Palliative radiation therapy.[2,3]
4. Palliative chemotherapy.[4-10]
5. Palliative chemoradiation.[11,12]
6. Chemotherapy alone for local control.
7. Palliative, endoscopic-placed stents to relieve obstruction.[13]

Treatment options for systemic control:

1. Resection of liver metastases in selected patients (5-year cure rate with resection of solitary metastases exceeds 20%).[14-23]
2. Resection of isolated pulmonary or ovarian metastases.
3. Systemic chemotherapy (see below).
4. Clinical trials evaluating new drugs.

Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment. For patients with hepatic metastasis considered to be resectable (i.e., based on limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative margin resection has been associated with 5-year survival rates of 25% to 40% in nonrandomized studies (such as the NCCTG-934653 trial).[24-28][Level of evidence: 3iiiDiv] Better surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.[29]

Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer: 5-FU, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab. When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[5,30] as well as improved survival and quality of life for patients receiving chemotherapy compared with best supportive care.[31-33] Several trials have analyzed the activity and toxic effects of various 5-FU-leucovorin regimens, using different doses and administration schedules, and showed essentially equivalent results with a median survival time in the 12-month range.[34] Prior to the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU-leucovorin.[35,36][Level of evidence: 1iiA]

Drug combinations described in this section:

• The Arbeitsgemeinschaft Internische Onkologie (AIO) or German AIO regimen (folic acid, 5-FU, and irinotecan):
  • Irinotecan (100 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (500 mg/m²) administered as a 2-hour infusion on day 1; followed by 5-FU (2,000 mg/m²) intravenous (IV) bolus via ambulatory pump administered for a period of 24 hours on a weekly basis four times a year (52 weeks).
• The CAPOX regimen (capecitabine and oxaliplatin):
  • Capecitabine (1,000 mg/m²) twice a day on days 1 through 14 plus oxaliplatin (70 mg/m²) on days 1 and 8 every 3 weeks.
• The Douillard regimen (folic acid, 5-FU, and irinotecan):
  • Irinotecan (180 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m²) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m²) IV bolus, then 5-FU (600 mg/m²) via ambulatory pump administered for a period of 22 hours on day 1 and day 2 every 2 weeks.
• The FOLFOX4 regimen (oxaliplatin, leucovorin, and 5-FU):
  • Oxaliplatin (85 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m²) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m²) IV bolus, then 5-FU (600 mg/m²) administered via ambulatory pump for a period of 22 hours on day 1 and day 2 every 2 weeks.
• The FOLFOX6 regimen (oxaliplatin, leucovorin, and 5-FU):
  • Oxaliplatin (85–100 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m²) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m²) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m²) administered via ambulatory pump for a period of 46 hours every 2 weeks.
• The FOLFIRI regimen (folic acid, 5-FU, and irinotecan):
  • Irinotecan (180 mg/m²) administered as a 2-hour infusion on day 1; leucovorin (400 mg/m²) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m²) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m²) administered via ambulatory pump for a period of 46 hours every 2 weeks.
• The FUFOX regimen (fluorouracil, leucovorin, and oxaliplatin):
  • Oxaliplatin (50 mg/m²) plus leucovorin (500 mg/m²) plus 5-FU (2,000 mg/m²) as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.
• The FUOX regimen (fluorouracil plus oxaliplatin):
  • Continuous infusion 5-FU (2,250 mg/m²) during 48 hours on days 1, 8, 15, 22, 29 and 36 plus oxaliplatin (85 mg/m²) on days 1, 15, and 29 every 6 weeks.
• IFL (or Saltz) regimen (irinotecan, 5-FU, and leucovorin):
  • Irinotecan (125 mg/m²), 5-FU (500 mg/m²) IV bolus, and leucovorin (20 mg/m²) IV bolus administered weekly for 4 out of 6 weeks.
• The XELOX regimen (capecitabine plus oxaliplatin):
  • Oral capecitabine (1,000 mg/m²) twice a day for 14 days plus oxaliplatin (130 mg/m²) on day 1 every 3 weeks.

Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[37-39] Intergroup study N9741 then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced improved PFS (median, 6.9 months vs. 8.7 months; P = .014; hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR = 0.66; 95% CI, 0.54–0.82) compared with patients randomly assigned to IFL.[Level of evidence: 1iiA] Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over after progression on first-line therapy, respectively.[40,41][Level of evidence: 1iiDiii] PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.

The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial evaluated several different irinotecan-based regimen in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI).[42] The study randomly assigned 430 patients and was closed early due to poor accrual. The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6 months vs. 5.9 months, P = .004) or CAPIRI (7.6 months vs. 5.8 months, P = .015). Patients who received CAPIRI had the highest (grade 3 or higher) rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome. After bevacizumab was approved, the BICC-C trial was amended and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab. Although the primary endpoint of PFS was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (28.0 months vs. 19.2 months, P = .037; HR for death = 1.79, 95% CI 1.12 to 2.88). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[42][Level of evidence: 1iiDiii]

Randomized phase III trials have addressed the equivalence of oral FUOX substituting for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[43,44] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1 months for the CAPOX arm and 8.0 months for the FUFOX arm (HR = 1.17; 95% CI, 0.96–1.43: P = .117), and the HR was in the prespecified equivalence range.[44] The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[43] The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[43][Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL plus bevacizumab.[45] The patients randomly assigned to IFL plus bevacizumab experienced a significantly better PFS (10.6 months with IFL and bevacizumab compared to 6.2 months with IFL plus placebo; HR for disease progression = 0.54; P <.001) and OS (20.3 months with IFL plus bevacizumab compared to 15.6 months with IFL plus placebo; HR for death = 0.66; P <.001).[45] Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had progressed on 5-FU-leucovorin and irinotecan to either FOLFOX or FOLFOX plus bevacizumab. The results demonstrated that patients randomly assigned to FOLFOX plus bevacizumab experienced a statistically significant improvement in PFS (7.3 months vs. 4.7 months: HR for progression = 0.61; P <.0001) and OS (12.9 months vs. 10.8 months; HR for death = 0.75; P = .0011).[46][Level of evidence: 1iiA] Based on these two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared to either infusional 5-FU or supportive care.[2,23,47,48] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU-leucovorin to bolus and infusional 5-FU-leucovorin (LV5FU2), single-agent oxaliplatin, or FOLFOX4. Median TTP for FOLFOX4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[49][Level of evidence: 1iiDiii]

Erbitux is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of erbitux or irinotecan plus erbitux. Median TTP for patients receiving erbitux was 1.5 months compared to median TTP of 4.2 months for patients receiving irinotecan and erbitux.[50][Level of evidence: 3iiiDiv] On the basis of this study, erbitux was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial that has not yet been reported, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced improved OS. Despite the preliminary nature of this study, the FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[51]

Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metaschronous hepatic metastasis following resection of the primary tumor.[52-54] Although only a small proportion of patients with liver metastasis are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy provide a number of treatment options.

For patients with hepatic metastasis considered to be resectable (based on a limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative-margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[17,21,55-58] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.[29] Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[59-65] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.[66-68]

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[69,70] Patients with limited pulmonary metastasis, and patients with both pulmonary and hepatic metastasis, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[71-73]

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine and dexamethasone plus systemic fluorouracil (5-FU) and leucovorin compared to systemic 5-FU plus leucovorin alone showed improved 2-year PFS (57% vs. 42%, P=.07) and overall survival (OS) (86% vs. 72%, P = .03) for patients in the combined therapy arm; median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P=.21).[74][Level of evidence: 1iiA]

A second trial preoperatively randomly assigned patients with one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.[75] Among those randomized, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival. Although liver recurrence was decreased, median or 4-year survival was not significantly different between the patient groups. Additional studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone would provide similar results compared to hepatic intra-arterial therapy plus systemic treatment.

Hepatic intra-arterial chemotherapy with floxuridine for liver metastasis has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.[16,76-80] Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of combination intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation.[81] Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV rectal cancer and recurrent rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following an initial, attempted curative resection, aggressive local therapy with repeat LAR and coloanal anastomosis, APR, or posterior or total pelvic exenteration can lead to long-term disease-free survival (DFS).[82] 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.[83,84] Intraoperative radiation therapy in patients who received previous external-beam radiation may improve local control in patients with locally recurrent disease, with acceptable morbidity.[3] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[85] 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.[71-73]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV rectal cancer and recurrent rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Wanebo HJ, Koness RJ, Vezeridis MP, et al.: Pelvic resection of recurrent rectal cancer. Ann Surg 220 (4): 586-95; discussion 595-7, 1994.  [PUBMED Abstract]
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Wadler S, Lembersky B, Atkins M, et al.: Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 9 (10): 1806-10, 1991.  [PUBMED Abstract]
   
   
10. Grem JL, Jordan E, Robson ME, et al.: Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. J Clin Oncol 11 (9): 1737-45, 1993.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. Scheele J, Stangl R, Altendorf-Hofmann A, et al.: Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 110 (1): 13-29, 1991.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. Adson MA, van Heerden JA, Adson MH, et al.: Resection of hepatic metastases from colorectal cancer. Arch Surg 119 (6): 647-51, 1984.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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): 703-10; discussion 710-1, 1994.  [PUBMED Abstract]
    
    
22. Fernández-Trigo V, Shamsa F, Sugarbaker PH: Repeat liver resections from colorectal metastasis. Repeat Hepatic Metastases Registry. Surgery 117 (3): 296-304, 1995.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. Weeks JC, Nelson H, Gelber S, et al.: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA 287 (3): 321-8, 2002.  [PUBMED Abstract]
    
    
25. Higgins GA Jr, Amadeo JH, McElhinney J, et al.: Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report. Cancer 53 (1): 1-8, 1984.  [PUBMED Abstract]
    
    
26. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer. Why we still don't know. JAMA 259 (24): 3571-8, 1988.  [PUBMED Abstract]
    
    
27. Laurie JA, Moertel CG, Fleming TR, et al.: Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 7 (10): 1447-56, 1989.  [PUBMED Abstract]
    
    
28. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.  [PUBMED Abstract]
    
    
29. Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23 (9): 2038-48, 2005.  [PUBMED Abstract]
    
    
30. 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. J Clin Oncol 5 (10): 1559-65, 1987.  [PUBMED Abstract]
    
    
31. Scheithauer W, Rosen H, Kornek GV, et al.: Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306 (6880): 752-5, 1993.  [PUBMED Abstract]
    
    
32. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 10 (6): 904-11, 1992.  [PUBMED Abstract]
    
    
33. Buyse M, Thirion P, Carlson RW, et al.: Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 356 (9227): 373-8, 2000.  [PUBMED Abstract]
    
    
34. 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.  [PUBMED Abstract]
    
    
35. Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19 (21): 4097-106, 2001.  [PUBMED Abstract]
    
    
36. Hoff PM, Ansari R, Batist G, et al.: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19 (8): 2282-92, 2001.  [PUBMED Abstract]
    
    
37. 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.  [PUBMED Abstract]
    
    
38. de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18 (16): 2938-47, 2000.  [PUBMED Abstract]
    
    
39. 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.  [PUBMED Abstract]
    
    
40. Tournigand C, André T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22 (2): 229-37, 2004.  [PUBMED Abstract]
    
    
41. Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.  [PUBMED Abstract]
    
    
42. Fuchs CS, Marshall J, Mitchell E, et al.: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25 (30): 4779-86, 2007.  [PUBMED Abstract]
    
    
43. Díaz-Rubio E, Tabernero J, Gómez-España A, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 25 (27): 4224-30, 2007.  [PUBMED Abstract]
    
    
44. Porschen R, Arkenau HT, Kubicka S, et al.: Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 25 (27): 4217-23, 2007.  [PUBMED Abstract]
    
    
45. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.  [PUBMED Abstract]
    
    
46. Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. [Abstract] J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005. 
    
    
47. 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.  [PUBMED Abstract]
    
    
48. 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.  [PUBMED Abstract]
    
    
49. Rothenberg ML, Oza AM, Bigelow RH, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21 (11): 2059-69, 2003.  [PUBMED Abstract]
    
    
50. Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 (4): 337-45, 2004.  [PUBMED Abstract]
    
    
51. Van Cutsem E, Peeters M, Siena S, et al.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 (13): 1658-64, 2007.  [PUBMED Abstract]
    
    
52. Power DG, Healey-Bird BR, Kemeny NE: Regional chemotherapy for liver-limited metastatic colorectal cancer. Clin Colorectal Cancer 7 (4): 247-59, 2008.  [PUBMED Abstract]
    
    
53. Khatri VP, Chee KG, Petrelli NJ: Modern multimodality approach to hepatic colorectal metastases: solutions and controversies. Surg Oncol 16 (1): 71-83, 2007.  [PUBMED Abstract]
    
    
54. Pawlik TM, Choti MA: Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg 11 (8): 1057-77, 2007.  [PUBMED Abstract]
    
    
55. Hughes KS, Simon R, Songhorabodi S, et al.: Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 100 (2): 278-84, 1986.  [PUBMED Abstract]
    
    
56. Schlag P, Hohenberger P, Herfarth C: Resection of liver metastases in colorectal cancer--competitive analysis of treatment results in synchronous versus metachronous metastases. Eur J Surg Oncol 16 (4): 360-5, 1990.  [PUBMED Abstract]
    
    
57. Rosen CB, Nagorney DM, Taswell HF, et al.: Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 216 (4): 493-504; discussion 504-5, 1992.  [PUBMED Abstract]
    
    
58. Fong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230 (3): 309-18; discussion 318-21, 1999.  [PUBMED Abstract]
    
    
59. Rossi S, Buscarini E, Garbagnati F, et al.: Percutaneous treatment of small hepatic tumors by an expandable RF needle electrode. AJR Am J Roentgenol 170 (4): 1015-22, 1998.  [PUBMED Abstract]
    
    
60. Solbiati L, Livraghi T, Goldberg SN, et al.: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 221 (1): 159-66, 2001.  [PUBMED Abstract]
    
    
61. Lencioni R, Goletti O, Armillotta N, et al.: Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial. Eur Radiol 8 (7): 1205-11, 1998.  [PUBMED Abstract]
    
    
62. Curley SA, Izzo F, Delrio P, et al.: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 230 (1): 1-8, 1999.  [PUBMED Abstract]
    
    
63. Oshowo A, Gillams A, Harrison E, et al.: Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg 90 (10): 1240-3, 2003.  [PUBMED Abstract]
    
    
64. Livraghi T, Solbiati L, Meloni F, et al.: Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the "test-of-time approach". Cancer 97 (12): 3027-35, 2003.  [PUBMED Abstract]
    
    
65. Pawlik TM, Izzo F, Cohen DS, et al.: Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 10 (9): 1059-69, 2003.  [PUBMED Abstract]
    
    
66. Jarnagin WR, Fong Y, Ky A, et al.: Liver resection for metastatic colorectal cancer: assessing the risk of occult irresectable disease. J Am Coll Surg 188 (1): 33-42, 1999.  [PUBMED Abstract]
    
    
67. Ravikumar TS, Kaleya R, Kishinevsky A: Surgical ablative therapy of liver tumors. Cancer: Principles and Practice of Oncology Updates 14 (3): 1-12, 2000. 
    
    
68. Seifert JK, Morris DL: Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 228 (2): 201-8, 1998.  [PUBMED Abstract]
    
    
69. 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.  [PUBMED Abstract]
    
    
70. Ravikumar TS: Interstitial therapies for liver tumors. Surg Oncol Clin N Am 5 (2): 365-77, 1996.  [PUBMED Abstract]
    
    
71. 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.  [PUBMED Abstract]
    
    
72. 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.  [PUBMED Abstract]
    
    
73. 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.  [PUBMED Abstract]
    
    
74. 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.  [PUBMED Abstract]
    
    
75. Kemeny MM, Adak S, Gray B, et al.: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol 20 (6): 1499-505, 2002.  [PUBMED Abstract]
    
    
76. 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.  [PUBMED Abstract]
    
    
77. 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.  [PUBMED Abstract]
    
    
78. 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.  [PUBMED Abstract]
    
    
79. 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.  [PUBMED Abstract]
    
    
80. 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.  [PUBMED Abstract]
    
    
81. McGinn CJ, Lawrence TS: Clinical Results of the Combination of Radiation and Fluoropyrimidines in the Treatment of Intrahepatic Cancer. Semin Radiat Oncol 7 (4): 313-323, 1997.  [PUBMED Abstract]
    
    
82. Ogunbiyi OA, McKenna K, Birnbaum EH, et al.: Aggressive surgical management of recurrent rectal cancer--is it worthwhile? Dis Colon Rectum 40 (2): 150-5, 1997.  [PUBMED Abstract]
    
    
83. 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.  [PUBMED Abstract]
    
    
84. 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.  [PUBMED Abstract]
    
    
85. 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.  [PUBMED Abstract]
    
    

Back to Top

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office

Suite 3036A

6116 Executive Boulevard, MSC8322

Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Back to Top

Changes to This Summary (12/12/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was extensively revised.

Back to Top

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

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).

Back to Top