General Information About Rectal Cancer

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

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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

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

Estimated new cases and deaths from rectal cancer in the United States in 2011:[1]

• New cases: 39,870 (rectal cancer only).
• Deaths: 49,380 (colon and rectal cancers combined).

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

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

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

Gastrointestinal stromal tumors can occur in the rectum. (Refer to the PDQ summary on Gastrointestinal Stromal Tumors Treatment for more information.)

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

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

Nonpolyposis disorders

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

Polyposis disorders

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

Hamartomatous disorders

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

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

More common conditions with an increased risk include:

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

These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.[15] (Refer to the PDQ summaries on Colorectal Cancer Screening and Colorectal Cancer Prevention for more information.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• Polypectomy for select T1 cancers.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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