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Rectal Cancer Treatment (PDQ®)

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Table of Contents

General Information About Rectal Cancer

Incidence and Mortality

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 2012, there were an estimated 1.36 million new cases of colorectal cancer and 694,000 deaths.[1]

Estimated new cases and deaths from rectal cancer in the United States in 2014:[2]

  • New cases of rectal cancer: 40,000.
  • New cases of colon cancer: 96,830.
  • Deaths: 50,310 (colon and rectal cancers combined).

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]

Anatomy

Gastrointestinal (digestive) system anatomy; shows esophagus, liver, stomach, colon, small intestine, rectum, and anus.
Anatomy of the lower gastrointestinal system.


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.[5] 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.[6]

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.[5]

Risk Factors

Hereditary syndromes

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 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 related genes that are involved include the following:[6-8]

Nonpolyposis disorders

  • Lynch syndrome (hereditary nonpolyposis colorectal cancer) mismatch repair genes: Defects in mismatch repair genes (involving MSH2, MLH1, PMS1, PMS2, or MSH6) represent the most common form of hereditary colorectal cancer and account for approximately 3% to 5% of all colorectal malignancies.[7] The majority of genetically defined cases involve MSH2 on chromosome 2p and MLH1 on chromosome 3p. In affected families, 15% to 60% of family members are found to have mutations in MSH2 or MLH1; the mutation prevalence depends on features of the family history.[9] (Refer to the Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

Polyposis disorders

  • Familial adenomatous polyposis: APC gene.
  • Attenuated familial adenomatous polyposis: APC gene.
  • Turcot syndrome: APC gene; mismatch repair genes.
  • Hyperplastic polyposis syndrome: BRAF and KRAS2 genes.
  • MYH-associated polyposis: MYH gene.

Ashkenazi Jews also have an increased risk of colorectal cancer related to a mutation in the APC gene (I1307K), which occurs in 6% to 7% of the Ashkenazi Jewish population.[10]

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.

Other genetic risk factors

Other factors more common than hereditary syndromes that increase the risk of rectal cancer include the following:

  • Personal history of colorectal cancer or colorectal adenomas.
  • First-degree relative (parent, sibling, or offspring) with a history of colorectal cancer or colorectal adenomas.[11]
  • Personal history of ovarian, endometrial, or breast cancer.[12,13]

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.[14] (Refer to the PDQ summary on Colorectal Cancer Prevention for more information.)

Screening

Evidence supports screening for rectal cancer as a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer, for the following reasons:

  • Incidence of the disease in those 50 years and older.
  • Ability to identify high-risk groups.
  • Slow growth of primary lesions.
  • Better survival of patients with early-stage lesions.
  • Relative simplicity and accuracy of screening tests.

(Refer to the PDQ summary on Colorectal Cancer Screening for more information.)

Clinical Features

Similar to colon cancer, symptoms of rectal cancer may include the following:[15]

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

With the exception of obstructive symptoms, these symptoms do not necessarily correlate with the stage of disease or signify a particular diagnosis.[16]

Diagnostic Evaluation

The initial clinical evaluation may include the following:

  • Physical exam and history.
  • Digital rectal exam.
  • Colonoscopy.
  • Biopsy.
  • Carcinoembryonic antigen (CEA) assay.
  • Reverse-transcription polymerase chain reaction test.
  • Immunohistochemistry.

Physical examination may reveal a palpable mass and bright blood in the rectum. Adenopathy, hepatomegaly, or pulmonary signs may be present with metastatic disease.[6] Laboratory examination may reveal iron-deficiency anemia and electrolyte and liver function abnormalities.

Prognostic Factors

The prognosis of patients with rectal cancer is related to several factors, including the following:[6,17-25]

  • Tumor adherence to or invasion of adjacent organs.[17]
  • Presence or absence of tumor involvement in the lymph nodes and the number of positive lymph nodes.[6,18-21]
  • Presence or absence of distant metastases.[6,17]
  • Perforation or obstruction of the bowel.[6,25]
  • Presence or absence of high-risk pathologic features, including the following:[23,24,26]
    • Positive surgical margins.
    • Lymphovascular invasion.
    • Perineural invasion.
    • Poorly differentiated histology.
  • Circumferential resection margin (CRM) or depth of penetration of the tumor through the bowel wall.[6,22,27] Measured in millimeters, CRM is defined as the retroperitoneal or peritoneal adventitial soft-tissue margin closest to the deepest penetration of tumor.

Only disease stage (designated by tumor [T], nodal status [N], and distant metastasis [M]) has been validated as a prognostic factor in multi-institutional prospective studies.[17-22] A major pooled analysis evaluating the impact of T and N stage and treatment on survival and relapse in patients with rectal cancer who are treated with adjuvant therapy has been published and confirms these findings.[28]

A large number of studies have evaluated other clinical, pathologic, and molecular parameters.[29-35] As yet, none has been validated in multi-institutional prospective trials. For example, microsatelite instability–high, also associated with Lynch syndrome–related 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.[36] 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 stages II and III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiation therapy.[37,38]

Racial and ethnic differences in overall survival (OS) after adjuvant therapy for rectal cancer have been observed, with shorter OS for blacks than for whites. Factors contributing to this disparity may include tumor position, type of surgical procedure, and presence of comorbid conditions.[39]

Follow-up After Treatment

The primary goals of postoperative surveillance programs for rectal cancer are:[40]

  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 treatment for rectal cancer may lead to earlier identification and management of recurrent disease.[40-44] 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 reported a statistically significant improvement in survival for patients who were intensively followed.[40,45,46]

Guidelines for surveillance after initial treatment with curative intent for colorectal cancer vary between leading U.S. and European oncology societies, and optimal surveillance strategies remain uncertain.[47,48] Large, well-designed, prospective, multi-institutional, randomized studies are required to establish an evidence-based consensus for follow-up evaluation.

Carcinoembryonic antigen (CEA)

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:[40]

  • Serum CEA testing is not a valuable screening tool for rectal cancer because of its low sensitivity and low specificity.
  • Postoperative CEA testing is typically restricted to patients who are potential candidates for further intervention, as follows:
    • Patients with stage II or III rectal cancer (every 2–3 months for at least 2 years after diagnosis).
    • Patients with rectal cancer who would be candidates for resection of liver metastases.

In one Dutch retrospective study of total mesorectal excision 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.[49,50]

Related Summaries

Other PDQ summaries containing information related to rectal cancer include the following:

References

  1. Ferlay J, Soerjomataram I, Ervik M, et al.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer, 2013. Available online. Last accessed December 08, 2014.
  2. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed November 24, 2014.
  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. 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]
  6. Libutti SK, Willett CG, Saltz LB: Cancer of the rectum. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1127-41.
  7. Strate LL, Syngal S: Hereditary colorectal cancer syndromes. Cancer Causes Control 16 (3): 201-13, 2005. [PUBMED Abstract]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. Weinberg DS, Newschaffer CJ, Topham A: Risk for colorectal cancer after gynecologic cancer. Ann Intern Med 131 (3): 189-93, 1999. [PUBMED Abstract]
  13. Burstein HJ, Winer EP: Primary care for survivors of breast cancer. N Engl J Med 343 (15): 1086-94, 2000. [PUBMED Abstract]
  14. Winawer SJ: Screening for colorectal cancer. Cancer: Principles and Practice of Oncology Updates 2(1): 1-16, 1987.
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
  27. 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]
  28. 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]
  29. McLeod HL, Murray GI: Tumour markers of prognosis in colorectal cancer. Br J Cancer 79 (2): 191-203, 1999. [PUBMED Abstract]
  30. 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]
  31. 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]
  32. Roth JA: p53 prognostication: paradigm or paradox? Clin Cancer Res 5 (11): 3345, 1999. [PUBMED Abstract]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. 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]
  40. 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]
  41. 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]
  42. 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]
  43. 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]
  44. Khoury DA, Opelka FG, Beck DE, et al.: Colon surveillance after colorectal cancer surgery. Dis Colon Rectum 39 (3): 252-6, 1996. [PUBMED Abstract]
  45. 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]
  46. 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]
  47. 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]
  48. Li Destri G, Di Cataldo A, Puleo S: Colorectal cancer follow-up: useful or useless? Surg Oncol 15 (1): 1-12, 2006. [PUBMED Abstract]
  49. 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]
  50. 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

Adenocarcinomas account for the vast majority of rectal tumors in the United States. Other histologic types account for an estimated 2% to 5% of colorectal tumors.[1]

The World Health Organization classification of tumors of the colon and rectum includes the following:[2]

Epithelial Tumors

Adenoma

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

Carcinoma

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

Carcinoid (well-differentiated neuroendocrine neoplasm)

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

Intraepithelial neoplasia (dysplasia) associated with chronic inflammatory diseases

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

Mixed carcinoma-adenocarcinoma

  • Others.

Nonepithelial Tumors

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.

(Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

References

  1. 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]
  2. Hamilton SR, Aaltonen LA: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2000.

Stage Information for Rectal Cancer

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 following:[1-7]

  • The depth of tumor invasion.
  • The distance from the sphincter complex.
  • The potential for achieving negative circumferential (radial) margins.
  • The involvement of locoregional lymph nodes or adjacent organs.

Staging Evaluation

Clinical evaluation and staging procedures may include the following:

  • Digital-rectal examination (DRE): DRE and/or rectovaginal exam and rigid proctoscopy to determine if sphincter-saving surgery is possible.[1,2,5]
  • Colonoscopy: Complete colonoscopy to rule out cancers elsewhere in the bowel.[5]
  • Computed tomography (CT): Pan-body CT scan to rule out metastatic disease.[5]
  • Magnetic resonance imaging (MRI): MRI of the abdomen and pelvis to determine the depth of penetration and the potential for achieving negative circumferential (radial) margins and to identify locoregional nodal metastases and distant metastatic disease. MRI may be particularly helpful in determining sacral involvement in local recurrence.[1]
  • Endorectal ultrasound: Endorectal ultrasound with a rigid probe or a flexible scope for stenotic lesions to determine the depth of penetration and identify locoregional nodal metastases.[2,4]
  • Positron emission tomography (PET): PET to image distant metastatic disease.[1]
  • Carcinoembryonic antigen (CEA): Measurement of the serum CEA level for prognostic assessment and the determination of response to therapy.[6,7]

In the tumor (T) staging of rectal carcinoma, several studies indicate that the accuracy of endorectal ultrasound 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 endorectal ultrasound is approximately 70% to 75% compared with 55% to 65% for CT and 60% to 70% for MRI.[2] In a meta-analysis of 84 studies, none of the three imaging modalities, including endorectal ultrasound, CT, and MRI, were found to be significantly superior to the others in staging nodal (N) status.[8] Endorectal ultrasound using a rigid probe may be similarly accurate in T and N staging when compared with endorectal ultrasound using a flexible scope; however, a technically difficult endorectal ultrasound may give an inconclusive or inaccurate result for both T stage and N stage. In this case, further assessment by MRI or flexible endorectal ultrasound may be considered.[4,9]

In patients with rectal cancer, the circumferential resection margin 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.[10]

TNM Classification System

AJCC stage groupings and TNM definitions

The American Joint Committee on Cancer (AJCC) has designated staging by tumor, node, and metastasis (TNM) classification to define rectal cancer.[11] The same classification is used for both clinical and pathologic staging.[11] Treatment decisions are made with reference to the TNM classification system, rather than the older Dukes or Modified Astler-Coller classification schema.

The AJCC staging system for rectal cancer does not apply to the following histologies:

Lymph node status

The AJCC and a National Cancer Institute-sponsored panel suggested that at least 10 to 14 lymph nodes be examined in radical colon and rectum resections in patients who did not receive neoadjuvant therapy. In cases in which tumor is resected for palliation or in patients who have received preoperative radiation therapy, fewer lymph nodes may be removed or present.[10-12] This 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 [EST-2288], have demonstrated that the number of lymph nodes examined during colon and rectal surgery may be associated with patient outcome.[13-16]

A new tumor-metastasis staging strategy for node-positive rectal cancer has been proposed.[17]

Table 1. Definitions of TNM Stage 0
StageTNMa,bDukescMACdDescriptionIllustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Reprinted with permission from AJCC: Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-164.
The explanations for superscripts a–g are at the end of Table 5.
0Tis, N0, M0Tis = Carcinoma in situ: intraepithelial or invasion of lamina propria.e
Stage 0 colon/rectal carcinoma in situ; shows a cross-section of the colon/rectum. An inset shows the layers of the colon/rectum wall with abnormal cells in the mucosa layer. Also shown are the submucosa, muscle layers, serosa, a blood vessel, and lymph nodes.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage I
StageTNMa,bDukescMACdDescriptionIllustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Reprinted with permission from AJCC: Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-164.
The explanations for superscripts a–g are at the end of Table 5.
IT1, N0, M0AAT1 = Tumor invades submucosa.
Stage I colorectal cancer; shows a cross-section of the colon/rectum. An inset shows the layers of the colon/rectum wall with cancer in the mucosa, submucosa, and muscle layers. Also shown are the serosa, a blood vessel, and lymph nodes.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T2, N0, M0AB1T2 = Tumor invades muscularis propria.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stage II
StageTNMa,bDukescMACdDescriptionIllustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Reprinted with permission from AJCC: Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-164.
The explanations for superscripts a–g are at the end of Table 5.
IIAT3, N0, M0BB2T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
Stage II colorectal cancer; shows a cross-section of the colon/rectum and a three-panel inset. Each panel shows the layers of the colon/rectum wall: mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. First panel shows stage IIA with cancer in the mucosa, submucosa, muscle layers, and serosa. Second panel shows stage IIB with cancer in all layers and spreading through the serosa. Third panel shows stage IIC with cancer spreading to nearby organs.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIBT4a, N0, M0BB2T4a = Tumor penetrates to the surface of the visceral peritoneum.f
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IICT4b, N0, M0BB3T4b = Tumor directly invades or is adherent to other organs or structures.f,g
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage III
StageTNMa,bDukescMACdDescriptionIllustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Reprinted with permission from AJCC: Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-164.
The explanations for superscripts a–g are at the end of Table 5.
IIIAT1–T2, N1/N1c, M0CC1T1 = Tumor invades submucosa.
Stage IIIA colorectal cancer; shows a cross-section of the colon/rectum and a two-panel inset. Each panel shows the layers of the colon/rectum wall: mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. First panel shows cancer in the mucosa, submucosa, muscle layers, and 2 lymph nodes. Second panel shows cancer in the mucosa, submucosa, and 5 lymph nodes.
T2 = Tumor invades muscularis propria.
N1 = Metastases in 1–3 regional lymph nodes.
N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis.
M0 = No distant metastasis.
T1, N2a, M0CC1T1 = Tumor invades submucosa.
N2a = Metastases in 4–6 regional lymph nodes.
M0 = No distant metastasis.
IIIBT3–T4a, N1/N1c, M0CC2T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
Stage IIIB colorectal cancer; shows a cross-section of the colon/rectum and a two-panel inset. Each panel shows the layers of the colon/rectum wall: mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. First panel shows cancer in all layers, spreading through the serosa, and in 3 lymph nodes. Second panel shows cancer in all layers and in 5 lymph nodes. Third panel shows cancer in the mucosa, submucosa, muscle layers, and 7 lymph nodes.
T4a = Tumor penetrates to the surface of the visceral peritoneum.f
N1 = Metastases in 1–3 regional lymph nodes.
N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis.
M0 = No distant metastasis.
T2–T3, N2a, M0CC1/C2T2 = Tumor invades muscularis propria.
T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
N2a = Metastases in 4–6 regional lymph nodes.
M0 = No distant metastasis.
T1–T2, N2b, M0CC1T1 = Tumor invades submucosa.
T2 = Tumor invades muscularis propria.
N2b = Metastases in ≥7 regional lymph nodes.
M0 = No distant metastasis.
IIICT4a, N2a, M0CC2T4a = Tumor penetrates to the surface of the visceral peritoneum.f
Stage IIIC colorectal cancer; shows a cross-section of the colon/rectum wall and a three-panel inset. Each panel shows the layers of the colon/rectum wall: mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. First panel shows cancer in all layers, spreading through the serosa, and in 4 lymph nodes. Second panel shows cancer in all layers and in 7 lymph nodes. Third panel shows cancer in all layers, spreading through the serosa, in 2 lymph nodes, and spreading to nearby organs.
N2a = Metastases in 4–6 regional lymph nodes.
M0 = No distant metastasis.
T3–T4a, N2b, M0CC2T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
T4a = Tumor penetrates to the surface of the visceral peritoneum.f
N2b = Metastases in ≥7 regional lymph nodes.
M0 = No distant metastasis.
T4b, N1–N2, M0CC3T4b = Tumor directly invades or is adherent to other organs or structures.f,g
N1 = Metastases in 1–3 regional lymph nodes.
N2 = Metastases in ≥4 regional lymph nodes.
M0 = No distant metastasis.
Table 5. Definitions of TNM Stage IV
StageTNMa,bDukescMACdDescriptionIllustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
Reprinted with permission from AJCC: Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-164.
acTNM is the clinical classification, and pTNM is the pathologic classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (e.g., ypTNM). Patients who have a complete pathologic response (ypT0, N0, cM0) may be similar to stage group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease-free interval (rTNM).
bA satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumor Deposits.
cDukes B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) prognostic groups, as is Dukes C (any T, N1, M0 and any T, N2, M0).
dMAC is the modified Astler-Coller classification.
eTis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.
fDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).
gTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1–4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site-specific factor should be used for perineural invasion.
IVAAny T, Any N, M1aTX = Primary tumor cannot be assessed.
Stage IV rectal cancer; drawing shows other parts of the body where rectal cancer may spread, including lymph nodes, lung, liver, abdominal wall, and ovary. Inset shows cancer spreading through the blood and lymph nodes to other parts of the body.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ: intraepithelial or invasion of lamina propria.e
T1 = Tumor invades submucosa.
T2 = Tumor invades muscularis propria.
T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
T4a = Tumor penetrates to the surface of the visceral peritoneum.f
T4b = Tumor directly invades or is adherent to other organs or structures.f,g
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastases in 1–3 regional lymph nodes.
N1a = Metastasis in 1 regional lymph node.
N1b = Metastases in 2–3 regional lymph nodes.
N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis.
N2 = Metastases in ≥4 regional lymph nodes.
N2a = Metastases in 4–6 regional lymph nodes.
N2b = Metastases in ≥7 regional lymph nodes.
M1a = Metastasis confined to 1 organ or site (e.g., liver, lung, ovary, nonregional node).
IVBAny T, Any N, M1bTX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ: intraepithelial or invasion of lamina propria.e
T1 = Tumor invades submucosa.
T2 = Tumor invades muscularis propria.
T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
T4a = Tumor penetrates to the surface of the visceral peritoneum.f
T4b = Tumor directly invades or is adherent to other organs or structures.f,g
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastases in 1–3 regional lymph nodes.
N1a = Metastasis in 1 regional lymph node.
N1b = Metastases in 2–3 regional lymph nodes.
N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis.
N2 = Metastases in ≥4 regional lymph nodes.
N2a = Metastases in 4–6 regional lymph nodes.
N2b = Metastases in ≥7 regional lymph nodes.
M1b = Metastases in >1 organ/site or the peritoneum.

References

  1. Schmidt CR, Gollub MJ, Weiser MR: Contemporary imaging for colorectal cancer. Surg Oncol Clin N Am 16 (2): 369-88, 2007. [PUBMED Abstract]
  2. 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]
  3. 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]
  4. 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]
  5. Libutti SK, Willett CG, Saltz LB: Cancer of the rectum. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1127-41.
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Colon and rectum. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 143-64.
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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

The management of rectal cancer varies somewhat from that of colon cancer because of the increased risk of local recurrence and a poorer overall prognosis. 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 function, and sexual function.[1,2]

The approach to the management of rectal cancer is multimodal and involves a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.

Table 6. Standard Treatment Options for Stages 0–III Rectal Cancer
Stage (TNM Staging Criteria) Standard Treatment Options
Stage 0 Rectal CancerPolypectomy or surgery
Stage I Rectal CancerSurgery with or without chemoradiation therapy
Stages II and III Rectal CancerSurgery
Preoperative chemoradiation therapy
Short-course preoperative radiation therapy
Postoperative chemoradiation therapy
Table 7. Treatment Options for Stage IV and Recurrent Rectal Cancer
Stage (TNM Staging Criteria) Treatment Options
Stage IV and Recurrent Rectal CancerSurgery with or without chemotherapy or radiation therapy
First-line chemotherapy and targeted therapy
Second-line chemotherapy
Palliative therapy
Liver MetastasesSurgery
Neoadjuvant chemotherapy
Local ablation
Adjuvant chemotherapy
Intra-arterial chemotherapy

Primary Surgical Therapy

The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. The surgical approach to treatment varies according to the following:

  • Tumor location.
  • Stage of disease.
  • Presence or absence of high-risk features (i.e., positive margins, lymphovascular invasion, perineural invasion, and poorly differentiated histology).

Types of surgical resection include the following:[1-3]

  • Polypectomy for select T1 cancers.
  • Transanal local excision and transanal endoscopic microsurgery for select clinically staged T1/T2 N0 rectal cancers.
  • Total mesorectal excision with autonomic nerve preservation techniques via low-anterior resection.
  • Total mesorectal excision via abdominoperineal resection for patients who are not candidates for sphincter-preservation, leaving patients with a permanent end-colostomy.

Polypectomy alone may be used in certain instances (T1) in which polyps with invasive cancer can be completely resected with clear margins and have favorable histologic features.[4,5]

Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all other tumors, a mesorectal excision is the treatment of choice. Very select patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% after rectal resection with appropriate mesorectal excision (total mesorectal excision for low/middle rectal tumors and mesorectal excision at least 5 cm below the tumor for high rectal tumors) have been reported.[6-10]

For patients with advanced cancers of the mid- to upper rectum, low-anterior resection followed by the creation of a colorectal anastomosis may be the treatment of choice. For locally advanced rectal cancers for which radical resection is indicated, however, total mesorectal excision with autonomic nerve preservation techniques via low-anterior resection is preferable to abdominoperineal resection.[1,2]

The low incidence of local relapse after 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.[11]

Chemoradiation Therapy

Preoperative chemoradiation therapy

Neoadjuvant therapy for rectal cancer, using preoperative chemoradiation therapy, is the preferred treatment option for patients with stages II and III disease. However, postoperative chemoradiation therapy for patients with stage II or III rectal cancer remains an acceptable option.[12][Level of evidence: 1iA]

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III), based on the results of several studies:

Multiple phase II and III studies examined the benefits of preoperative chemoradiation therapy, which include the following:[12]

  • Tumor regression and downstaging of the tumor.
  • Improved tumor resectability.
  • Higher rate of local control.
  • Improved toxicity profile of chemoradiation therapy.
  • Higher rate of sphincter preservation.

Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[15-22] However, preoperative radiation therapy is associated with increased complications compared with surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[23-26]

(Refer to the Preoperative chemoradiation therapy section in the Stages II and III Rectal Cancer section of this summary for more information about these studies.)

Postoperative chemoradiation therapy

Preoperative chemoradiation therapy is the current standard of care for stages II and III rectal cancer. However, before 1990, the following studies noted an increase in both disease-free survival (DFS) and overall survival (OS) with the use of postoperative combined-modality therapy:

  1. The Gastrointestinal Tumor Study Group trial (GITSG-7175).
  2. The Mayo/North Central Cancer Treatment Group trial (NCCTG-794751).
  3. The National Surgical Adjuvant Breast and Bowel Project trial (NSABP-R-01).

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems.

Fluorouracil (5-FU): The following studies examined optimal delivery methods for adjuvant 5-FU:

  1. Intergroup protocol 86-47-51 trial (MAYO-864751).[27][Level of evidence: 1iiA]
  2. Intergroup 0114 trial (INT-0114 [CLB-9081]).[25][Level of evidence: 1iiA]
  3. Intergroup 0144 ( SWOG-9304 [NCT00002551]).[28]

(Refer to the Stages II and III Rectal Cancer section of this summary for detailed information about these study results.)

Acceptable postoperative chemoradiation 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 (LV).

Findings from the NSABP-R-01 trial compared surgery alone with surgery followed by chemotherapy or radiation therapy.[29] Subsequently, the NSABP-R-02 study, addressed whether adding postoperative radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[30][Level of evidence: 1iiA]

In the NSABP-R-02 study, the addition of radiation therapy significantly reduced local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02) but failed to demonstrate a significant survival benefit. Radiation therapy appeared to improve survival among patients younger than 60 years and among patients who underwent abdominoperineal resection.

While this trial has initiated discussion in the oncologic community about the proper role of postoperative radiation therapy, omission of radiation therapy seems premature because of the serious complications of locoregional recurrence.

Chemotherapy regimens

Table 8 describes the chemotherapy regimens used to treat rectal cancer.

Table 8. Drug Combinations Used to Treat Rectal Cancer
Regimen NameDrug CombinationDose
5-FU = fluorouracil; IV = intravenous; LV = leucovorin.
Arbeitsgemeinschaft Internistische Onkologie (AIO) or German AIOFolic acid, 5-FU, and irinotecanIrinotecan (100 mg/m2) and LV (500 mg/m2) administered as 2-hour infusions on day 1, followed by 5-FU (2,000 mg/m2) IV bolus administered via ambulatory pump weekly over 24 hours, 4 times a year (52 weeks).
CAPOXCapecitabine and oxaliplatinCapecitabine (1,000 mg/m2) twice daily on days 1 through 14, plus oxaliplatin (70 mg/m2) on days 1 and 8 every 3 weeks.
DouillardFolic acid, 5-FU, and irinotecanIrinotecan (180 mg/m2) administered as a 2-hour infusion on day 1, LV (200 mg/m2) administered as a 2-hour infusion on days 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 hours every 2 weeks on days 1 and 2.
FOLFIRILV, 5-FU, and irinotecanIrinotecan (180 mg/m2) and LV (400 mg/m2) administered as 2-hour infusions 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 over 46 hours every 2 weeks.
FOLFOX4Oxaliplatin, LV, and 5-FUOxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1, LV (200 mg/m2) administered as a 2-hour infusion on days 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 hours every 2 weeks on days 1 and 2.
FOLFOX6Oxaliplatin, LV, and 5-FUOxaliplatin (85–100 mg/m2) and LV (400 mg/m2) administered as 2-hour infusions 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 over 46 hours every 2 weeks.
FOLFOXIRIIrinotecan, oxaliplatin, LV, 5-FUIrinotecan (165 mg/m2) administered as a 60-minute infusion, then concomitant infusion of oxaliplatin (85 mg/m2) and LV (200 mg/m2) over 120 minutes, followed by 5-FU (3,200 mg/m2) administered as a 48-hour continuous infusion.
FUFOX5-FU, LV, and oxaliplatinOxaliplatin (50 mg/m2) plus LV (500 mg/m2) plus 5-FU (2,000 mg/m2) administered as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.
FUOX5-FU plus oxaliplatin5-FU (2,250 mg/m2) administered as a continuous infusion over 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)Irinotecan, 5-FU, and LVIrinotecan (125 mg/m2) plus 5-FU (500 mg/m2) IV bolus and LV (20 mg/m2) IV bolus administered weekly for 4 out of 6 weeks.
XELOXCapecitabine plus oxaliplatinOral capecitabine (1,000 mg/m2) administered twice daily for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.

Treatment toxicity

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 after 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.[31] Patients treated with radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than do patients who undergo surgical resection alone.[24,32-37]

An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction than do patients who undergo surgical resection alone.[38] A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with radiation therapy.[31]

Improved radiation therapy planning and techniques may minimize these acute and late treatment-related complications. These techniques include the following:[39-43]

  • The use of high-energy radiation machines.
  • The use of multiple pelvic radiation fields.
  • Prone patient positioning.
  • Customized patient molds (belly boards) to exclude as much small bowel as possible from the radiation fields and immobilize patients during treatment.
  • Bladder distention during radiation therapy to exclude as much small bowel as possible from the radiation 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 3-dimensional or other advanced radiation planning techniques.

In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy  × five daily treatments) followed by surgery one week later, rather than the long-course chemoradiation approach used in the United States. One reason for this difference is the concern in the United States for heightened late effects when high radiation doses per fraction are given.

A Polish study randomly assigned 316 patients to preoperative long-course chemoradiation therapy (50.4 Gy in 28 daily fractions with 5-FU and LV) or short-course preoperative radiation therapy (25 Gy in five fractions).[37] 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

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  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. 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]
  40. 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]
  41. 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]
  42. Koelbl O, Richter S, Flentje M: Influence of patient positioning on dose-volume histogram and normal tissue complication probability for small bowel and bladder in patients receiving pelvic irradiation: a prospective study using a 3D planning system and a radiobiological model. Int J Radiat Oncol Biol Phys 45 (5): 1193-8, 1999. [PUBMED Abstract]
  43. Gunderson LL, Russell AH, Llewellyn HJ, et al.: Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 11 (7): 1379-93, 1985. [PUBMED Abstract]

Stage 0 Rectal Cancer

Standard Treatment Options for Stage 0 Rectal Cancer

Stage 0 rectal cancer or carcinoma in situ is the most superficial of all rectal lesions and is limited to the mucosa without invasion of the lamina propria.

Standard treatment options for stage 0 rectal cancer include the following:

Polypectomy or surgery

Local excision or simple polypectomy may be indicated for stage 0 rectal cancer tumors.[1] Because of its localized nature at presentation, stage 0 rectal cancer has a high cure rate. For large lesions not amenable to local excision, full-thickness rectal resection by the transanal or transcoccygeal route may be performed.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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]

Stage I Rectal Cancer

Standard Treatment Options for Stage I 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 rectal cancer has a high cure rate.

Standard treatment options for stage I rectal cancer include the following:

Surgery with or without chemoradiation therapy

There are three potential options for surgical resection in stage I rectal cancer:

  • Local excision. Local excision is restricted to tumors that are 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 is associated with a higher risk of local and systemic failure and is applicable to only very select patients with T2 tumors. Local transanal or other resection [1,2] with or without perioperative external-beam radiation therapy (EBRT) plus fluorouracil (5-FU) may be indicated.
  • Low-anterior resection. Wide surgical resection and anastomosis are options when an adequate low-anterior resection can be performed with sufficient distal rectum to allow a conventional anastomosis or coloanal anastomosis.
  • Abdominoperineal resection. Wide surgical resection with abdominoperineal resection is used for lesions too distal to permit low-anterior resection.

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. Patients may want to consider additional therapy, such as radiation therapy and chemotherapy, or wide surgical resection of the rectum.[3] Patients with poor histologic features or positive margins after local excision may consider low-anterior resection or abdominoperineal resection and postoperative treatment as dictated by full surgical staging.

For patients with T1 and T2 tumors, no randomized trials are available to compare local excision with or without postoperative chemoradiation therapy to wide surgical resection (low-anterior resection and abdominoperineal resection).

Evidence (surgery):

  1. Investigators with the Cancer and Leukemia Group B 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 after surgery, whereas patients with T2 tumors were treated with EBRT (54 Gy in 30 fractions, 5 days/week) and 5-FU (500 mg/m2 on days 1 through 2 and days 29 through 31 of radiation therapy).[4]
    • For patients with T1 tumors, at 48 months median follow-up, the 6-year failure-free survival was 83% and OS rate was 87%.
    • For patients with T2 tumors, the 6-year failure-free survival was 71% and the OS rate was 85%.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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. 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]
  4. 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]

Stages II and III Rectal Cancer

Standard Treatment Options for Stages II and III Rectal Cancer

Standard treatment options for stages II and III rectal cancer include the following:

Surgery

Total mesorectal excision with either low anterior resection or abdominoperineal resection is usually performed for stages II and III rectal cancer before or after chemoradiation therapy.

Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with surgery and no additional therapy have a very low risk of local and systemic recurrence.[1]

Preoperative chemoradiation therapy

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.

Evidence (preoperative chemoradiation therapy):

  1. The German Rectal Cancer Study Group (CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society]) randomly assigned 823 patients with ultrasound-staged T3 or 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 fluorouracil [5-FU] 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy).[2][Level of evidence: 1iA] All patients underwent total mesorectal excision and received four additional cycles of 5-FU-based chemotherapy.
    • The 5-year overall survival (OS) rates were 76% for preoperative chemoradiation therapy and 74% for postoperative chemoradiation therapy (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to the preoperative chemoradiation therapy group and 13% for patients in the postoperative chemoradiation therapy group (P = .006).
    • Grade 3 or 4 acute toxic effects occurred in 27% of patients in the preoperative-treatment group and in 40% of patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).
    • The same number of patients underwent 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). These results have now been updated with a median follow-up of 11 years.[3]
    • The 10-year OS was equivalent in both arms, (59.6% in the preoperative group vs. 59.9% in the postoperative group; P = .85). However, a local control benefit persists among patients treated with preoperative chemoradiation therapy compared with patients treated with postoperative chemoradiation therapy (10-year cumulative incidence of local relapse: 7.1% in the preoperative group vs. 10.1% in the postoperative group; P = .048). There were no significant differences detected for 10-year cumulative incidence of distant metastases or disease-free survival (DFS).[3]
    • Among the patients assigned to the postoperative chemoradiation therapy treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal ultrasound to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.
  2. The NSABP R-03 trial similarly compared preoperative versus postoperative chemoradiation therapy for patients with clinically staged T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of 5-FU/leucovorin (LV) with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients.[4][Level of evidence: 1iiA]
    • With a median follow-up of 8.4 years, preoperative chemoradiation therapy was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients; P = .011).
    • Similar to the German Rectal Cancer Study, there was no significant difference in OS between treatment arms (74.5% for preoperative chemoradiation therapy vs. 65.6% for postoperative chemoradiation therapy; P =. 065).
Short-course preoperative radiation therapy

The use of short-course radiation therapy before surgery has been a standard approach in parts of Europe and Australia.

Evidence (short-course preoperative radiation therapy):

  1. The use of short-course radiation therapy was evaluated in a randomized study in the Swedish Rectal Cancer Trial (NCT00337545).[5][Level of evidence: 1iiA] In the trial, 1,168 patients younger than 80 years with stage I to stage III resectable rectal adenocarcinoma were randomly assigned to receive preoperative radiation therapy (25 Gy in five fractions) or to undergo immediate surgery. Patients did not receive adjuvant chemotherapy.
    • The 5-year OS rate was 58% in the radiation therapy group and 48% in the surgery group (P = .005).
    • The rate of local control was 11% in the radiation therapy group and 27% in the surgery group (P < .001).

    Subsequently, the Polish Rectal Trial and the Trans-Tasman Radiation Oncology Group (TROG) compared short-course preoperative radiation therapy with the standard long-course preoperative chemoradiation therapy administered with 5-FU.

  2. In the Polish Rectal Trial, 312 patients with clinical stage T3 or T4 rectal cancer were randomly assigned to receive preoperative radiation therapy (25 Gy in five fractions) followed by total mesorectal excision within 7 days, 6 months of adjuvant 5-FU/LV or preoperative chemoradiation therapy (50.4 Gy in 28 fractions with concurrent bolus 5-FU/LV), total mesorectal excision in 4 to 6 weeks after completion of radiation therapy, and 4 months of adjuvant 5-FU/LV.[6] The primary endpoint of the study was to detect a difference of at least 15% in sphincter preservation with a power of 80%.
    • The rates of sphincter preservation were 61.2% in the short-course group and 58% in the chemoradiation therapy group (P = .570).
    • The actuarial 4-year survival rate was 67.2% in the short-course group and 66.2% in the chemoradiation therapy group (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.69–1.48; P = .960).
    • The HR for local recurrence in the short-course group compared with the chemoradiation therapy group was 0.65 (95% CI, 0.32–1.28; P = .210).
    • There was no difference in late toxicity between the short-course group and the chemoradiation therapy group.
  3. In the TROG trial (TROG 01.04), 326 patients with ultrasound- or magnetic resonance imaging (MRI)–staged T3, N0 to N2, M0 rectal adenocarcinoma within 12 cm from the anal verge were randomly assigned to receive short-course radiation therapy (25 Gy in five fractions) followed by surgery 3 to 7 days later or long-course chemoradiation therapy (50.4 Gy in 28 fractions with concurrent continuous infusional 5-FU) followed by surgery in 4 to 6 weeks. All patients received adjuvant chemotherapy (5-FU/LV) after surgery. The trial was designed to have 80% power to detect a 10% difference in local recurrence at 3 years with a two-sided test at the 5% level of significance.[7]
    • Cumulative incidence of local recurrence at 3 years was 7.5% for the short-course group and 4.4% for the long-course group (P = .24).
    • OS at 5 years was 74% for the short-course group and 70% for the long-course group (HR, 1.12; 95% CI, 0.76–1.67; P = .62).
  4. The Medical Research Council of the United Kingdom and the National Cancer Institute of Canada built on the short-course experience and conducted a randomized study (MRC CR07 and NCIC-CTG C016) that compared short-course preoperative radiation therapy with selective postoperative chemoradiation therapy.[8] In the trial, 1,350 patients from 80 centers who had resectable rectal adenocarcinomas that were less than 15 cm from the anal verge were randomly assigned. Of note, pelvic MRI or ultrasound was not mandated. Patients randomly assigned to short-course radiation therapy received 25 Gy in five fractions followed by total mesorectal excision and then adjuvant chemotherapy according to the local center policy about nodal and margin status. Patients randomly assigned to selective postoperative chemoradiation therapy received immediate surgery followed by postoperative chemoradiation (45 Gy in 25 fractions with concurrent 5-FU) if their circumferential resection margin was 1 mm or smaller. Adjuvant chemotherapy for the group that received selective chemoradiation therapy was again given on the basis of local standards regarding nodal and margin status. [8]
    • The risk of local recurrence at 3 years was 4.4% in the preoperative short-course group and 10.6% in the selective chemoradiation therapy group (HR, 0.39; 95% CI, 0.27–0.58; P < .0001).
    • OS did not differ between the groups.

Taken together, these studies demonstrate that short-course preoperative radiation therapy and long-course preoperative chemoradiation therapy are both reasonable treatment strategies for patients with stage II or III rectal adenocarcinoma.

Postoperative chemoradiation therapy

Progress in the development of postoperative treatment regimens relates to the integration of systemic chemotherapy and radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stages II and III rectal cancer was established by a series of prospective, randomized clinical trials, including the following:[9-11][Level of evidence: 1iiA]

  • Gastrointestinal Tumor Study Group (GITSG-7175).
  • Mayo/North Central Cancer Treatment Group (NCCTG-794751).
  • National Surgical Adjuvant Breast and Bowel Project (NSABP-R-01).

These studies demonstrated an increase in DFS interval and OS when radiation therapy was combined with chemotherapy after surgical resection. After the publication in 1990 of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference recommended postoperative combined-modality treatment for patients with stages II and III rectal carcinoma.[12] Since that time, preoperative chemoradiation therapy has become the standard of care, although postoperative chemoradiation therapy is still an acceptable alternative. (Refer to the Preoperative chemoradiation therapy section of this summary for more information.)

Additional evidence (postoperative chemoradiation therapy):

  1. Intergroup protocol 86-47-51 (MAYO-864751) compared continuous-infusion 5-FU (225 mg/m2/day throughout the entire course of radiation therapy) with bolus 5-FU (500 mg/m2/day for 3 consecutive days during the first and fifth weeks of radiation therapy).[13][Level of evidence: 1iiA]
    • A 10% improvement in OS was demonstrated with the use of continuous-infusion 5-FU.
  2. SWOG-9304 (NCT00002551), a three-arm randomized trial, determined whether continuous-infusion 5-FU given throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU given only during pelvic radiation therapy. Median follow-up was 5.7 years.[14]
    1. 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.
    2. 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.
    3. Arm 3 received bolus 5-FU/LV in two 5-day cycles before (5-FU 425 mg/m2/day; LV 20 mg/m2/day) and after (5-FU 380 mg/m2/day; LV 20 mg/m2/day) radiation therapy, and bolus 5-FU/LV (5-FU 400 mg/m2/day; LV 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.
      • No DFS, OS, or locoregional failure difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; locoregional failure, 4.6% to 8%).
      • Lethal toxicity was less than 1%, with grades 3 to 4 hematologic toxicity in 55% of patients in arm 1 and in 49% of the patients in arm 3, versus in 4% of patients in the continuous-infusion arm.[14][Level of evidence: 1iiA]
  3. The final study results of Intergroup trial 0114 (INT-0114) showed no survival or local-control benefit with the addition of LV, levamisole, or both to 5-FU administered postoperatively for patients with stages II and III rectal cancers at a median follow-up of 7.4 years.[15][Level of evidence: 1iiA]
  4. 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 (OS, 84%) compared favorably with the survival rates of patients treated with surgery plus radiation therapy and bolus chemotherapy (OS, 76%) or surgery plus radiation therapy and protracted-infusion chemotherapy (OS, 80%).[16]

Chemotherapy Regimens

Many academic oncologists suggest that LV/5-FU/oxaliplatin (FOLFOX) be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data about rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. An Eastern Cooperative Oncology Group trial (ECOG-E5202 [NCT00217737]) randomly assigned patients with stage II or III rectal cancer who received preoperative or postoperative chemoradiation therapy to 6 months of FOLFOX with or without bevacizumab, but this trial closed because of poor accrual; no efficacy data are available.

Preoperative oxaliplatin with chemoradiation therapy

Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models.[17] Phase II studies that combined oxaliplatin with fluoropyrimidine-based chemoradiation therapy have reported pathologic complete response rates ranging from 14% to 30%.[18-22] Data from multiple studies have demonstrated a correlation between rates of pathologic complete response and endpoints including distant metastasis-free survival, DFS, and OS.[23-25]

There is no current role for off-trial use of concurrent oxaliplatin and radiation therapy in the treatment of patients with rectal cancer.

Evidence (preoperative oxaliplatin with chemoradiation therapy):

  1. The ACCORD 12/0405-Prodige 2 trial, which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible by digital rectal examination to either preoperative radiation therapy (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily 5 of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly). Total mesorectal excision was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation therapy was completed.[26]
    • Pathologic complete response was the primary endpoint (albeit never validated as a true surrogate of OS). A higher percentage of patients achieved a pathologic complete response in the oxaliplatin-treated group (19.2% vs. 13.9%); however, the difference did not reach statistical significance (P = .09).
    • The rate of grade 3 or 4 toxicity was significantly higher in the oxaliplatin-treated group (25% vs. 11%; P < .001), and there was no difference in the rate of sphincter-sparing surgery (75% vs. 78%).
  2. Similarly, the STAR-01 trial investigated the role of oxaliplatin combined with 5-FU chemoradiation for locally advanced rectal cancer.[27][Level of evidence: 1iiA] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation therapy or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary endpoint was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported.
    • The rate of pathologic complete response was equivalent at 16% in both arms (odds ratio, 0.98; 95% CI, 0.66–1.44; P = .904).
    • There was no difference noted in the rate of pathologically positive lymph nodes, tumor infiltration beyond the muscularis propria, or the rate of circumferential margin positivity.
    • An increase in grades 3 to 4 treatment-related acute toxicity was noted with the addition of oxaliplatin (24% vs. 8%; P <.001). Longer-term outcomes including OS have not yet been reported.
  3. The NSABP-R-04 trial randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:
    1. Intravenous continuous infusion 5-FU with radiation therapy.
    2. Capecitabine with radiation therapy.
    3. Intravenous continuous infusion 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.[28][Level of evidence: 1iiD] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following:

    • There was no significant difference in the rates of pathologic complete response, sphincter-sparing surgery, or surgical downstaging between the 5-FU and capecitabine regimens or between the regimens with and without oxaliplatin.
    • Patients treated with oxaliplatin had significantly higher rates of grade 3 and grade 4 acute toxicity (15.4% vs. 6.6%; P < .001).
  4. The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation therapy with 5-FU (week 1 and week 5) or concurrent chemoradiation therapy with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[29][Level of evidence: 1iiD]
    • In contrast to the previous studies, a significantly higher rate of pathologic complete response was achieved in patients who received oxaliplatin (17% vs. 13%; P = .038).
    • There was no significant difference in rates of overall grades 3 and 4 toxicity; however, diarrhea and nausea and vomiting were more common among those treated with oxaliplatin.
    • The 5-FU schedules in this study differed between the two arms, which may have contributed to the difference in outcomes noted. Longer follow-up will be necessary to determine the effect on the primary endpoint of the study, DFS.

Postoperative oxaliplatin-containing regimens

On the basis of results of several studies, oxaliplatin as a radiation sensitizer does not appear to add any benefit in terms of primary tumor response, and it has been associated with increased acute treatment-related toxicity. The question of whether oxaliplatin should be added to adjuvant 5-FU/LV for postoperative management of stages II and III rectal cancer is an ongoing debate. There are no randomized phase III studies to support the use of oxaliplatin for the adjuvant treatment of rectal cancer. However, the addition of oxaliplatin to 5-FU/LV for the adjuvant treatment of colon cancer is now considered standard care.

Evidence (postoperative oxaliplatin):

  1. In the randomized Multicenter International Study of Oxaliplatin/5-Fluorouracil/LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, the toxic effects and efficacy of FOLFOX4 (a 2-hour infusion of 200 mg/m2 LV, 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 LV) were compared with the same 5-FU/LV regimen without oxaliplatin when administered for 6 months. Each arm of the trial included 1,123 patients.[30]
    1. Preliminary results of the study, with 37 months of follow-up, demonstrated a significant improvement in DFS at 3 years in favor of FOLFOX4 (77.8% vs. 72.9%; P = .01). When initially reported, there was no difference in OS.[31][Level of evidence: 1iiDii]
    2. Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS, 78.5% FOLFOX4 vs. 76.0% 5-FU/LV group; HR, 0.84; 95% CI, 0.71–1.00).
      • On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients who received FOLFOX4 and 68.9% in the patients who received 5-FU/LV (HR, 0.80; 95% CI, 0.65–0.97; P = .023).[31][Level of evidence: 1iiA]
      • 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).
  2. The results of the now completed NSABP-C-07 (NCT00004931) study confirmed and extended the results of the MOSAIC trial.[32] In NSABP C-07, 2,492 patients with stage II or III colon or rectal 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 LV plus bolus 500 mg/m2 5-FU 1 hour after the start of the LV 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 HR was 0.80 (95% CI, 0.69–0.93), a 20% risk reduction in favor of FLOX (P < .004).

It is unclear whether the results these colon cancer trials can be applied to the management of patients with rectal cancer. There are no randomized phase III studies to support the routine practice of administering FOLFOX as adjuvant therapy to patients with rectal cancer.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II rectal cancer and 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. 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]
  2. 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]
  3. Sauer R, Liersch T, Merkel S, et al.: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30 (16): 1926-33, 2012. [PUBMED Abstract]
  4. Roh MS, Colangelo LH, O'Connell MJ, et al.: Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27 (31): 5124-30, 2009. [PUBMED Abstract]
  5. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336 (14): 980-7, 1997. [PUBMED Abstract]
  6. 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]
  7. Ngan SY, Burmeister B, Fisher RJ, et al.: Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 30 (31): 3827-33, 2012. [PUBMED Abstract]
  8. Sebag-Montefiore D, Stephens RJ, Steele R, et al.: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373 (9666): 811-20, 2009. [PUBMED Abstract]
  9. 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]
  10. 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]
  11. 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]
  12. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (11): 1444-50, 1990. [PUBMED Abstract]
  13. O'Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994. [PUBMED Abstract]
  14. 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]
  15. 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]
  16. 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]
  17. Cividalli A, Ceciarelli F, Livdi E, et al.: Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule. Int J Radiat Oncol Biol Phys 52 (4): 1092-8, 2002. [PUBMED Abstract]
  18. Gérard JP, Chapet O, Nemoz C, et al.: Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 phase II trial. J Clin Oncol 21 (6): 1119-24, 2003. [PUBMED Abstract]
  19. Machiels JP, Duck L, Honhon B, et al.: Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann Oncol 16 (12): 1898-905, 2005. [PUBMED Abstract]
  20. Rödel C, Liersch T, Hermann RM, et al.: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25 (1): 110-7, 2007. [PUBMED Abstract]
  21. Ryan DP, Niedzwiecki D, Hollis D, et al.: Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901. J Clin Oncol 24 (16): 2557-62, 2006. [PUBMED Abstract]
  22. Valentini V, Coco C, Minsky BD, et al.: Randomized, multicenter, phase IIb study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy versus cisplatin + 5-fluorouracil + radiotherapy. Int J Radiat Oncol Biol Phys 70 (2): 403-12, 2008. [PUBMED Abstract]
  23. García-Aguilar J, Hernandez de Anda E, Sirivongs P, et al.: A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum 46 (3): 298-304, 2003. [PUBMED Abstract]
  24. Guillem JG, Chessin DB, Cohen AM, et al.: Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241 (5): 829-36; discussion 836-8, 2005. [PUBMED Abstract]
  25. Rödel C, Martus P, Papadoupolos T, et al.: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23 (34): 8688-96, 2005. [PUBMED Abstract]
  26. Gérard JP, Azria D, Gourgou-Bourgade S, et al.: Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 28 (10): 1638-44, 2010. [PUBMED Abstract]
  27. Aschele C, Cionini L, Lonardi S, et al.: Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 29 (20): 2773-80, 2011. [PUBMED Abstract]
  28. Roh MS, Yothers GA, O'Connell MJ, et al.: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. [Abstract] J Clin Oncol 29 (Suppl 15): A-3503, 2011.
  29. Rödel C, Liersch T, Becker H, et al.: Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13 (7): 679-87, 2012. [PUBMED Abstract]
  30. 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]
  31. André T, Boni C, Navarro M, et al.: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27 (19): 3109-16, 2009. [PUBMED Abstract]
  32. 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.

Stage IV and Recurrent Rectal Cancer

Treatment of patients with advanced or recurrent rectal cancer depends on the location of the disease.

Metastatic and Recurrent Rectal Cancer

Standard treatment options for stage IV and recurrent rectal cancer include the following:

Surgery with or without chemotherapy or radiation therapy

For patients with locally recurrent, liver-only, or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.[1] 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.[2-5] The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[6]

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone after an initial, attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival (DFS).[7,8]

The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation.[9,10] Intraoperative radiation therapy in patients who underwent previous external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity.[11]

First-line chemotherapy and targeted therapy

Currently, there are eight active U.S. Food and Drug Administration (FDA)-approved drugs for patients with metastatic colorectal cancer that are used alone and in combination with other drugs:

5-FU

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,[12,13] and improved survival and quality of life in patients who received chemotherapy versus best supportive care.[14-16] Several trials have analyzed the activity and toxic effects of various 5-FU/leucovorin (LV) regimens, using different doses and administration schedules, and showed essentially equivalent results with a median survival time of approximately 12 months.[17]

Irinotecan and oxaliplatin

Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and overall survival (OS) when irinotecan or oxaliplatin was combined with 5-FU/LV.[18-20]

Evidence (irinotecan versus oxaliplatin):

  1. An intergroup study (NCCTG-N9741) compared irinotecan/5-FU/LV (IFL) with oxaliplatin/LV/5-FU (FOLFOX4) in first-line treatment for patients with metastatic colorectal cancer. [21]; [Level of evidence: 1iiA]
    • Patients assigned to FOLFOX4 experienced improved PFS compared with patients randomly assigned to IFL (median, 8.7 months vs. 6.9 months; P = .014; hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (19.5 months vs. 15.0 months; P = .001; HR, 0.66; 95% CI, 0.54–0.82).
  2. Two studies compared FOLFOX with LV/5-FU/irinotecan (FOLFIRI), and patients were allowed to cross over after progression on first-line therapy.[22,23][Level of evidence: 1iiDiii]
    • PFS and OS were identical between the treatment arms in both studies.
  3. The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial evaluated several different irinotecan-based regimens in patients with previously untreated metastatic colorectal cancer: FOLFIRI; irinotecan plus bolus 5-FU/LV (mIFL); and capecitabine/irinotecan (CAPIRI).[24] 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.

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. However, when using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[24][Level of evidence: 1iiDiii]

Capecitabine

Before 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/LV.[25,26][Level of evidence: 1iiA]

Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated capcetabine/oxaliplatin (CAPOX) versus 5-FU/oxaliplatin regimens (FUOX or FUFOX).[27,28]

Evidence (oxaliplatin versus capecitabine):

  1. The Arbeitsgemeinschaft Internische Onkologie (AIO) Colorectal Study Group randomly assigned 474 patients to either CAPOX or FUFOX.
    • 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.[28]
  2. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[27]Level of evidence: 1iiDiii
    • The TTP was 8.9 months for CAPOX versus 9.5 months for FUOX (P = .153) and met the prespecified range for noninferiority.

When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a 5-FU/oxaliplatin regimen.

Bevacizumab

Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer. There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in second-line or third-line treatment after progressing on a first-line bevacizumab regimen extends survival.

Evidence (bevacizumab):

  1. 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.[24]
    • Although the primary endpoint of PFS was not significantly different, patients who received FOLFIRI/bevacizumab had a significantly better OS (28.0 months vs. 19.2 months; P = .037; HR for death, 1.79; 95% CI, 1.12–2.88).
  2. In the Hurwitz study, patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL/bevacizumab.[29]
    • The patients randomly assigned to IFL/bevacizumab experienced a significantly better PFS (10.6 months with IFL/bevacizumab compared with 6.2 months with IFL/placebo; HR for disease progression, 0.54; P <.001) and OS (20.3 m with IFL/bevacizumab compared with 15.6 months with IFL/placebo; HR for death, 0.66; P <.001).[29]
  3. Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of NCCTG-N9741.[21] Subsequently, in a randomized phase III study, 1,401 patients with untreated, stage IV colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX4, then to bevacizumab versus placebo. PFS was the primary endpoint. [30][Level of evidence: 1iiDiii]
    • The median PFS was 9.4 months for patients who received bevacizumab and 8.0 months for the patients who received placebo (HR, 0.83; 97.5% CI, 0.72–0.95; P = .0023).
    • Median OS was 21.3 months for patients who received bevacizumab and 19.9 months for patients who received placebo (HR, 0.89; 97.5% CI, 0.76–1.03; P = .077).
    • The median PFS (intention-to-treat analysis) was 8.0 months in the pooled CAPOX-containing arms versus 8.5 months in the FOLFOX4-containing arms (HR, 1.04; 97.5% CI, 0.93–1.16), with the upper limit of the 97.5% CI being below the predefined noninferiority margin of 1.23.[30,31]
    • The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.
  4. Investigators from the Eastern Cooperative Oncology Group randomly assigned patients who had progressed on 5-FU/LV and irinotecan to either FOLFOX or FOLFOX and bevacizumab.
    • Patients randomly assigned to FOLFOX/bevacizumab experienced a statistically significant improvement in PFS compared with patients assigned to FOLFOX alone (7.43 months vs. 4.7 months; HR, 0.61; P < .0001) and OS (12.9 months vs. 10.8 months; HR, 0.75; P = .0011).[32][Level of evidence: 1iiA]
FOLFOXIRI

Evidence (FOLFOXIRI):

  1. The combination of FOLFOXIRI with bevacizumab was compared with FOLFIRI with bevacizumab in a randomized, phase III study of 508 patients with untreated metastatic colorectal cancer.[33]
    • The median PFS was 12.1 months in the FOLFOXIRI group, compared with 9.7 months in the FOLFIRI group (HR for progression, 0.75; 95% CI, 0.62–0.90; P = .003). OS was not significantly different between the groups (31.0 vs. 25.8 months; HR for death, 0.79; 95% CI, 0.63–1.00; P = .054).[33][Level of evidence: 1iiDiii]
    • Patients who received FOLFOXIRI had significantly more grade 3 and 4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy.
Cetuximab

Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

Evidence (cetuximab):

  1. For patients who have progressed on irinotecan-containing regimens, a randomized, phase II study was performed that used either cetuximab or irinotecan/cetuximab.[34][Level of evidence: 3iiiDiv]
    • The median TTP for patients who received cetuximab was 1.5 months, compared with median TTP of 4.2 months for patients who received irinotecan and cetuximab. On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
  2. The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[35][Level of Evidence: 1iiDii]
    • The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99; P = .048 by a stratified log rank test) but not OS.
    • Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-EGFR antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at codon 12 or 13 of the KRAS gene).
    • A subset analysis evaluating efficacy vis a vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among KRAS wild-type patients, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50–0.94).
  3. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[36][Level of evidence: 1iiDiii]
    • The median PFS was 9.4 months in the group who received cetuximab and 10.7 months in the group who did not receive cetuximab (P = .01).
    • In a subset analysis, cetuximab-treated patients with tumors bearing a mutated KRAS gene had significantly decreased PFS compared with cetuximab-treated patients with wild-type KRAS tumors (8.1 months vs. 10.5 months; P = .04).
    • Cetuximab-treated patients with mutated KRAS tumors had a significantly shorter PFS than patients with mutated KRAS tumors who did not receive cetuximab (8.1 months vs. 12.5 months; P = .003) and a significantly shorter OS (17.2 months vs. 24.9 months; P = .03).
  4. The Medical Research Council (MRC) (UKM-MRC-COIN-CR10 [NCT00182715] or COIN trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[37,38] In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:
    • Arm A: fluoropyrimidine/oxaliplatin.
    • Arm B: fluoropyrimidine/oxaliplatin/cetuximab.
    • Arm C: intermittent fluoropyrimidine/oxaliplatin.

    The comparisons between arms A and B and arms A and C were analyzed and published separately.[37,38]

    1. In patients with KRAS wild-type tumors (arm A, n = 367; arm B, n = 362), OS did not differ between treatment groups (median survival, 17.9 months [interquartile range, 10.3–29.2] in the control group vs. 17.0 m [interquartile range, 9.4–30.1] in the cetuximab group; HR, 1.04; 95% CI, 0.87–1.23; P = .67). Similarly, there was no effect on PFS (8.6 months [interquartile range, 5.0–12.5] in the control group vs. 8.6 months [interquartile range, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[37,38][Level of evidence: 1iiA]
    2. The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less in patients treated with cetuximab.
    3. There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C).
      • Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (interquartile range, 9.4–26.1) in arm A and 14.4 months (interquartile range, 8.0–24.7) in arm C (HR, 1.084; 80% CI, 1.008–1.165).
      • In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (interquartile range, 13.0–28.1) in arm A and 18.0 months (interquartile range, 12.1–29.3) in arm C (HR, 1.087, 95% CI, 0.986–1.198).
    4. The upper limits of CIs for HRs in both analyses were greater than the predefined noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.
Panitumumab

Panitumumab is a fully humanized antibody against the EGFR. The FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.

Evidence (panitumumab):

  1. In a phase III trial, patients with chemotherapy-refractory colorectal cancer were randomly assigned to panitumumab or best supportive care.[39]
    • Patients who received panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks; HR, 0.54; 95% CI, 0.44–0.66; P < .0001).[39][Level of evidence: 1iiDiii]
    • There was no difference in OS, which was thought to be the result of 76% of patients on best supportive care crossing over to panitumumab.
  2. In the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME [20050203 or NCT00364013]) study, 1,183 patients were randomly assigned to FOLFOX4 with or without panitumumab as first-line therapy for metastatic colorectal cancer.[40][Level of evidence: 1iiDiii] The study was amended to enlarge the sample size to address patients with KRAS wild-type tumors and patients with mutant KRAS tumors separately.
    1. For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab/FOLFOX4 compared with those who received only FOLFOX4 (HR, 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).
    2. Median PFS was 9.6 m (95% CI, 9.2–11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5–9.3 months) for patients who received FOLFOX4. OS was not significantly different between the groups (HR, 0.83; 95% CI, 0.67–1.02; P = .072).
    3. For patients with mutant KRAS tumors, PFS was worse with the addition of panitumumab (HR, 1.29; 95% CI, 1.04–1.62; P = .02, stratified log-rank test).
      • Median PFS was 7.3 months (95% CI, 6.3–8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7–9.4 months) for FOLFOX4 alone.
  3. Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity than a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic rectal cancer (11.4 months vs. 10.0 months; HR, 1.27; 95% CI, 1.06–1.52).[41][Level of evidence: 1iiDiii]
  4. In another study (NCT00339183 [20050181]), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI/panitumumab.[42][Level of evidence: 1iiDiii]
    1. In a post hoc analysis, patients with KRAS wild-type tumors experienced a statistically significant PFS advantage (HR, 0.73; 95% CI, 0.59–0.90; P = .004, stratified log-rank).[42]
      • Median PFS was 5.9 months (95% CI, 5.5–6.7 months) for FOLFIRI/panitumumab and 3.9 months (95% CI, 3.7–5.3 months) for FOLFIRI alone.
    2. OS was not significantly different. Median OS was 14.5 months for the FOLFIRI/panitumumab group versus 12.5 months for the FOLFIRI alone group.
    3. Patients with mutant KRAS tumors experienced no benefit from the addition of panitumumab.

Second-line chemotherapy

Second-line chemotherapy with irinotecan in patients treated with 5-FU/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[43-46]

Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV, single-agent oxaliplatin, or FOLFOX4. The median TTP for FOLFOX4 versus 5-FU/LV was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[47][Level of evidence: 1iiDiii]

Palliative therapy

Palliative radiation therapy[11,46], chemotherapy,[13,48-53] and chemoradiation therapy [54,55] may be indicated. Palliative, endoscopically-placed stents may be used to relieve obstruction.[56]

Treatment of Liver Metastasis

Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis after resection of the primary tumor.[57-59] 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. These include the following:

Surgery

Hepatic metastasis may be considered to be resectable based on the following factors:[45,60-72]

  • Limited number of lesions.
  • Intrahepatic locations of lesions.
  • Lack of major vascular involvement.
  • Absent or limited extrahepatic disease.
  • Sufficient functional hepatic reserve.

For patients with hepatic metastasis considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies (e.g., the North Central Cancer Treatment Group trial, NCCTG-934653).[73-77][Level of evidence: 3iiiDiv] Improved 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 neoadjuvant chemotherapy.[78]

Neoadjuvant chemotherapy

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. [78]

Local ablation

Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[79-85] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that are not resectable and for patients who are not candidates for liver resection.[86-88] Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[89-91]

Adjuvant chemotherapy

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.

Evidence (adjuvant chemotherapy):

  1. A trial of hepatic arterial floxuridine and dexamethasone plus systemic 5-FU/LV compared with systemic 5-FU/LV alone showed improved 2-year PFS (57% vs. 42%; P =.07) and OS (86% vs. 72%; P = .03) for patients in the combined therapy arm but did not show a significant statistical difference in median survival when compared with systemic 5-FU therapy alone.[92][Level of evidence: 1iiA]
    • Median survival in the combined therapy arm was 72.2 months versus 59.3 months in the monotherapy arm (P = .21).
  2. 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.[93] Among those randomly assigned patients, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival.
    • While 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 results similar to hepatic intra-arterial therapy plus systemic treatment.

Intra-arterial chemotherapy

Hepatic intra-arterial chemotherapy with floxuridine for liver metastasis has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[68,94-98] Controversy regarding the efficacy of regional chemotherapy was the basis of a large multicenter phase III trial (Leuk-9481) (NCT00002716) 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.[99]

Increased local toxic effects after hepatic infusional therapy are seen, including liver function abnormalities and fatal biliary sclerosis.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.

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Changes to This Summary (12/16/2014)

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 comprehensively reviewed and reformatted, and some content was added.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of rectal cancer. It 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.

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The lead reviewers for Rectal Cancer Treatment are:

  • Russell S. Berman, MD (New York University School of Medicine)
  • Jason E. Faris, MD (Massachusetts General Hospital)
  • David P. Ryan, MD (Massachusetts General Hospital)
  • Jennifer Wo, MD (Massachusetts General Hospital)

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National Cancer Institute: PDQ® Rectal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/rectal/HealthProfessional. Accessed <MM/DD/YYYY>.

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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 the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

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).

  • Updated: December 16, 2014