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.

The colorectum is the portion of the gastrointestinal tract most frequently affected by tumors. The majority of colonic tumors are benign epithelial polyps. "Polyp" is an inexact term that indicates a protuberance of tissue into the colonic lumen. The most common polyp and the only one that can become an adenocarcinoma is the adenomatous polyp. Both the size and degree of villous features are predictive of the risk of malignancy within the polyp.

Hyperplastic polyps are the second most common type of polyp, accounting for up to 30% of colonic polyps. Hyperplastic polyps are most often found in the rectosigmoid and are believed to have no clinical significance. Unfortunately, hyperplastic polyps and adenomas are indistinguishable on endoscopy. Therefore, all polyps detected in the colon and rectum should be removed and sent for histologic analysis.

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

The incidence of colorectal carcinoma has been decreasing on an average of 1.5% annually since the mid-1980s. Research suggests that the decline may be due to an increased use of screening and polyp removal, which prevents progression from polyp 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 nearly 6% for the development of invasive colorectal cancer (Table 1).¹ It is estimated that approximately 135,000 new cases of colorectal cancer will have been diagnosed in 2001, and that 57,000 deaths from colorectal cancer will occur. The only known race predilection is in African Americans, who have higher colorectal cancer incidence and mortality rates.

In nearly all cases, colorectal carcinoma arises from an adenomatous polyp. Observational studies suggest that the adenoma-to-carcinoma sequence takes approximately 10 years. Although nearly 40% of Americans aged 50 years or older harbor adenomatous polyps, it is estimated that only 2% of adenomas will progress to cancer.

Colorectal cancer arises from a series of histopathologic and molecular changes caused by complex interactions between genetic susceptibility and environmental factors. These molecular changes include multiple, acquired genetic alterations within colonocyte oncogenes (promoting malignant transformation) and tumor suppressor genes (causing loss of the inhibition of cellular proliferation). A newly discovered pathway for carcinogenesis involves mutations in the genes responsible for repair of mismatched DNA base pairs (eg, mismatch repair genes). Mismatch-repair-gene inactivation is present in approximately 15% of sporadic colorectal cancers, but is the major cause of cancers in hereditary nonpolyposis colorectal cancer (HNPCC).

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. Approximately 70% of newly diagnosed colorectal cancers arise in patients without known risk factors. In approximately 30% of patients with colorectal cancer, risk factors have been identified (Table 2):

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 one of the dominantly inherited colorectal cancer syndromes:

Familial adenomatous polyposis (FAP) is due to 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.

An attenuated form of colonic polyposis has been found and named "attenuated FAP." The number of colonic polyps is usually 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.

Hereditary nonpolyposis colorectal cancer is caused by genetic alterations in one of the mismatch repair genes. Alterations in these genes prevent adequate repair of DNA, resulting in an accumulation of mutations in daughter cells and leading to carcinogenesis. Germline mutations in one of six genes have been identified in up to 60% 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. Extracolonic cancers such as endometrial, ovarian, small-bowel, transitional cell of the ureter or bladder, and gastric 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 cancer 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:

• Three or more relatives with colorectal cancer, with one a first-degree relative of the other two,
• At least two successive generations affected,
• 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 testing.² The other criteria include the Amsterdam II and Bethesda criteria. Amsterdam II includes extracolonic cancers (endometrial, small-bowel, ureter, and renal pelvis) in addition to colorectal cancer. The Bethesda criteria include young adenomas, colorectal or endometrial cancers, and individuals with 2 HNPCC-related cancers (synchronous or metachronous).

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%.

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.

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
In the past decade, many groups, including the American Cancer Society, the United States Preventive Service Task Force, and a collaboration of surgical and gastroenterologic associations under the auspices of the Agency for Health Care Policy and Research, have established guidelines for colorectal cancer screening and surveillance.^3,4,5 A variety of options are recommended for average-risk individuals (Table 3). 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 and annual fecal occult blood testing (FOBT) and flexible sigmoidoscopy every 5 years as an acceptable alternative is available.⁵ This guideline also reviews the advantages and limitations of each screening method.

The evidence to support colonoscopy is derived from data showing a decreased incidence of colorectal cancer mortality in subjects who have undergone colonoscopic adenoma removal.^6,7 Additionally, colonoscopic screening has been shown to have favorable cost effectiveness when compared to other screening strategies.^8,9

Patients with symptoms of colorectal cancer and those with greater than moderate-to-high risk for colorectal cancer should undergo colonoscopy (Table 4). The American College of Gastroenterology has developed clinical practice guidelines for subjects with an increased risk of colorectal cancer as well as surveillance for subjects with adenomas. ^5,10 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 have 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 found the incidence of colorectal cancer was reduced by 20% in an annually screened group. This is likely due to polypectomy in patient's whose positive FOBT was evaluated by colonoscopy.

Since large polyps and cancers intermittently bleed, 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 (eg, a meat-free, high-residue diet without vegetables having 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%. Any positive FOBT should be evaluated by colonoscopy.

Sigmoidoscopy
Results of several case-control studies show a reduction in deaths from colorectal cancer in subjects who undergo 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 to 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 third of the colorectal mucosa to be visualized directly and diagnostic biopsy to be performed at the time of examination. Both the sensitivity and the specificity are high for detection of polyps and cancer in the segment of the bowel examined. Unfortunately, however, nearly 50% of polyps and cancers are beyond the limits of detection of the longest (eg, 60 cm) flexible sigmoidoscope.

Opinions vary regarding the need for colonoscopy for patients in whom a single, small (< 1 cm) adenoma is found on flexible sigmoidoscopy. Many 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 is strongly recommended.

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 FOBT and rigid sigmoidoscopy. Annual FOBT and flexible sigmoidoscopy is the preferred screening alternative to colonoscopy screening.⁵

Barium Enema
Barium enema has the advantage of imaging the entire colon. However, recent evidence suggests 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%.¹¹ 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.⁵ 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 which colonic polyps were not removed and one general-population registry.⁶ It can be completed in more than 95% of examinations with negligible risk. Colonoscopic screening in individuals with average risk 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 under the age of 65 have health care benefits that would cover the charges for colonoscopy which may impact on 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 known as the Dukes' classification. Since then, many modifications in the Dukes' scheme have been made. This has led to confusion because most of the schemes utilize the letters A, B, C and D but indicate different depths of tumor invasion. 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.

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 (Table 5). For more advanced stages, surgery and adjuvant therapy are recommended to prevent recurrence and prolong survival.¹²

Adjuvant Treatment:

Colon Cancer
Studies over the last 10 years have proven the benefit of adjuvant chemotherapy in prolonging disease-free and overall survival in patients with stage II colon cancer compared with patients who received surgery alone.¹³ Currently, patients with stage III colon cancer should receive adjuvant therapy with 5-fluorouracil (5-FU) and leucovorin for 6 to 8 months. Patients with stage II colon cancer should be encouraged to participate in ongoing trials because adjuvant therapy has not yet proved to offer a survival benefit.

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, while the addition of systemic chemotherapy further enhances local control and improves survival.¹⁴ A 1990 NIH Consensus Development Conference recommended that postoperative 5-FU-based chemotherapy combined with irradiation should be the standard clinical practice in stage II and III rectal cancer because of its proven decrease in local recurrence, cancer-related deaths, and overall mortality.¹²

In the last decade, subsequent randomized trials are 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 together with 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. A recent study compared the use of TME with preoperative radiotherapy versus TME alone.¹⁵ 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 less toxicity and may increase the chance of sphincter preservation. The collected information from all controlled trials reported so far shows that the proportion of local recurrences is reduced to less than one half 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 stage II and III rectal cancer.

Chemoprevention:

Epidemiologic studies have found a modest decrease in colorectal cancer in patients utilizing nonsteroidal anti-inflammatory drugs, particularly aspirin, and folate.¹⁶ Unfortunately, randomized controlled trials of the use of chemopreventive agents are limited. 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.¹⁷ The US 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 in the sporadic adenoma population is not known. Two randomized, placebo-controlled trials found a moderate reduction in recurrent adenomas with calcium supplementation.^18,19 These results support the use of calcium for a moderate-risk reduction of recurrent colorectal adenomas. 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.²⁰

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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