Colorectal cancer is one of the few preventable cancers. The removal of precancerous adenomatous polyps during colonoscopy inhibits their progression to cancer. Widely available screening tests such as the fecal occult blood test (FOBT), sigmoidoscopy, and colonoscopy are associated with a decrease in colorectal cancer mortality. Unfortunately, fewer than 50% of eligible Americans have undergone screening, and more than 45% of patients are diagnosed at a time when the cancer is incurable.

Definition

The colorectum is the portion of the gastrointestinal tract most frequently affected by tumors. Most colonic tumors are benign epithelial polyps. Polyp is an inexact term that indicates a protuberance of tissue into the colonic lumen. There are many histologic types of polyps but the only one that can become an adenocarcinoma is the adenomatous polyp. The size, number of adenomas, and degree of villous features are predictive of the future risk of advanced neoplasia, including malignancy in individuals who harbor adenomas. Recently, an alternative route to sporadic colorectal cancer has been discovered, which includes the hyperplastic serrated adenoma pathway. ¹ Serrated adenomas have microscopic elements of hyperplastic and adenomatous polyps and should be managed similarly to adenomas.

This chapter will focus on the neoplastic epithelial tumors, including adenomatous polyps and adenocarcinoma of the colon and rectum.

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Prevalence and Risk Factors

The incidence of colorectal carcinoma has been decreasing on an average of 1.5% annually since the mid-1980s. Research has suggested that the decline may be caused by an increased use of screening and polyp removal, which prevents progression from polyp to cancer. Although almost 40% of Americans 50 years and older harbor adenomatous polyps, it is estimated that only 2% of adenomas will progress to cancer.

Adenocarcinoma of the colon and rectum is the third most common cancer and cause of cancer deaths in the United States. Both men and women face a lifetime risk of almost 6% for the development of invasive colorectal cancer (Table 1 ). ² It has been estimated that approximately 154,000 new cases of colorectal cancer will have been diagnosed in 2007, and that 53,000 deaths from colorectal cancer will occur. The only known race predilection is in African Americans, who have higher colorectal cancer incidence and mortality rates.

Epidemiologic studies have implicated a number of environmental cofactors in the development of colorectal cancer. They include, in order of strength of association, advanced age, high red meat diet, high-fat diet, smoking, alcohol consumption, and obesity. In approximately 30% of patients with colorectal cancer, risk factors have been identified (Box 1 ), and the remaining 70% of newly diagnosed colorectal cancers arise in patients without any identifiable risk factors.

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Pathophysiology and Natural History

In almost all cases, colorectal carcinoma arises from an adenomatous polyp. Observational studies have suggested that the adenoma-to-carcinoma sequence takes approximately 10 years. Colorectal tumorigenesis has traditionally been believed to result from multiple acquired genetic alterations in tumor tissue that in turn promote malignant transformation. This chromosomal instability pathway is believed to lead to the majority of known colorectal cancers through the adenoma–carcinoma sequence. Alterations in DNA repair (i.e., mismatch repair) genes are implicated in carcinogenesis in approximately 20% of patients with sporadic colorectal cancer (and most individuals with hereditary nonpolyposis colorectal cancer [HNPCC]). This pathway is characterized by extensive instability in simple repeat nucleotide sequences (microsatellites). During the last decade an alternative cancer pathway has been recognized and is believed to account for up to 30% of colorectal cancers. This pathway is initiated and promoted by widespread hypermethylation of the CpG islands (CIMP) in gene promoter regions. ¹

A personal history of adenomatous polyps or colorectal cancer increases the risk for metachronous colorectal cancer. First-degree relatives of patients with colorectal cancer have a two- to threefold increased risk for colorectal cancer and adenomatous polyps. Recent work has proven that first-degree family members of patients with adenomatous polyps also have an increased risk of colorectal cancer themselves, particularly when the relative's adenoma is diagnosed before age 60 years. Patients with the highest risk for colorectal cancer are those who have a hereditary colorectal cancer syndrome. The dominantly inherited syndromes include familial adenomatous polyposis (FAP) and HNPCC. Recently, an autosomal recessive colon cancer syndrome has been discovered, called MYH-associated polyposis (MAP). FAP is caused by a mutation in the tumor suppressor gene APC on the long arm of chromosome 5. Germline mutations in APC can be detected in approximately 80% of patients with FAP. The APC mutation results in the development of hundreds to thousands of colonic adenomas, usually by the second decade of life. Colon cancer develops in all FAP patients by age 40 years if prophylactic colectomy is not performed. Attenuated FAP is a phenotypically distinct form of colonic polyposis. The number of colonic polyps in these patients usually numbers less than 100, and the age of onset of polyposis and cancer is shifted 1 to 2 decades later. Duodenal adenomas are common in either form of FAP, and periampullary cancer is the second leading cause of cancer deaths in this population. Gardner's syndrome is a phenotypic variant of FAP. In addition to colonic polyposis, other manifestations may be seen, such as benign soft tissue tumors, osteomas, supernumerary teeth, desmoid tumors, and congenital hypertrophy of the retinal pigment epithelium.

MAP is associated with mutations of the MYH gene on chromosome 5. Biallelic germline mutations in MYH are responsible for 10% of the APC-negative cases of FAP and up to 29% of individuals with numerous adenomas (more than 15) during their lifetime. The affected individuals have fewer than 100 colorectal adenomas and an increased risk of cancer. ³ Hereditary HNPCC is caused by genetic alterations in one of the mismatch repair genes. Alterations in these genes prevent adequate repair of DNA, resulting in a change of length of nucleotide bases (MSI) when compared with those of normal tissues and that can be tested for in tumor tissue. Germline mutations in one of six genes have been identified in up to 70% of patients with HNPCC. Colorectal cancer occurs in up to 80% of those affected, usually by the age of 50, and is often right-sided and associated with unusual pathologic features. Extracolonic cancers, such as endometrial, ovarian, small bowel, transitional cell of the ureter or bladder, and gastric cancer, often occur in patients with HNPCC. The risk of endometrial carcinoma has been reported in up to 60% and ovarian carcinoma in up to 20% of patients with HNPCC. Therefore, aggressive gynecologic screening for endometrial and ovarian cancers is recommended in women in HNPCC kindreds.

Diagnosing families with HNPCC is most often based on clinical criteria. The strictest criteria are the Amsterdam criteria:

1. Three or more relatives with colorectal cancer, with one a first-degree relative of the other two
2. At least two successive generations affected
3. One cancer diagnosed before age 50 years

Many researchers have found the Amsterdam criteria neither sufficiently sensitive nor specific for use as the sole criterion for determining which families should undergo intensive surveillance or genetic evaluation. ⁴ This criticism of the traditional Amsterdam criteria has resulted in its revision and creation of the Amsterdam II criteria, which identify families with three or more relatives with HNPCC-associated cancers, including colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis.

The Bethesda guidelines were created to identify families who did not meet Amsterdam criteria, but who might still benefit from genetic evaluation. The revised Bethesda guidelines have recommended testing tumors from individuals with colorectal cancer for MSI in the following situations: ⁵

1. Colorectal cancer diagnosed under the age of 50 years
2. Presence of synchronous or metachronous colorectal, or other HNPCC-associated tumors, regardless of age
3. Colorectal cancer with MSI diagnosed in a patient younger than 60 years
4. Colorectal cancer diagnosed in a patient with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years
5. Colorectal cancer diagnosed in a patient with two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age

The chronic inflammatory colitides, ulcerative colitis and Crohn's disease, are associated with an increased risk of colorectal cancer. The proximal extent of colonic involvement and the duration of disease (not activity) stratify the level of risk. Risk is highest in patients with pancolitis and negligible in patients with proctitis. After a decade of disease, the cancer risk increases yearly by 1% to 2%.

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Signs and Symptoms

Colon polyps and early colon cancer are often asymptomatic until they are advanced. Gastrointestinal blood loss is the most common sign and may include a positive FOBT result, iron deficiency anemia, or hematochezia. When tumors are advanced, unexplained anorexia, weight loss, or symptoms from obstruction or local invasion, such as a change in bowel habits, abdominal pain, or obstruction, may occur.

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Diagnosis

The diagnosis of colorectal polyps and cancer is most often made during a colonic evaluation performed for gastrointestinal symptoms, colorectal cancer screening, or as part of endoscopic surveillance.

Screening

National organizations, including the American Cancer Society, United States Preventive Service Task Force, and U.S. Multi-Society Task Force on Colorectal Cancer, have established guidelines for colorectal cancer screening and surveillance. ^6–8 Various options are recommended for average-risk individuals (Table 2 ). ⁹ Colonoscopy was added as a screening option to guidelines in 1997 and has gained acceptance as the preferred strategy. One of the first guidelines to recommend colonoscopy as the preferred screening strategy, with an annual FOBT and flexible sigmoidoscopy every 5 years as an acceptable alternative, is available. ⁸ This guideline also reviews the advantages and limitations of each screening method.

The evidence to support colonoscopy has been derived from data showing a decreased incidence of colorectal cancer mortality in subjects who have undergone colonoscopic adenoma removal. ^10,11 Additionally, colonoscopic screening has been shown to have favorable cost effectiveness when compared with other screening strategies. ^12,13 Unfortunately, lesions may be missed on colonoscopy, and up to 5% of individuals who have undergone colonoscopy within the 3 years before will be diagnosed with colorectal cancer. ¹⁴

Patients with symptoms of colorectal cancer and those with more than a moderate to high risk for colorectal cancer should undergo colonoscopy (Table 3 ). The U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society have developed clinical practice guidelines for subjects with an increased risk of colorectal cancer, as well as surveillance for subjects with adenomas. ⁷ These guidelines put into perspective the rationale behind differing surveillance intervals based on adenoma size, number, histology, and family history.

Fecal Occult Blood Test

Randomized trials have found that the use of annual FOBTs has decreased the mortality from colorectal cancer by up to 33%. The reductions in mortality are associated with a shift to detection of earlier stage cancer. In addition, one study has found that the incidence of colorectal cancer was reduced by 20% in an annually screened group. This is likely the result of polypectomy in patients whose positive FOBT was evaluated by colonoscopy.

Because large polyps and cancers bleed intermittently, the peroxidase activity of hemoglobin in the stool can be detected by a color change when it catalyzes the oxidation of guaiac by a peroxide reagent. A special diet (e.g., a meat-free, high-residue diet without vegetables that have peroxidase activity, such as turnips and horseradish) is recommended for at least 24 hours before three separate stool specimens are collected at least 1 day apart. Unrehydrated test sensitivity is low at approximately 80%, with a specificity of up to 98%. A newer, immunochemical method for FOBT (i-FOBT) uses antibodies to human globin. The potential advantages of the i-FOBT include automation of test results and a potential increase in compliance, because no dietary restrictions are needed because the antibodies do not cross-react with non-human hemoglobin or peroxidases from food sources, and the collection method is simpler. In addition, because globin does not survive passage through the upper GI tract, the test is specific for bleeding in the colon and rectum.

Although i-FOBT has not been studied in widespread, randomized, controlled screening trials, in case control studies a reduction of colorectal cancer mortality of up to 80% has been shown. ^15–17

Sigmoidoscopy

Results of several case-control studies have shown a reduction in deaths from colorectal cancer in subjects who have undergone sigmoidoscopic examinations. The reported reduction in mortality varies between 59% and 80%. The most well-known study compared the use of rigid sigmoidoscopic screening in 261 patients who died from cancer of the distal colon or rectum with 868 control subjects. Screening reduced the rectosigmoid cancer mortality rate by 60%, and the protective effect of sigmoidoscopy was noted to last for up to 10 years. This reduction in mortality may have resulted from earlier detection of cancer and removal of premalignant polyps. Sigmoidoscopic screening allows the lower one third of the colorectal mucosa to be visualized directly and diagnostic biopsy to be performed at the time of examination. Both the sensitivity and specificity are high for the detection of polyps and cancer in the segment of the bowel examined. Unfortunately, however, almost 50% of polyps and cancers are beyond the limits of detection of the longest (e.g., 60 cm) flexible sigmoidoscope. ¹⁸

Opinions vary regarding the need for colonoscopy for patients in whom a single small (less than 1 cm) adenoma is found on flexible sigmoidoscopy. Studies have shown that the prevalence of advanced proximal neoplasms in patients with distal adenomas is up to 9%. Therefore, the use of colonoscopy to detect proximal neoplasia in patients with distal adenomas continues to be recommended. Additionally, a recent multicenter study of average-risk women has determined that advanced neoplasia would be missed in almost two thirds of women undergoing only flexible sigmoidoscopy. ¹⁹

Sigmoidoscopy Combined with Fecal Occult Blood Testing

In one controlled trial, 12,479 people underwent annual screening with rigid sigmoidoscopy or rigid sigmoidoscopy combined with FOBT. A reduction in the colorectal cancer mortality rate, detection of earlier stage cancer, and longer survival were seen in patients undergoing both an FOBT and rigid sigmoidoscopy. Annual FOBT and flexible sigmoidoscopy is the preferred screening alternative to colonoscopy screening. ⁸

Barium Enema

Barium enema has the advantage of imaging the entire colon. However, recent evidence has suggested that it is inaccurate for detection of polyps and early cancers and suboptimal for colorectal cancer screening or surveillance. In a prospective study comparing the use of double-contrast barium enema and colonoscopy, the miss rate of barium enema for polyps larger than 1 cm was 52%. ²⁰ If barium enema is the only option for screening or surveillance, it should be coupled with flexible sigmoidoscopy. The use of flexible sigmoidoscopy allows visualization of the rectosigmoid, which may not be well seen on barium enema because of the overlapping loops of bowel. Lesions detected on barium enema warrant colonoscopic evaluation.

Colonoscopy

Colonoscopy is the gold standard for the detection of colonic neoplasms and the preferred colorectal cancer screening strategy. ⁸ The incidence rate of colorectal cancer has been shown to be reduced up to 90% in subjects who had polypectomy versus patients in three reference groups, including two cohorts in whom colonic polyps were not removed and one general population registry. ¹⁰ Colonoscopy can be completed in more than 95% of examinations with negligible risk. Colonoscopic screening in average-risk individuals has been found to be cost effective, and similar to cervical or breast cancer screening techniques in cost effectiveness per life-year saved. Medicare has approved the use of screening colonoscopy in average-risk beneficiaries. Unfortunately, not all Americans younger than 65 years have health care benefits that cover the charges for colonoscopy, which could affect patient compliance with screening colonoscopy.

The stage of colorectal cancer is the most important feature predicting curability and survival in colorectal cancer. The depth of tumor invasion and lymph node involvement are the two major components constituting the basis for colorectal cancer tumor staging. The first colorectal cancer staging system was developed in 1932 and is known as the Dukes' classification. Since then, many modifications in the Dukes' scheme have been made. In an effort to minimize confusion over which Dukes' stage is implied and to standardize all organ system cancer staging, the TNM (tumor, nodal status, and presence of metastases) system has been adopted (Table 4 ). The TNM staging of colon cancer underwent modification by the American Joint Committee on Cancer in 2002. Stages II and III have been further stratified based on tumor size. In addition, investigators used the Surveillance, Epidemiology, and End Results (SEER) data to calculate 5-year survival rates, and patients with stage IIIA colon cancer were found to have significantly better survival than patients with stage IIB disease.

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Treatment

The primary treatment of colorectal cancer is surgical resection of the primary tumor and regional lymph nodes. Surgery is curative for most early stage colorectal tumors. For more advanced stages, surgery and adjuvant therapy are recommended to prevent recurrence and prolong survival. ²¹

Colon Cancer

Studies have proven the benefit of adjuvant chemotherapy in prolonging disease-free and overall survival in patients with stage III colon cancer compared with patients who received surgery alone. ²² Patients with stage III colon cancer who undergo surgery alone have a 50% risk of relapse; these patients benefit from 5-fluorouracil (5-FU)–based adjuvant therapy, with a 30% reduction in risk of death. ²³ Despite this recommendation for postoperative chemotherapy, there is documented underuse of adjuvant therapy in patients with stage III colon cancer.

Use of adjuvant therapy in patients with stage II colon cancer has been actively debated. ²⁴ Presently, the American Society of Clinical Oncologists does not recommend routine use of adjuvant chemotherapy in patients with stage II colon cancer. Certain patient populations, however, may be considered for adjuvant treatment, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. Additionally, patients with stage II disease should be encouraged to participate in clinical trials aimed at determining the true benefit, if any, of adjuvant therapy in this patient population.

Rectal Cancer

The major limitation of rectal cancer surgery is the inability to obtain wide margins because of the confined space of the bony pelvis. Adjuvant radiation therapy decreases the rate of local recurrence, whereas the addition of systemic chemotherapy further enhances local control and improves survival. ²⁵ A 1990 NIH Consensus Development Conference recommended that postoperative 5-FU–based chemotherapy combined with irradiation should be the standard clinical practice in stages II and III rectal cancer because of its proven decrease in local recurrence, cancer-related deaths, and overall mortality. ²¹

In the last decade, subsequent randomized trials have been challenging that recommendation. The debate is fueled, in part, by refinements in surgical techniques. Total mesorectal excision (TME) is one of the most exciting recent developments in surgical oncology. The sharp dissection follows along the mesorectal fascia, with removal of the rectum and of all tissue invested by the adjacent visceral fascia, including fatty tissue, lymph nodes, and lymphatic vessels. This technique has been associated with a reduction in local recurrence rates from 39% to below 10%. These low rates have led some investigators to question the routine use of adjuvant radiation therapy. One study has compared the use of TME with preoperative radiotherapy versus TME alone. ²⁵ Short-term survival was no different in the two groups, but the rate of local recurrence was 2.4% for TME with preoperative radiotherapy versus 8.2% for TME alone.

There is also controversy over the best timing of radiotherapy. Compared with postoperative irradiation, preoperative treatment may have lower toxicity and may increase the chance of sphincter preservation. The information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than 50% when radiotherapy, up to moderately high doses, is given preoperatively. This reduction is smaller with postoperative radiotherapy, even if higher doses are used. Improved survival has been seen in trials using postoperative radiotherapy, but only when combined with chemotherapy. In one trial, a survival benefit was incurred with preoperative radiotherapy versus surgery alone. Randomized trials comparing preoperative and postoperative combined modality therapy are in progress.

Outside of clinical trials, curative intent surgery combined with radiochemotherapy remains the recommended standard for treatment of stages II and III rectal cancer.

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Prevention

Epidemiologic studies have found a modest decrease in colorectal cancer in patients using nonsteroidal anti-inflammatory drugs, particularly aspirin. ²⁶ Two randomized controlled trials have found that aspirin substantially reduces the risk of recurrent and advanced adenomas in high-risk populations. ^27,28 Two randomized placebo-controlled trials have found a moderate reduction in recurrent adenomas with calcium supplementation. ^29,30

A 6-month placebo-controlled trial of a selective cyclooxygenase (COX)-2 inhibitor, celecoxib, in FAP patients resulted in a 28% reduction in polyp size and number. ³¹ The U.S. Food and Drug Administration has approved the use of celecoxib as an adjunct for the management of colorectal adenomas in patients with FAP. The value of COX-2 inhibitors celecoxib and rofecoxib in the sporadic adenoma population has been investigated in three large multicenter studies of patients with a history of colorectal adenoma. The efficacy results of these 3 year trials all demonstrated a significant reduction in the recurrence of both adenomas and advanced adenomas. Unfortunately the studies were stopped prematurely because of adverse cardiovascular events. ^32–35

The increased cardiovascular risk of COX-2 inhibitors appears to outweigh the potential for prevention of colorectal neoplasia in patients with sporadic colorectal adenomas. ³⁶ The effectiveness and cost-effectiveness of chemopreventive agents in different risk populations needs to be confirmed before widespread recommendations for their use can be given.

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Conclusions

Colorectal cancer is one of the leading causes of cancer and death from carcinoma in the United States. Increasing awareness regarding the preventable nature of this disease, along with widespread use of screening, should favorably affect the incidence of colorectal cancer. Colorectal cancer screening and polyp removal can save lives, and the most exciting area of future research will be the primary prevention of adenomas and colorectal cancer through chemoprevention.

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Summary

• Adenocarcinoma of the colon and rectum is the third most common cancer and cause of cancer deaths in the United States, but studies have suggested that the incidence is declining because of the increased use of screening and polyp removal.
• Colon cancer screening and surveillance strategies must be individualized based on a patient's risk factors, including personal history of adenomas or colorectal cancer, family history of adenomas or colorectal cancer, family history of an inherited colorectal cancer syndrome, and personal history of inflammatory bowel disease.
• The stage of colorectal cancer is the most important feature predicting curability and survival in colorectal cancer.
• Continued investigations of chemopreventive agents are needed to identify a means of primary prevention of adenomas and colorectal cancer.

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Suggested Readings

• Baron J, Cole B , Sandler R. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 348: 2003; 891-899.
• Benson AB. Adjuvant chemotherapy of stage III colon cancer. Semin Oncol. 32: 2005; S74-S77.
• Giardello FM, Brensinger JD , Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 121: 2001; 198-213.
• Lieberman DA, Weiss DG. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med. 345: 2001; 555-560.
• Sieber OM, Lipton L , Crabtree M. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 348: 2003; 791-799.
• Solomon S, McMurray J , Pfeffer M. for the Adenoma Prevention with Celecoxib (APC) Study Investigators: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 352: 2005; 1071-1080.
• Umar A, Boland C , Terdiman J. Revised Bethesda guidelines for HNPCC and microsatellite instability. J Natl Cancer Inst. 96: 2004; 261-268.
• Winawer S, Fletcher R , Rex D. Colorectal cancer screening and surveillance: Clinical guidelines and rationale—update based on new evidence. Gastroenterology. 124: 2003; 544-560.
• Winawer S, Zauber A , Fletcher R. US Multi-Society Task Force on Colorectal Cancer; American Cancer Society: Guidelines for colonoscopy surveillance after polypectomy: A consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology. 130: 2006; 1872-1885.