Rectal Cancer

INTRODUCTION

Background: Approximately 135,000 new cases of colorectal cancer occur in the United States each year, resulting in approximately 55,000 deaths per year. Two thirds of these cases occur in the colon and one third in the rectum. The incidence and epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. These areas are addressed together.

Adenocarcinomas (98%) comprise most rectal cancers and are the focus of this discussion. Other rare rectal cancers, including carcinoid (0.1%), lymphoma (1.3%), and sarcoma (0.3%), are not discussed. Squamous cell carcinomas may develop in the transition area from rectum to anal verge and are considered anal carcinomas. Very rare cases of squamous cell carcinoma of the rectum have been reported.

Pathophysiology: Carcinomas are found in as many as 4% of neoplastic polyps. Cells must accumulate 4-5 molecular defects, including activation of oncogenes and inactivation of tumor suppressor genes, to undergo malignant transformation. In normal mucosa, the surface epithelium regenerates approximately every 6 days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation, maturation, and, ultimately, lose the ability to replicate.

In adenomas, several genetic mutations alter this process, starting with inactivation of the adenomatous polyposis coli (APC) gene, allowing unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and give the cell eternal life.

Frequency:

• In the US: The lifetime risk of developing a colorectal malignancy is approximately 5.9% in the general population.

Race:

• Western nations tend to have a higher incidence than Asian and African countries; however, within the United States, little difference in incidence exists among whites, African Americans, and Asian Americans.

• Among religious denominations, colorectal cancer occurs more frequently in the Jewish population.

Sex: The incidence of colorectal malignancy is slightly higher in males than in females.

Age: Incidence peaks in the seventh decade; however, cases have been reported in young children.


CLINICAL

History:

• All patients should undergo a complete history, including a family history and assessment of risk factors for the development of rectal cancer.

• Many rectal cancers produce no symptoms and are discovered during digital or proctoscopic screening examinations.

• Bleeding

• This is the most common symptom of rectal cancer and occurs in 60% of patients.

• Bleeding often is attributed to other causes (eg, hemorrhoids), especially if the patient has a history of other problems.

• Profuse bleeding and anemia are rare.

• Bleeding may be accompanied by the passage of mucus, which warrants further investigation.

• Change in bowel habits

• Present in 43% of patients, this symptom has several different presentations. Often, it occurs in the form of diarrhea, particularly if the tumor has a large villous component.

• These patients may have hypokalemia on laboratory studies.

• The capacity of the rectal reservoir may mask the presence of a small lesion.

• Some patients experience a change in caliber of the stool.

• Large tumors can cause obstructive symptoms.

• Tumors located low in the rectum can cause a feeling of incomplete evacuation and tenesmus.

• Occult bleeding: This is detected on screening fecal occult blood test (FOBT) in 26% of cases.

• Abdominal pain

• Partial large-bowel obstruction may cause colicky abdominal pain and bloating and is present in 20% of cases.

• Back pain is usually a late sign caused by a tumor invading or compressing nerve trunks.

• Urinary symptoms may occur if the tumor is invading or compressing the bladder or prostate.

• Malaise: This nonspecific entity is the presenting symptom in 9% of cases.
• Bowel obstruction: Complete obstruction of the large bowel is rare and is the presenting symptom in 9% of cases.
• Pelvic pain: This late symptom usually indicates nerve trunk involvement and is present in 5% of cases.
• Other presentations include emergencies such as peritonitis from perforation (3%) or jaundice, which may occur with liver metastases (less than 1%).

Physical:

• Physical examination is performed with specific attention to possible metastatic lesions, including enlarged lymph nodes or hepatomegaly. The remainder of the colon is also examined.

• Digital rectal examination

• The easy accessibility of the rectum provides an opportunity to readily detect abnormal lesions via digital rectal examination (DRE). The average finger can reach approximately 8 cm above the dentate line.

• Tumors can be assessed for size, ulceration, and presence of any pararectal lymph nodes. Fixation of the tumor to surrounding structures (eg, sphincters, prostate, vagina) also can be assessed.

• DRE also permits a cursory evaluation of the patient's sphincter function. This information is necessary when determining whether a patient is a candidate for a sphincter-sparing procedure.

Causes:

• The etiology of colorectal cancer is unknown, but colorectal cancer appears to be multifactorial in origin and includes environmental factors and a genetic component. Diet may have an etiologic role, especially diet with high fat content.

• Approximately 75% of colorectal cancers are sporadic and develop in people with no specific risk factors. The remaining 25% of cases occur in people with significant risk factors. Most (15-20%) colorectal cancers develop in people with either a positive family history or a personal history of colorectal cancer or polyps. The remaining cases occur in people with certain genetic predispositions, such as hereditary nonpolyposis colorectal cancer (HNPCC, 4-7%) or familial adenomatous polyposis (FAP, 1%) or in people with inflammatory bowel disease (IBD, 1%).

• Environmental factors

• Diet
  • A high-fat, low-fiber diet is implicated in the development of colorectal cancer. Specifically, people who ingest a diet high in unsaturated animal fats and highly saturated vegetable oils (eg, corn, safflower) have a higher incidence of colorectal cancer. The mechanism by which these substances are related to the development of colorectal cancer is unknown.
  • Saturated fats from dairy products do not have the same effect, nor do oils containing oleic acid (eg, olive, coconut, fish oils). Omega-3 monounsaturated fatty acids and omega-6 monounsaturated fatty acids also appear to be less carcinogenic than unsaturated or polyunsaturated fats. In fact, recent epidemiologic data suggest that high fish consumption may provide a protective effect against development of colorectal cancer.
  • Long-term diets high in red meat or processed meats appear to increase the risk of distal colon and rectal cancers.
  • The ingestion of a high-fiber diet may be protective against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes out carcinogens; it also decreases colonic transit time, allowing less time for harmful substances to contact the mucosa. The decreased incidence of colorectal cancer in African individuals is attributed to their high-fiber, low–animal-fat diet. This favorable statistic is reversed when African people adopt a western diet.
  • Increased dietary intake of calcium appears to have a protective effect on colorectal mucosa by binding with bile acids and fatty acids. The resulting calcium salts may have antiproliferative effects, decreasing crypt cell production in the mucosa.
  • Other dietary components, such as selenium, carotenoids, and vitamins A, C, and E, may have protective effects by scavenging free-oxygen radicals in the colon.
• Alcohol: Daily alcohol drinkers experience a 2-fold increased risk of developing colorectal carcinoma. Specifically, beer consumption in excess of 15 liters per month increases the risk of rectal cancer in men.
• Tobacco: Smoking, and in particular, smoking starting at a young age, increases the risk of colorectal cancer. Possible mechanisms for tumor development include the production of toxic polycyclic aromatic amines and the induction of angiogenic mechanisms by tobacco smoke.

• Bile acids: After cholecystectomy, bile acids circulate continuously, increasing exposure to the degrading action of intestinal bacteria. While this process is known to occur in the formation of certain carcinogens, a direct connection between cholecystectomy and the development of colorectal cancer has not been established.

• Hereditary factors

• Family history: The relative risk of developing colorectal cancer is increased in the first-degree relatives of affected patients. The relative risk of developing this malignancy if one first-degree family member is affected with colorectal cancer is 1.72; with two first-degree family members affected, the relative risk increases to 2.75. If the first-degree family member is younger than 45 years at the time of diagnosis, the risk increases to 5.37.

• Personal history of colorectal cancer or polyps: Of patients with colorectal cancer, 30% have synchronous lesions, usually adenomatous polyps. Approximately 40-50% of patients have polyps on follow-up colonoscopy. Of patients who have adenomatous polyps on colonoscopy, 29% have additional polyps on repeat colonoscopy 1 year later. Malignancy develops in 2-5% of patients. The risk of cancer in people who have had polyps removed is 2.7-7.7 times that of the general population.

• Genetic disorders

• Familial adenomatous polyposis
  • FAP is an autosomal dominant inherited syndrome that results in the development of more than 100 adenomatous polyps and a variety of extraintestinal manifestations.
  • The defect is in the APC gene, which is located on chromosome 5 at locus q21.
  • The disease process causes the formation of hundreds of intestinal polyps, osteomas of the bone, desmoid tumors, and, occasionally, brain tumors.
  • Individually, the polyps do not have a risk of malignant transformation greater than polyps in the general population. The increased number of polyps, however, predisposes patients to a greater risk of cancer. If left untreated, colorectal cancer develops in nearly 100% of these patients by age 40 years.
  • While the hereditary link is documented, approximately 20% of FAP cases are caused by spontaneous mutation.

• Hereditary nonpolyposis colorectal cancer
  • HNPCC is an autosomal dominant inherited syndrome that occurs because of defective mismatch repair genes located on chromosomes 2, 3, and 7.
  • Patients have the same number of polyps as the general population, but their polyps are more likely to become malignant. These patients also have a higher incidence of endometrial, gastric, thyroid, and brain cancers.
  • The revised Amsterdam criteria are used to select at-risk patients (all criteria must apply): 3 or more relatives who are diagnosed with an HNPCC-associated cancer (colorectal, endometrium, small bowel, ureter, or renal pelvis); 1 affected person is a first-degree relative of the other 2; 1 or more cases of cancer are diagnosed before age 50 years; at least 2 generations are affected; FAP has been excluded, and tumors have undergone pathology review.

• Inflammatory bowel disease

• Ulcerative colitis
  • The incidence of malignancy increases with duration. After 10 years, the incidence of colorectal cancer in ulcerative colitis (UC) is approximately 1% per year.
  • Evaluate patients for dysplastic changes with annual colonoscopy. Dysplasia is a precursor of cancer and, when present, the risk of cancer is 30%.

• Crohn disease
  • The incidence of colorectal cancer in patients with Crohn disease is 4-20 times greater than that of the general population. Cancer occurs in patients with disease of at least 10 years' duration. The average age at diagnosis (ie, 46-55 y) is younger than that of the general population.
  • Cancers often develop in areas of strictures and in defunctionalized segments of intestine. In patients with perianal Crohn disease, malignancy often presents in fistulous tracts.
  • Patients with Crohn colitis undergo the same surveillance regimen as those with UC.

WORKUP

Lab Studies:

• Routine laboratory studies should include a complete blood count; serum chemistries, including liver and kidney function tests; and a carcinoembryonic antigen (CEA) test. A cancer antigen (CA) 19-9, if available, may also be useful to monitor disease.

• Screening CBC may demonstrate a hypochromic, microcytic anemia, suggesting iron deficiency. The combined presence of vitamin B-12 or folate deficiency may result in a normocytic or macrocytic anemia. All men and postmenopausal women with iron deficiency anemia require GI evaluation.

• Liver function tests are usually part of the preoperative workup; these test results are often normal, even with metastases to the liver.

• Perform a CEA test in all patients with rectal cancer. A baseline level is obtained before surgery and a follow-up level is obtained after surgery. This may alert to a possible recurrence if a previously normalized CEA begins to rise in the postoperative period. A CEA higher than 100 ng/mL usually indicates metastatic disease and warrants a thorough investigation.

Imaging Studies:

• Rigid proctosigmoidoscopy

• Rigid proctosigmoidoscopy can be performed without an anesthetic, allows direct visualization of the lesion, and provides an estimation of the size of the lesion and degree of obstruction.

• This procedure is used to obtain biopsies of the lesion, assess ulceration, and determine the degree of fixation. In addition, it gives an accurate measurement of the distance of the lesion from the dentate line; the latter is critical in deciding which operation is appropriate.

• Endorectal ultrasound

• Endorectal ultrasound (ERUS) is an invaluable tool in assessing depth of invasion of rectal cancers; it is 72-94% accurate.

• The accuracy of detection of lymph node involvement ranges from 73-86%. Most of these nodes are larger than 1 cm. Smaller nodes can be detected, but the accuracy of determining tumor involvement is substantially lower.

• Overestimation of staging and nodal involvement occurs more often than understaging. This probably is due to the inflammatory process caused by the tumor.

• ERUS visualizes the rectal wall as alternating hyperechoic and hypoechoic layers of tissue. The first layer is the hyperechoic water-filled balloon or mucosal interface, which is bounded by the hypoechoic mucosa and muscularis mucosa, the hyperechoic submucosa, the hypoechoic muscularis propria, and, finally, the hyperechoic muscularis mucosa or perirectal fat interface. Depth of penetration is determined by identifying which of these layers is disrupted by the tumor.

• ERUS is also useful in determining invasion of surrounding structures and the presence of local recurrence when used after surgery.

• Endorectal surface-coil MRI: An alternative to ERUS, this technique is touted as equally or more accurate than ERUS in lymph node staging.

• Metastatic workup

• Chest radiograph: Obtain a chest radiograph to rule out pulmonary metastases and to determine whether the patient has any gross underlying pulmonary disease, including emphysema.

• CT scan: This study is generally used to determine the presence or absence of metastases.
  • CT scans can identify lesions in the liver, adrenals, ovaries, lymph nodes, and other organs. In 10% of patients, the CT scan misses small liver lesions. When combined with an angiogram, a CT scan is 95% accurate in identifying liver metastases.
  • Some information can be gleaned from a CT scan regarding depth of penetration of the primary rectal tumor. When performed with rectal contrast given as an enema, CT scans can determine the depth of penetration accurately in 84% of cases.
  • CT scan detects lymph nodes larger than 1 cm in 75% of cases.
  • CT scans are helpful in determining whether patients require preoperative chemoradiation therapy.

• MRI actually is the most sensitive test for determining the presence of liver metastases and often is used if liver resection is considered.

• Positron emission tomography: The major advantage of a positron emission tomography (PET) scan is to differentiate between recurrent tumor and scar tissue by measuring tissue metabolism of an injected glucose-based substance. Scar tissue is inactive, whereas tumor generally is hypermetabolic. This test generally is not used in a routine preoperative metastatic workup.

• CEA scan: If routine imaging studies cannot detect the area of metastatic disease, a CEA scan can be performed. Radioimmunoscintigraphy uses radiolabeled antibodies to CEA and total-body scanning to determine the location of CEA-producing metastases. This test is not used routinely in the preoperative evaluation, and its value is controversial.

Other Tests:

• Screening: The process of malignant transformation from adenoma to carcinoma takes several years. The purpose of screening is to eradicate potential cancers while they are still in the benign stage of the adenoma-carcinoma sequence. Screening also increases the likelihood of discovering existing cancers while they are still in the early stage.

• Average-risk screening (see Table 1): People who are asymptomatic, younger than 50 years, and have no other risk factors are considered at average risk for developing colorectal cancer. Begin screening this population at age 50 years.

• Fecal occult blood test: Perform yearly FOBT by testing 2 samples from each of 3 consecutive stools. If any of the 6 samples is positive, recommend that the patient have the entire colon studied via colonoscopy or flexible sigmoidoscopy with double-contrast barium enema. FOBT has significant false-positive and false-negative rates.

• Flexible sigmoidoscopy: Perform this test every 5 years. Perform a biopsy of any lesions identified, and perform a full colonoscopy. Lesions present beyond the reach of the sigmoidoscope may be missed.

• Combined FOBT and flexible sigmoidoscopy: Theoretically, the combination of these 2 tests may overcome the limitations of each test.

• Double-contrast barium enema: This test is offered every 5-10 years, usually in combination with flexible sigmoidoscopy. Lesions detected by this method may still require colonoscopy for biopsy or excision.

• Colonoscopy: This procedure is recommended every 5-10 years. Colonoscopy allows full visualization of the colon and excision and biopsy of any lesions. The likelihood is extremely low that a new lesion could develop and progress to malignancy between examinations.

• Table 1. Average Risk Colon and Rectal Cancer Patients Who Should be Screened

  Risk Category	Signs and Symptoms
  Average risk	No symptoms and age older than 50 years
  Average risk	No symptoms requesting screening
  Average risk	Change in bowel habits Rectal and anal bleeding Unclear abdominal pain Unclear iron-deficiency anemia

• High-risk screening (see Table 2): People at increased risk for colorectal cancer include those with affected first-degree relatives, those with a family history of FAP or HNPCC, and those with a personal history of adenomatous polyps, colorectal cancer, or IBD.

• First-degree relative affected: Offer family members the same screening tests as the general population; however, begin the screening at age 40 years rather than age 50 years. These people often undergo colonoscopy as their initial screening test, particularly if the relative was diagnosed with cancer at a young age.

• Family history of FAP (see Table 2)
  • Genetic counseling and genetic testing are recommended to determine whether the person is a gene carrier. Current tests are approximately 80% accurate. In the remaining 20%, the mutation cannot be identified.
  • Genetic testing is useful only if the test result is positive or if the test is a true negative (ie, mutation present in other family members is not identified in the patient being tested).
  • Offer flexible sigmoidoscopy to known gene carriers and persons with an indeterminate carrier status every year to look for the presence of polyps. When polyposis develops, consider colectomy.

• Family history of HNPCC (see Table 2)
  • Offer genetic counseling and genetic testing to individuals whose family histories meet the Amsterdam criteria.
  • Patients with documented HNPCC should undergo colonoscopy every 1-2 years when aged 20-40 years and every year when older than 40 years.
  • Since these cancers tend to be located on the right side of the colon, flexible sigmoidoscopy is not recommended.

• Personal history of adenomatous polyps: Patients who have adenomatous polyps removed colonoscopically should have a repeat examination at 3 years. If the findings of this examination are normal, follow up at 5 years.

• Personal history of colorectal cancer: Patients who have colorectal cancer and undergo resection for cure should have a repeat colonoscopy after 1 year. If this examination reveals no abnormalities, follow up at 3 years. In the absence of disease, perform colonoscopy every 5 years thereafter.

• Personal history of IBD: Surveillance colonoscopy is performed to look for dysplasia as a marker for colorectal cancer in patients with long-standing IBD. These patients should undergo colonoscopy every 1-2 years after 8 years of diffuse disease or after 15 years of localized disease. Random biopsies are performed at specific intervals throughout the colon and rectum. Colectomy is recommended when dysplasia is present.

• Table 2. High Risk Colon and Rectal Cancer Patients Who Should be Included in Surveillance Programs

  Risk Category	Signs and Symptoms
  High-risk patients due to family history	Family history of colon and rectal cancer First-degree relative with adenoma aged younger than 60 years Genetic family syndromes HNPCC FAP
  High-risk patients due to personal history	Personal history of inflammatory bowel disease Personal history of adenomas Personal history of colon and rectal cancer Personal history of genetic family syndromes

Staging:

• Dukes classification: In 1932, Cuthbert E. Dukes, a pathologist at St. Mark Hospital in England, introduced a staging system for rectal cancer.

• His system divided tumor classification into 3 stages, as follows:
  • Those limited to the rectal wall (Dukes A)
  • Those that extended through the rectal wall into extra-rectal tissue (Dukes B)
  • Those with metastases to regional lymph nodes (Dukes C)
• This system was modified by others to include subdivisions of stages B and C, as follows:
  • Stage B became B1 (ie, tumor penetration into muscularis propria) and B2 (ie, tumor penetration through muscularis propria).
  • Stage C became C1 (ie, tumor limited to the rectal wall with nodal involvement) and C2 (ie, tumor penetrating through the rectal wall with nodal involvement).

• Stage D was added to indicate distant metastases.

• Tumor, node, metastasis (TNM) system: This system was introduced in 1954 by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (IUAC). The TNM system is a universal staging system for all solid cancers that is based on clinical and pathologic information. Each category is independent (see Table 3).
• Neither the Dukes nor the TNM system includes prognostic information such as histologic grade, vascular or perineural invasion, or tumor DNA ploidy. TNM staging of rectal cancer correlates well with 5-year survival rates of patients with rectal cancer (see the TNM stage-–dependent 5-year survival rate for rectal carcinomas).
• TNM classification for cancer of the colon and rectum (AJCC)

• Primary tumor (T)
  • TX - Primary tumor cannot be assessed or depth of penetration not specified
  • T0 - No evidence of primary tumor
  • Tis - Carcinoma in situ (mucosal); intraepithelial or invasion of the lamina propria
  • T1 - Tumor invades submucosa
  • T2 - Tumor invades muscularis propria
  • T3 - Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissue
  • T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum.
• Regional lymph nodes (N)
  • NX - Regional lymph nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in 1-3 pericolic or perirectal lymph nodes
  • N2 - Metastasis in 4 or more pericolic or perirectal lymph nodes
  • N3 - Metastasis in any lymph node along the course of a named vascular trunk
• Distant metastasis (M)
  • MX - Presence of metastasis cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis

• Table 3. Comparison of AJCC Definition of TNM Staging System to Dukes Classification

  Stage	T	N	M	Dukes Stage
  I	Tis	N0	M0	A
  	T1	N0	M0
  	T2	N0	M0
  II	T3	N0	M0	B
  	T4	N0	M0
  III	Any T	N1	M0	C
  	Any T	N2, N3	M0
  IV	Any T	Any N	M1

• The TNM stage-–dependent 5-year survival rate for rectal carcinomas is as follows:

• Stage I, 72%

• Stage II, 54%

• Stage III, 39%
• Stage IV, 7%

TREATMENT

Medical Care:

• Although radical resection of rectum is the mainstay of therapy, surgery alone has a high recurrence rates. The local recurrence rate for surgery alone is 30-50%. Rectal adenocarcinomas are sensitive to ionizing radiation. Radiation therapy can be delivered preoperatively, intraoperatively, or postoperatively with or without chemotherapy.

• There are many described benefits of preoperative radiation therapy. These potential advantages of preoperative radiation are tumor down-staging; an increase in resectability, possibly with a sphincter-sparing procedure; and a decrease in tumor viability, which may decrease the risk of local recurrence. Preoperative radiation therapy works better in well-oxygenated tissues prior to surgery. Postoperative tissues are relatively hypoxic as a result of surgery and may be more resistant to radiotherapy. In patients with postoperative complications, there may be delay in adjuvant therapy. Preoperative radiation therapy also minimizes the radiation of small bowel loops due to pelvic adhesions following surgery.

• The disadvantages of preoperative radiation therapy include delay in definitive resection, possible loss of accurate pathologic staging, possible over-treatment of early stage (stage I and II) rectal cancer and increased postoperative complications, and morbidity and mortality rates secondary to radiation injury. Preoperative radiation therapy decreases the risk of tumor recurrence in patients with stage II or III disease; however, this does not translate into a decrease in distant metastases or an increase in survival rate. Some recent reports cite an increase in survival; however, this is still the minority opinion. The authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement.

• The advantages of postoperative radiation therapy include immediate definitive resection and accurate pathologic staging information before beginning ionizing radiation. The disadvantages of postoperative radiation therapy include possible delay in adjuvant radiation therapy if postoperative complications ensue, no effect on tumor cell spread at the time of surgery, and decreased effect of radiation in surgically induced tissue hypoxia. Published randomized trials suggest that preoperative or postoperative radiation therapy appears to have significant impact on local recurrence but does not increase survival rates.

• The most useful chemotherapeutic agent for colorectal carcinoma is 5-fluorouracil (5-FU), an antimetabolite. The prodrug, 2-deoxy-5-floxuridine (5-FUDR), is rapidly converted to 5-FU and is used for metastatic liver disease by continuous intrahepatic infusion. Fluorouracil is a fluorinated pyrimidine, which blocks the formation of thymidylic acid and DNA synthesis. Clinically, it offers good radiosensitization without severe side effects, although diarrhea can be dose limiting and, if severe, life threatening. 5-FU has been used in conjunction with radiation (combined modality) therapy before surgery (neoadjuvant), as well as after surgery.

• The use of adjuvant (postoperative) chemotherapy is recommended as a criterion standard for patients with stage III rectal cancer (any T and N 1 and 2). These recommendations are based on studies that showed the combination of 5-fluorouracil and levamisole had a reduced risk of carcinoma recurrence of 43% and overall death rate was reduced by 33% in colorectal cancer. The benefit of chemotherapy for stage II disease remains unclear; therefore, it should be administered on an individualized basis. Combined modality adjuvant radiation therapy and chemotherapy with fluorouracil improved local control, distant spread, and survival. The basis of this improvement is believed to be the activity of 5-fluorouracil as a radiosensitizer.
• Combined modality therapy involves using preoperative or postoperative radiation therapy and 5-fluorouracil with a variety of other drugs such as leucovorin and irinotecan. In a recent study of neoadjuvant chemoradiation, 28% of surgical specimens inspected after 5-FU, irinotecan, and hyperfractionated radiotherapy have shown a complete pathologic response with no evidence of residual tumor.
• In patients with stage III rectal cancer, the best results have been obtained with combined modality therapy, with local recurrence rate of 11%, distant metastasis rate of 26% and 5-year survival rate of 59%. In the same study, local recurrence rate for the surgery alone group was 24%, distant metastasis rate was 34%, and 5-year survival rate was 43%.
• Intraoperative radiation therapy is recommended in patients with large, bulky, fixed, unresectable cancers. The direct delivery of high-dose radiotherapy is believed to improve local disease control. Intraoperative radiation therapy requires specialized, expensive operating room equipment, limiting its use.
• In the last 10 years, several new chemotherapeutic agents have become available, such as irinotecan, oxaliplatin, bevacizumab, and cetuximab. The prognosis has been significantly improved with the addition of these agents, with median survival of approximately 20 months in patients with metastatic colorectal cancer. Drug development for colorectal cancer has significantly increased, which holds promise to further improve adjuvant therapy in patients with metastatic colorectal cancer.
• Experimental, epidemiologic, and clinical studies provide some evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) act as chemopreventive agents.

Surgical Care:

• Transanal excision
  • The transanal excision method of local excision of rectal cancer is reserved for only the most superficial lesions. Patients with stage 0 or stage I cancer with a T1 lesion are candidates for this procedure.
  • Tis and T1 lesions are confined to the submucosa of the rectal wall. Lesions in the lower one third of the rectum are the most easily accessible and are suited best for transanal excision. Preferably, they also should be polypoid, involve less than one third of the circumference of the rectal wall, be mildly to moderately well differentiated, and not involve the sphincters. The likelihood of lymph node involvement in this type of lesion ranges from 0-12%.
  • Perform preoperative ERUS. If nodes are identified as suggestive of cancer, do not perform transanal excision.
  • The lesion is excised with full thickness of the rectal wall, leaving a 1-cm margin of normal tissue. The defect is usually closed, although some surgeons leave it open.
  • Positive resection margins or involved lymph nodes mandate definitive resection. Usually, an abdominal perineal proctosigmoidectomy is performed, although some facilities attempt sphincter-sparing resections.
  • The 5-year survival rate after transanal excision ranges from 65-100% (including some T2 lesions). The local recurrence rate ranges from 0-40%.
  • Lesions that display unfavorable histologic features but are excised completely may be treated with adjuvant radiation therapy.

• Endocavitary radiation
  • This RT method differs from external-beam RT in that a larger dose of radiation can be delivered to a smaller area over a shorter period.
  • Selection criteria for this procedure are similar to that for transanal excision. The lesion can be as far as 10 cm from the anal verge and no larger than 3 cm.
  • Radiation is delivered via a special proctoscope and is performed in the operating room with sedation. The patient can be discharged on the same day.
  • The dose of RT is 3,000 cGy per session, totaling 9,000-15,000 cGy.
  • The 5-year survival rate is 76%, with a local recurrence rate as high as 30%.
  • External-beam RT no longer is used commonly as local treatment of rectal cancer.

• Transanal endoscopic microsurgery
  • Transanal endoscopic microsurgery is another form of local excision that uses a special operating proctoscope that distends the rectum with insufflated carbon dioxide and allows the passage of dissecting instruments.
  • This method can be used on lesions located higher in the rectum and even the distal sigmoid colon.
  • Transanal endoscopic microsurgery has not come into wide use yet because of a significant learning curve and a lack of availability.

• Sphincter-sparing procedures: Procedures are described using the traditional open technique. All of these procedures, except the perineal portions, can and have been performed using laparoscopic techniques with excellent results. The nuances of the laparoscopic technique used are beyond the scope of this discussion.
• Low anterior resection

• Low anterior resection (LAR) is generally performed for lesions in the middle and upper third of the rectum and, occasionally, for lesions in the lower third.
• Because this is a major operation, patients who undergo LAR should be in good health. They should not have any preexisting sphincter problems or evidence of extensive local disease in the pelvis.
• Patients will not have a permanent colostomy but should be informed that a temporary colostomy or ileostomy may be necessary. They also must be willing to accept the possibility of slightly less-than-perfect continence after surgery, although this is not usually a major problem.
• Other possible disturbances in function include transient urinary dysfunction secondary to weakening of the detrusor muscle. This occurs in 3-15% of patients. Sexual dysfunction is more prominent and includes retrograde ejaculation and impotence. In the past, this has occurred in 5-70% of men, but recent reports indicate that the current incidence is lower.
• The operation entails full mobilization of the rectum, sigmoid colon, and, usually, the splenic flexure. Mobilization of the rectum requires a technique called total mesorectal excision (TME).
  • TME involves sharp dissection in the avascular plane that is created by the envelope that separates the mesorectum from the surrounding structures. This includes the anterior peritoneal reflection and Denonvilliers fascia anteriorly and preserves the inferior hypogastric plexus posteriorly and laterally.
  • TME is performed under direct visualization.
  • TME yields a lower local recurrence rate (4%) than transanal excision (20%), but it is associated with a higher rate of anastomotic leak (11%). For this reason, TME may not be necessary for lesions in the upper third of the rectum.
• The distal resection margin varies depending on the site of the lesion. A 2-cm margin distal to the lesion must be achieved. The procedure is performed with the patient in the modified lithotomy position with the buttocks slightly over the edge of the operating table to allow easy access to the rectum.
• A circular stapling device is used to create the anastomosis. A double-stapled technique is performed. This entails transection of the rectum distal to the tumor from within the abdomen using a linear stapling device. The proximal resection margin is divided with a purse-string device. After sizing the lumen, the detached anvil of the circular stapler is inserted into the proximal margin and secured with the purse-string suture. The circular stapler is inserted carefully into the rectum, and the central shaft is projected through or near the linear staple line. Then, the anvil is engaged with the central shaft, and, after completely closing the circular stapler, the device is fired. Two rings of staples create the anastomosis, and a circular rim or donut of tissue from the proximal and distal margins is removed with the stapling device.
• The anastomotic leak rate with this technique ranges from 3-11% for middle-third and upper-third anastomoses and to 20% for lower-third anastomoses. For this reason, some surgeons choose to protect the lower-third anastomosis by creating a temporary diverting stoma. This is especially important when patients have received preoperative RT. The rate of stenosis is approximately 5-20%. A hand-sewn anastomosis may be performed; if preferred, the anastomosis is performed as a single-layer technique. The leak and stenosis rates are the same.

• Coloanal anastomosis
  • Very distal rectal cancers that are located just above the sphincters occasionally can be resected without the need for a permanent colostomy. The procedure is as already described; however, the pelvic dissection is carried down to below the level of the levator ani muscles from within the abdomen. A straight-tube coloanal anastomosis (CAA) can be performed using the double-stapled technique, or a hand-sewn anastomosis can be performed transanally.
  • The functional results of this procedure have been poor in some patients, who experience increased frequency and urgency of bowel movements, as well as some incontinence to flatus and stool.
  • An alternative to the straight-tube CAA is creation of a colonic J pouch. The pouch is created by folding a loop of colon on itself in the shape of a J. A linear stapling or cutting device is inserted into the apex of the J, and the stapler creates an outer staple line while dividing the inner septum. The J-pouch anal anastomosis can be stapled or hand sewn.
  • An alternative to doing the entire dissection from within the abdomen is to begin the operation with the patient in the prone jackknife position. The perineal portion of this procedure involves an intersphincteric dissection via the anus up to the level of the levator ani muscles. After the perineal portion is complete, the patient is turned to the modified lithotomy position and the abdominal portion is performed. Either a straight-tube or colonic J-pouch anal anastomosis can be created; however, both must be hand sewn.
  • The advantages of the J pouch include decreased frequency and urgency of bowel movements because of the increased capacity of the pouch.
  • A temporary diverting stoma is performed routinely with any coloanal anastomosis.

• Abdominal perineal resection

• Abdominal perineal resection (APR) is performed in patients with lower-third rectal cancers who cannot undergo a sphincter-sparing procedure. This includes patients with complex involvement of the sphincters, preexisting significant sphincter dysfunction, or pelvic fixation, and sometimes is a matter of patient preference.
• A 2-team approach is often used, with the patient in modified lithotomy position. One team mobilizes the colon and rectum, transects the colon proximally, and creates an end-sigmoid colostomy.
  • The perineal team begins by closing the anus with a purse-string suture and making a generous elliptical incision. The incision is carried through the fat using electrocautery. The inferior rectal vessels are ligated and the anococcygeal ligament is divided. The dissection plane continues posteriorly, anterior to the coccyx to the level of the levator ani muscles. Then, the surgeon breaks through the muscles and retrieves the specimen that has been placed in the pelvis. The specimen is brought out through the posterior opening, and the anterior dissection is continued carefully. Care must be taken to avoid the prostatic capsule in the male and the vagina in the female (unless posterior vaginectomy was planned). The specimen is removed through the perineum, and the wound is irrigated copiously. A closed-suction drain is left in place, and the perineal wound is closed in layers by using absorbable sutures.
  • During this time, the abdominal team closes the pelvic peritoneum (this is not mandatory), closes the abdomen, and matures the colostomy.

• Treatment of colorectal cancer with liver metastasis: Chemotherapeutic regimens for liver metastasis including systemic and intrahepatic administration have only had limited benefit. Systemic chemotherapy had 18-28% response rates. It is well accepted that liver resections in selected patients are beneficial. Overall, 5-year survival rates following surgical resection of liver metastasis vary from 20- 40%.

MEDICATION

The goals of pharmacotherapy are to down-stage a tumor, induce remission, reduce morbidity, and prevent complications.

Drug Category: Antineoplastic agents -- Chemotherapy has been studied extensively in rectal cancer. The combination of preoperative RT and chemotherapy with fluorouracil improves local control, distant spread, and survival rate. The basis of this improvement is believed to be the activity of fluorouracil as a radiosensitizer.

Other drugs in combination with fluorouracil have demonstrated activity in neoadjuvant studies. These include leucovorin and irinotecan.

Drug Name	Fluorouracil (5-FU, Fluorouracil, Adrucil) -- Blocks methylation of deoxyuridylic acid to thymidylic acid, thereby interfering with DNA synthesis. Dose is body-weight dependent and varies with specific protocol in which patient is involved.
Adult Dose	Not to exceed 800 mg/d IV
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression; serious infection; topical administration; pregnancy
Interactions	Anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents increase risk of bleeding; other immunosuppressive agents exacerbate bone marrow toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment

Drug Name	Vincristine (Vincasar PFS, Oncovin) -- Mechanism of action uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production. It is mitotic spindle inhibitor.
Adult Dose	Dose determined by oncologist involved; not routinely used to treat rectal cancer
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Mitomycin-C may cause acute pulmonary reaction
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with severe cardiopulmonary or hepatic impairment or preexisting neuromuscular disease

Drug Name	Leucovorin (Wellcovorin) -- Potentiates effects of fluorouracil. Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Given just prior to fluorouracil.
Adult Dose	Dose determined by predetermined dosing regimen of fluorouracil
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer intrathecally or intraventricularly

Drug Name	Irinotecan (Camptosar, Camptothecin-11, CPT-11) -- Inhibits topoisomerase I, inhibiting DNA replication and, consequently, cell proliferation.
Adult Dose	Dose depends on protocol in which patient is involved
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression; renal function impairment
Interactions	Concomitant administration with other antineoplastics may result in prolonged neutropenia, thrombocytopenia, and increased morbidity/mortality rates
Pregnancy	D - Unsafe in pregnancy
Precautions	Adverse effects include myelosuppression, dermatitis, nausea, and vomiting; monitor bone marrow function

Drug Name	Oxaliplatin (Eloxatin) -- A platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. It forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. The cytotoxicity is cell-cycle nonspecific.
Adult Dose	Day 1: 85 mg/m2 IV over 2 h; administer simultaneously with leucovorin 200 mg/m2; followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV continuous infusion in 500 mL D5W over 22 h Day 2: Leucovorin 200 mg/m2 IV over 2 h, followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV as a continuous infusion in 500 mL D5W over 22 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to oxaliplatin or other platinum compounds
Interactions	May increase 5-FU serum concentration by approximately 20%
Pregnancy	D - Unsafe in pregnancy
Precautions	Anaphylaxis may occur within minutes of administration; may cause neuropathy, pulmonary fibrosis, bone marrow suppression, GI tract symptoms (eg, nausea, vomiting, stomatitis), renal or hepatic toxicity (decrease dose), or thromboembolism; dilute IV only in dextrose-containing solution

Drug Name	Cetuximab (Erbitux) -- Recombinant human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. Indicated for treating irinotecan-refractory, EGFR-expressed, metastatic colorectal carcinoma. Treatment is preferably combined with irinotecan. May be administered as monotherapy if irinotecan is not tolerated.
Adult Dose	First dose: 400 mg/m2 IV infused over 2 h Weekly maintenance doses: 250 mg/m2 IV infused over 1 h Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min); must administer with low-protein–binding 0.22 mm in-line filter; premedication with an H1 antagonist (eg, diphenhydramine 50 mg IV) recommended
Pediatric Dose	Not established
Contraindications	None reported
Interactions	Limited data exist; none reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution with documented hypersensitivity, including allergy to murine proteins; may cause infusion-related hypotension and airway distress (eg, bronchospasm, stridor, hoarseness), particularly with the first infusion (90%); premedicate with diphenhydramine 50 mg IV; decrease dose with mild or moderate (grade 1 or 2) infusion reaction and immediately and permanently discontinue with severe (grade 3 or 4) infusion reaction; common adverse effects include acnelike rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain; may rarely cause interstitial lung disease; do not shake or dilute solution; sunlight can exacerbate any skin reactions

Drug Name	Bevacizumab (Avastin) -- Indicated as a first-line treatment for metastatic colorectal cancer. Murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.
Adult Dose	5 mg/kg IV q2wk until disease progression detected
Pediatric Dose	Not established
Contraindications	None reported
Interactions	Coadministration with 5-fluorouracil increases frequency (2-fold) of serious and fatal arterial thromboembolic events (ie, CVA, MI, TIAs, angina)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Angiogenesis is critical to fetal development, and use of bevacizumab during pregnancy likely results in adverse fetal effects; common adverse effects include hypertension, fatigue, thrombosis, diarrhea, leukopenia, proteinuria, headache, anorexia, and stomatitis; may cause serious or fatal (but rare) events, including gastrointestinal tract perforation, intra-abdominal infections, impaired wound healing, hemoptysis (particularly with lung cancers), and internal bleeding; increases risk of serious and fatal arterial thrombotic events with 5-fluorouracil; do not initiate treatment for at least 28 d after major surgery (the surgical incision should be fully healed); breastfeeding should be discontinued during and for at least 20 d after treatment with bevacizumab

Drug Name	Panitumumab (Vectibix) -- Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated to treat colorectal cancer that has metastasized following standard chemotherapy.
Adult Dose	6 mg/kg IV infused over 60 min q2wk
Pediatric Dose	Not established
Contraindications	None known
Interactions	Data limited; none reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include rash, fatigue, abdominal pain, nausea, and diarrhea; serious adverse effects include pulmonary fibrosis, severe rash complicated by infections, infusion reactions (for grade I or II reaction, reduce infusion rate by 50%; for grade III or IV reaction, immediately discontinue permanently), ocular toxicity, abdominal pain, vomiting, and constipation; administer using low-protein–binding filter

FOLLOW-UP

Prognosis:

• Overall 5-year survival rates for rectal cancer are as follows:

• Stage I - 72%
• Stage II - 54%
• Stage III - 39%
• Stage IV - 7%

• Fifty percent of patients develop recurrence, which may be local, distant, or both.

• Local recurrence is more common in rectal cancer than in colon cancer.

• Disease recurs in 5-30% of patients, usually in the first year after surgery.

• Factors that influence the development of recurrence include surgeon variability, grade and stage of the primary tumor, location of the primary tumor, and ability to obtain negative margins.

• Surgical therapy may be attempted for recurrence and includes pelvic exenteration or APR in patients who had a sphincter-sparing procedure.

• RT generally is used as palliative treatment in patients who have locally unresectable disease.

Patient Education:

• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Colon Cancer, Colonoscopy, Sigmoidoscopy, Abdominal Pain in Adults, Rectal Bleeding, and Rectal Cancer.