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 ¹.

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 ² 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 ³, written in less technical language, and in Spanish ⁴.

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 ² for more information.)

Other PDQ summaries containing information related to rectal cancer include:

• Unusual Cancers of Childhood Treatment ⁵ (colorectal cancer in children).
• Genetics of Colorectal Cancer ⁶.
• Colorectal Cancer Prevention ⁷.
• Colorectal Cancer Screening ⁸.

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 ⁹ 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 ⁶ 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 ⁸ and Colorectal Cancer Prevention ⁷ 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 ¹⁰ 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. ¹¹ 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]
    
    

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]
   
   

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 ¹², 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 ⁹ for more information.)



• Lymphoma. (See the PDQ summary on Adult Hodgkin Lymphoma Treatment ¹³ for more information.)



• Carcinoid tumors. (See the PDQ summary on Gastrointestinal Carcinoid Tumors Treatment ¹⁴ for more information.)



• Melanoma. (See the PDQ summary on Melanoma Treatment ¹⁵ 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]
   
   

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 ² 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 ¹⁶), the Mayo/North Central Cancer Treatment Group (NCCTG-794751 ¹⁷), and the National Surgical Adjuvant Breast and Bowel Project (NSABP R-01 ¹⁸).[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 ¹⁹) 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) ²⁰ 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 ²¹), 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 ²² 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 ²³) 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 ²⁴ 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 ²⁵ 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 ²⁶, 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.