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Colon, Rectal, and Anal Cancers

Colon, Rectal, and Anal Cancers

Colorectal Cancer

Despite the existence of excellent screening and preventive strategies, colorectal carcinoma (CRC) remains a major public health problem in Western countries. The American Cancer Society (ACS) estimated that in 2012, CRC will be diagnosed in 143,460 people, and 51,690 will die of the disease. CRC is the third most common type of cancer in both sexes (after prostate and lung cancers in men and lung and breast cancers in women) and the second most common cause of cancer death in the United States.

About 72% of new CRCs arise in the colon, and the remaining 28% arise in the rectum. Rectal cancer is defined as cancer arising below the peritoneal reflection, up to approximately 12 to 15 cm from the anal verge.

The lifetime risk of CRC in the United States is estimated to be 5.9% for men and 5.5% for women.

FDA Approvals

In September 2012, the US Food and Drug Administration (FDA) approved the multikinase inhibitor regorafenib (Stivarga) to treat colorectal cancer that has metastasized following previous treatment. CORRECT, the phase III trial that led to approval of regorafenib, was conducted from May 2010 to March 2011 and involved 760 patients with metastatic colorectal cancer whose disease had progressed following earlier treatment. Patients received best supportive care and were randomized 2:1 to either regorafenib or placebo. Those treated with regorafenib had a median overall survival of 6.4 months vs 5 months for patients treated with placebo (P = .005). Median progression-free survival was 1.9 months for patients on regorafenib (95% confidence interval [CI]: 1.88–2.17) vs 1.7 months for those taking placebo (95% CI: 1.68–1.74). The disease control rate for patients on regorafenib was 44.8% vs 15.3% for placebo (P < .0001).

In August 2012, the FDA approved the angiogenesis inhibitor aflibercept (Zaltrap) to be used with the chemotherapy regimen FOLFIRI (irinotecan, 5-fluorouracil [5-FU], leucovorin) in the treatment of adults with colorectal cancer whose tumors have progressed after treatment with an oxaliplatin (Eloxatin)-containing regimen. VELOUR, the phase III trial that led to the approval, showed an increase in overall survival for patients who received the new drug. The FOLFIRI and aflibercept arm included 614 patients who were given aflibercept (4 mg/kg) intravenously every 2 weeks; the FOLFIRI and placebo arm included 612 patients. Progression-free survival for patients receiving aflibercept was 6.9 months compared with 4.7 months for those receiving placebo. Patients who were randomized to the aflibercept plus FOLFIRI combination had a median overall survival of 13.5 months compared to 12 months for those receiving FOLFIRI plus placebo.

In July 2012, the FDA approved a new genetic test to determine those patients whose tumors will respond to cetuximab (Erbitux). The therascreen KRAS RGQ PCR Kit can be used to determine whether or not patients with advanced colorectal cancer have a wild-type KRAS gene, indicating eligibility for cetuximab treatment. Simultaneously, cetuximab was given a new indication for first-line treatment in combination with the chemotherapy regimen FOLFIRI for patients with metastatic colorectal cancer who have epidermal growth factor receptor (EGFR)-expressing and KRAS wild-type tumors. The new first-line treatment indication for cetuximab is based on the open-label phase III CRYSTAL trial, conducted outside of the United States. Among patients whose tumors did not harbor KRAS mutations, those treated with cetuximab plus FOLFIRI  (irinotecan, 5-FU, leucovorin) had a median survival of 23.5 months, compared with 19.5 months for those who received only FOLFIRI.

Epidemiology

Gender

Overall, the incidence of CRC and mortality rates are higher in men than in women; tumors of the colon are slightly more frequent in women than in men (1.2:1), whereas rectal carcinomas are more common in men than in women (1.7:1).

Age

The vast majority, 90%, of all new CRC cases occur in individuals older than 50. In the United States, the median age at presentation is 72 years.

Race

The incidence and mortality rates of CRC are higher among African Americans than among whites (15% higher and 40% higher, respectively). The incidence rates among Asian Americans, Hispanics/Latinos, and American Indians/Alaskan natives are lower than those among whites.

Geography

The incidence of CRC is higher in developed regions (the United States, Canada, the Scandinavian countries, northern and western Europe, New Zealand, Australia) and lower in Asia, Africa (among blacks), and South America (except Argentina and Uruguay).

TABLE 1Five-year relative survival rates in colorectal cancer by stage at diagnosis (1995–2005)
Survival

Five-year survival rates (Table 1) for patients with CRC have improved in recent years. This fact may be due to wider surgical resections, modern anesthetic techniques, and improved supportive care. In addition, better preoperative staging and abdominal exploration reveal clinically occult disease and allow treatment to be delivered more accurately. Survival also has improved through the use of adjuvant chemotherapy for colon cancer and neoadjuvant chemoradiation therapy for rectal cancer. Mortality from CRC is decreasing, likely from earlier diagnosis and screening as well as improvements in treatment modalities.

Etiology and Risk Factors

TABLE 2Summary of selected risk factors for colorectal cancer

The specific causes of CRC are unknown, but environmental, nutritional, genetic, and familial factors, as well as preexisting diseases, have been found to be associated with this cancer. A summary of selected risk factors for CRC is shown in Table 2.

Environment

Asians, Africans, and South Americans who emigrate from low-risk areas assume the colon cancer risk of their adopted country, suggesting the importance of environmental factors in CRC. Smoking and alcohol intake (four or more drinks per week) increase the risk of CRC.

Diet

Diets rich in fat and cholesterol have been linked to an increased risk of colorectal tumors. Dietary fat causes endogenous production of secondary bile acids and neutral steroids and increases bacterial degradation and excretion of these acids and steroids, thereby promoting colonic carcinogenesis. Historically, diets rich in cereal fiber or bran and yellow and green vegetables are said to have protective effects, although epidemiologic studies have failed to prove a risk reduction with increased dietary fiber intake. A protective role also has been ascribed to calcium salts and calcium-rich foods, because they decrease colon-cell turnover and reduce the cancer-promoting effects of bile acid and fatty acids.

Physical activity

Several studies have reported a lower risk of CRC in individuals who participate in regular physical activity. High levels of physical activity may decrease the risk by as much as 50%. Being overweight or obese has been consistently associated with a higher risk of CRC.

Inflammatory bowel disease

Patients with inflammatory bowel disease (ulcerative colitis, Crohn's disease) have a higher incidence of CRC. The risk of CRC in patients with ulcerative colitis is associated with the duration of active disease, extent of colitis, development of mucosal dysplasia, and duration of symptoms.

The risk of CRC increases exponentially with the duration of colitis, from approximately 3% in the first decade to 20% in the second decade to more than 30% in the third decade. CRC risk also is increased in patients with Crohn's disease, although to a lesser extent.

Adenomatous polyps

Colorectal tumors develop more often in patients with adenomatous polyps than in those without polyps. There is approximately a 5% probability that carcinoma will be present in an adenoma; the risk correlates with the histology and size of the polyp. The potential for malignant transformation is higher for villous and tubulovillous adenomas than for tubular adenomas. Adenomatous polyps smaller than 1 cm have a slightly greater than 1% chance of being malignant, in comparison with adenomas larger than 2 cm, which have up to a 40% likelihood of malignant transformation if left untreated.

Cancer history

Patients with a history of CRC are at increased risk for a second primary colon cancer or other malignancy. The risk of a second CRC is higher if the first diagnosis was made before age 60.

Prior surgery

Following ureterosigmoidostomy, an increased incidence of colon cancer at or near the suture line has been reported. Cholecystectomy also has been associated with colon cancer in some studies but not in others.

Prior radiation

Prior radiation to the prostate has been associated with a 1.7 relative risk of rectal cancer compared with nonirradiated tissues. In this study, the effect was limited to the irradiated tissues only, not to the rest of the bowel.

TABLE 3Hereditary polyposis syndromes
Family history and genetic factors

Individuals with a first-degree relative with the disease have an increased risk of developing CRC. Those with two or more relatives with the disease make up about 20% of all people with CRC. The risk of developing CRC is significantly increased in several forms of inherited susceptibility (Table 3). About 5% to 10% of all patients with CRC have an inherited susceptibility to the disease. The risks of developing CRC in the subgroups of familial or hereditary CRC vary from 15% in relatives of patients with CRC diagnosed before 45 years of age, through 20% for family members with two first-degree relatives with CRC, to approximately 70% to 95% in patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis CRC (HNPCC).

Familial adenomatous polyposis

FAP is inherited as an autosomal dominant trait with variable penetrance. Patients characteristically develop pancolonic and rectal adenomatous polyps. Approximately 50% of patients with FAP will develop adenomas by 16 years of age, and 95% by age 35. Left untreated, almost 100% of patients with FAP will develop CRC, with an average age at diagnosis ranging from 34 to 43 years. Prophylactic surgery, either total colectomy with ileorectal anastomosis or restorative proctocolectomy with an ileal anal pouch anastomosis, performed in the mid to late teens, is the procedure of choice in this group of patients. The familial adenomatous polyposis coli (APC) gene has been localized to chromosome 5q21. Currently, it is possible to detect mutations in the APC gene in up to 82% of families with FAP. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac (Clinoril, nonspecific COX-1 [cyclooxygenase-1] and COX-2 inhibitor) and celecoxib (Celebrex, COX-2 inhibitor), have been shown to decrease the size and number of adenomas in FAP patients. However, these agents should not be a substitute for surgery. In a small study in pediatric patients, sulindac did not prevent the development of adenomas in APC mutation carriers who had not yet developed polyps at the time of enrollment in the study.

HNPCC is transmitted as an autosomal dominant trait. It is associated with germline mutations in DNA mismatch repair genes (MSH2, MLH1, PMS2, MSH6, and deletions of the 3' region of EPCAM [TACSTD1]). The incidence of a mutated mismatch repair (MMR) gene is approximately 1 in 1,000 people. In 1990 and 1991, the Amsterdam criteria were proposed and published, respectively. These criteria were proposed to identify high-risk families with suspected Lynch syndrome to further study and delineate the syndrome. In 1999, they were revised (Amsterdam II) to recognize extracolonic manifestations as part of the family history. The criteria include the following factors:

• Three or more relatives with a histologically verified HNPCC-associated cancer (colorectal, endometrial, small-bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two (FAP should be excluded)

• CRC involving at least two generations

• One or more CRCs diagnosed before the age of 50

The majority of CRC tumors from HNPCC patients have microsatellite instability (MSI-H). The Bethesda guidelines were developed to test tumors from high-risk individuals for MSI-H, to identify those who are at risk for HNPCC. These criteria are much less restrictive than the Amsterdam criteria and serve to help identify patients at risk for HNPCC who might benefit from further evaluation. They have been modified and include the following:

• CRC diagnosed in a patient who is younger than 50 years

• The presence of synchronous, metachronous CRC or other HNPCC-associated tumors regardless of age

• CRC with MSI-H histology diagnosed in a patient who is younger than 60 years

• CRC diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed in one younger than 50 years

• CRC diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors regardless of age

With newer molecular techniques, mutations in the DNA MMR genes, namely MLH-1, MSH-2, MSH-6, and on rare occasions PMS-2, have been found in as many as 90% of individuals meeting the original Amsterdam criteria, whereas detection of mutations has been lower using the other criteria or guidelines. Because MSI occurs in more than 90% of cases of CRC with Lynch syndrome compared with sporadic cases (in which it occurs in about 15% of colorectal tumors), MSI testing has been used to screen tumors before genetic testing. Immunohistochemistry (IHC) for DNA (MMR) has also been advocated for screening tumors before genetic testing. Both of these methods will not detect all tumors, but they are complementary. In addition to having MSI-H, MSH-6 colorectal tumors may be MSI-L (microsatellite instability low) or MSS (stable). Individuals with absence of protein expression of MSH-2 by IHC and MSI-H tumors where a mutation in the coding region of MSH-2 has not been detected should be tested for germline mutations in epithelial cell adhesion molecule (EPCAM). Deletions in the 3' region of EPCAM cause methylation of the promoter of MSH-2.

Chemoprevention

Chemoprevention aims to block the action of carcinogens on cells before the development of cancer.

Controlled trials of vitamins C and E and calcium have produced mixed results. Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas.

NSAIDs inhibit colorectal carcinogenesis, possibly by reducing endogenous prostaglandin production through COX inhibition. Sulindac has induced regression of large-bowel polyps in patients with FAP. Controlled studies have shown a reduction in the incidence of colorectal polyps with regular, long-term use of aspirin. Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the risk of CRC after extended treatment.

Women who use postmenopausal hormone replacement therapy appear to have a lower rate of CRC than those who do not. Postmenopausal hormones may increase the risk of other types of cancer, however.

Signs and Symptoms

During the early stages of CRC, patients may be asymptomatic or complain of vague abdominal pain and flatulence, which may be attributed to gallbladder or peptic ulcer disease. Minor changes in bowel movements, with or without rectal bleeding, are also seen; they are frequently ignored and/or attributed to hemorrhoids or other benign disorders.

Cancers occurring in the left side of the colon generally cause constipation alternating with diarrhea, abdominal pain, and obstructive symptoms, such as nausea and vomiting.

Right-sided colon lesions produce vague, abdominal aching, unlike the colicky pain seen with obstructive left-sided lesions. Anemia resulting from chronic blood loss, weakness, weight loss, and/or an abdominal mass may also accompany carcinoma of the right side of the colon.

Patients with cancer of the rectum may present with a change in bowel movements; rectal fullness, urgency, or bleeding; and tenesmus.

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