Colorectal Cancer-1

Cancer of the colon and rectum (colorectal cancer) affects nearly 160,000 Americans each year, causing approximately 62,070 deaths annually. Colorectal cancer ranks fourth worldwide in cancer occurrence and deaths (Shibuya K et al 2002), though it has a better prognosis than do most cancers. In the general population, the risk of developing colorectal cancer is approximately 19 percent, and it is estimated that 2 percent to 5 percent of sporadic polyps will develop into an invasive cancer (Markowitz AJ et al 1997). Therefore, early detection of colorectal cancer dramatically increases survival (Weir HK et al 2003). For example, 90 percent of patients who receive treatment before the cancer has spread are alive after five years, compared to only 10 percent who survive if the cancer is widespread and treated conventionally (Dashwood RH 1999).

Rate of Occurrence
The lifetime risk of developing colorectal cancer is 4.6 percent for men and 3.2 percent for women (Chu KC et al 1994). Its occurrence is higher in developed countries and in African-Americans versus Caucasians. The peak age of onset of colorectal cancer in the United States is 65 (Khan A et al 2002).

About the Colon and Rectum
Together, the colon and rectum make up the large intestine, which is located in the abdomen and pelvis, and the term “colorectal cancer” refers to cancers of both areas. The function of the colon is storage, concentration, and propulsion of undigested material toward the rectum and anus for the purpose of defecation (i.e., a bowel movement).

A colorectal carcinoma is a malignant (cancerous) new growth that arises from cells in the bowel lining. Carcinomas tend to invade nearby tissue and spread (metastasize) to distant organs such as the liver, lungs, bone, and brain. Adenocarcinoma of the colon and rectum develops in the glands of the intestine’s inner lining (mucosa) and accounts for 95 percent of colorectal cancer cases.

What Causes Colorectal Cancer?

Colorectal cancer develops through a process involving genetic change in the epithelial cells of the colon lining. The main factors that initiate colorectal cancer are consumption of cooked red meat (due to heterocyclic amines) (Gerhardsson de V et al 1991; Reddy S et al 1987), high intake of refined carbohydrates (Franceschi S et al 2001), poor vitamin and mineral intake, alcohol consumption, smoking, bile acids, fecal mutagens (DNA-damaging agents), fecal pH, and compromised detoxification enzymes (Winawer SJ et al 1992). An example of one important detoxification enzyme is N-acetyltransferase, which catalyzes the formation of DNA-damaging products from heterocyclic amines that form in cooked meats. Differences in the activity of this enzyme classify individuals as slow or fast acetylators. The level of red meat consumption in fast but not slow acetylators is associated with risk for colorectal cancer development (Welfare MR et al 1997).

Risk Factors
Individuals at high risk of developing colorectal cancer can be identified by their age (older than 40), genetic factors such as familial polyposis syndromes, hereditary nonpolyposis colon cancer (Boutron MC et al 1995; Grossman S et al 1988), or a personal or family history of colon carcinoma or polyps (Collett JA et al 1999; Foutch PG et al 1991). Other predisposing conditions include inflammatory bowel disease (particularly ulcerative colitis), Crohn’s disease (Karlen P et al 1999), pelvic irradiation (Neugut AI et al 1991), high fasting glucose level, high insulin level, and diabetes mellitus (Ma J et al 1999; Schoen RE et al 1999). Other risk factors include poor diet (Evans RC et al 2002; Martinez ME et al 1999; Russo A et al 1998), lifestyle, lack of exercise (Giovannucci E et al 1996a), tobacco (Lieberman DA et al 2003; Giovannucci E et al 1996b) and alcohol use (Nagata C et al 1999; Giovannucci E et al 1998, 2003), overeating, and nonsteroidal anti-inflammatory drug (NSAID) use.

Alkaline environment. Individuals with a more alkaline stool (i.e., a stool pH of greater than 7.0) have higher rates of colon carcinoma (Malhotra SL et al 1982). This may be because an alkaline environment in the stool maintains higher concentrations of potential carcinogens (substances that increase the risk of cancer) such as free bile acids (McKeown-Eyssen GE et al 1986), which damage the DNA of cells lining the colon.

Controllable Risk Factors

Dietary factors. In industrialized Western societies, both polyps and colon cancer occur more frequently due in part to diets low in fruits, vegetables, vegetable protein, and fiber (Satia-Aboutaj J et al 2003). Fecal mutagens are produced by certain diets such as those containing overcooked or burnt meat or fish. Increased intake of fiber, on the other hand, shortens the intestinal transit time, which in turn reduces the exposure of the colorectal lining to mutagens within the stool (Johansson G et al 1997).

Fat intake. A diet high in saturated animal fat, particularly dairy products and red meat (Jones et al R 2003), increases colorectal cancer risk (Pierre F et al 2003; Stadler J et al 1988). The digestion of fats requires the activity of normal bile acids that irritate and damage cells lining the colon. Consequently, bile acids activate factors associated with abnormal growth of these cells, resulting in an increased risk of colorectal cancer (Glinghammar B et al 1999; Suzuki K et al 1986). The ratio between the secondary bile acid deoxycholic acid and cholic acid may be an indicator of colorectal cancer risk (Kamano T et al 1999). Ingesting a sensible amount of calories and maintaining a desirable weight also play important roles in preventing colorectal cancer (Mason JB 2002).

Red meat intake. The heterocyclic amines when meat is cooked at high temperatures (e.g., by frying) are strongly associated with death from colorectal cancer (Bingham SA et al 1996; Armstrong B et al 1975). People who eat fried, well-cooked red meat more than once weekly are 2.2 times more likely to develop colorectal adenomas than are those who eat lightly browned red meat once a week or less frequently. Dietary beef induces, and dietary rye bran prevents, formation of intestinal polyps (Mutanen M et al 2000).

Folate. Low folate intake, especially when combined with alcohol consumption and a low-protein diet, increases colorectal cancer risk (Kato I et al 1999). Dietary folate influences DNA methylation, synthesis, and repair. Abnormalities in these DNA processes enhance cancer development, particularly in rapidly growing tissues such as the colorectal mucosa (Lengauer C et al 1997; Feinberg AP et al 1983). Higher folate intake from either dietary sources or supplements may protect against the initiation of colorectal cancer (Giovannucci E 2002, 1998).

Selenium. Low levels of selenium correlate with the presence of adenomas (benign tumors), whereas increased levels of selenium are associated with reduced risk of adenomas. Intervention trials have found a beneficial effect of selenium supplementation (Russo MW et al 1997).

Iron. Iron exposure is associated with the development of colorectal polyps (Bird CL et al 1996). Curcumin acts as an iron chelator (i.e., it binds excess iron) and is one of the more successful cancer-preventive compounds investigated in recent years (Jiao Y et al. 2006b).

Genetic Risk Factors
Familial adenomatous polyposis (FAP) is a rare syndrome in prone individuals, involving early onset of multiple polyps and virtually 100% risk of colorectal cancer development (Bussey HJ 1990). This condition is characterized by the presence of 500 to 2500 colon polyps, with a minimum of 100 needed for diagnosis of FAP. The polyps are not present at birth but develop over time.

Polyps of the colon or rectum may be single or multiple growths (adenomas) and are almost always benign (non-cancerous), but can also become pre-cancerous. Polyps usually produce no symptoms, but may cause rectal bleeding, which in turn may cause anemia. Polyps larger than 1 centimeter, or with atypical cells (hyperplastic), have an increased risk of progressing to colon cancer (Liljegren A et al 2003; O'Brien MJ et al 1990).

The cumulative risk of cancer developing in a polyp (if it is not removed) is 2.5 percent at 5 years, 8 percent at 10 years, and 24 percent at 20 years. If removed, the relative risk of developing colon cancer is 2.3 percent (Donovan JM et al 1998; Winawer SJ et al 1993).

Hereditary nonpolyposis colon cancer (HNPCC) accounts for approximately 1 percent to 6 percent of colorectal cancers (Marra G et al 1995). Individuals are at risk of HNPCC when there is a strong family history of colorectal cancer at an early age (averaging 46 years) (Peltomaki P et al 1997). Ninety percent of patients with HNPCC have tumors that show a measurable trait called microsatellite instability (Akiyama Y et al 1997).


Symptoms

Colorectal cancer can cause symptoms such as blood in the stool, changes in normal bowel habits (constipation and/or diarrhea), narrowing of the stool, abdominal pain and distension, anemia, weight loss, and constant fatigue. Individuals who have symptoms should undergo a total colon examination (barium enema or colonoscopy) to look for tumors.

Screening

Screening involves testing asymptomatic individuals to determine whether they have benign polyps or early-stage, surgically curable colorectal cancers.

Colonoscopy has become the established method of evaluating and treating diseases of the large intestine, including diagnosing pre-cancerous growths (polyps) or colon cancer. A colonoscopy uses a flexible tube to examine the entire colon (large intestine) and anal region. Asymptomatic individuals with no history of colorectal cancer should begin colonoscopy screening at 40 years of age and repeat it every five years. If polyps are detected, a colonoscopy should be performed every three years.

If abnormalities are detected during a colonoscopy procedure, such as a polyp or colonic masses, they may be completely removed by small instruments passed through the colonoscope. If bleeding is found in the colon, the physician can pass a laser or electrical probe or inject special medications through the scope to stop the bleeding.

Virtual colonoscopy uses computer-generated images of the colon constructed from data obtained during an abdominal CT (computed tomography) scan. Virtual colonoscopy is not as accurate as a flexible tube colonoscopy, and if suspicious lesions are found, a full colonoscopy should be performed anyway to remove and biopsy the lesion. Virtual colonoscopies also expose the patient to high amounts of radiation. Thus, flexible tube colonoscopy is recommended over virtual colonoscopy.

Screening of High-Risk Groups Includes:
Familial adenomatous polyposis (FAP): Start during adolescence, then colonoscopy after age 24 every 2 years until age 34, then every 3 years until age 44, then revert to general population screening.

Hereditary nonpolyposis colon cancer (HNPCC): Colonoscopy every 1 to 3 years, starting at age 25.

Family or personal history of colorectal cancer or adenomatous polyps: Beginning at age 40; individuals who have a relative with early-onset disease should start 3 to 10 years prior to the age of onset of their relative’s disease.

Inflammatory bowel disease: Colonoscopy after 8 years of disease in cases of pan-colitis or after 15 years with colitis (Provenzale D et al 1995).

Colorectal cancer follow-up: Individuals in whom colorectal cancer has been surgically removed should undergo a complete examination of the colon within 1 year after resection. If the results are normal, the individual can undergo evaluation in 3 years (Winawer SJ et al 1990).


Genetic tests that identify mutated DNA (e.g., adenomatous polyposis coli (APC) gene) in stool samples may significantly improve identification of patients with potentially pre-malignant colon polyps (Doxey BW et al. 2005); Traverso G et al 2002).

What You Have Learned So Far

1)Most colorectal cancers arise from malignant transformation of a benign polyp.

2)Colorectal cancer is initiated by heterocyclic amines from overcooked red meat, poor vitamin and mineral intake, fecal mutagens, and compromised detoxification enzymes.

3)Some types of colorectal cancer (5 percent) are inherited, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC).

4)Early detection of colorectal cancer dramatically increases the effectiveness of treatment and likelihood of survival.

5)A flexible tube colonoscopy should be used to screen for pre-cancerous lesions and colon cancer beginning at age 40, and should be repeated every five years thereafter. If polyps are found, then a colonoscopy should be repeated every three years.

6)Symptoms such as rectal bleeding, bowel problems, abdominal pain and bloating, or iron-deficiency anemia warrant a total examination of the colon.

7)Risk factors for colorectal cancer include poor diet and lifestyle, older age, predisposing conditions such as inflammatory bowel disease (ulcerative colitis), Crohn’s disease, and pelvic irradiation.


Diagnosing Colorectal Cancer
When diagnosing cancer, blood and pieces of tumor tissue are tested to determine the tumor’s growth rate and aggressiveness. In the 10 percent to 15 percent of patients who present with advanced (metastatic) disease, signs and symptoms are usually present. Colorectal cancer can spread locally or distantly via the lymphatic system, leading to enlarged lymph nodes. The cancer usually spreads to the liver, which is detected by an ultrasound (high-frequency sound waves). However, the cancer can also spread to the vertebrae, pelvis, and spine (Giess CS et al 1998), which can be determined by an x-ray or radionuclear bone scan.

Endoscopic ultrasonography, 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET), and a PET/CT hybrid system are the best ways to determine the staging (progression of) colorectal cancer prior to surgery (Dietlein M et al 2003; Kantorova I et al 2003; Kalantzis CH et al 2002).

Cancer Staging
The stage of the cancer (stage 0, I, II, III, or IV, or 0 to 4), or the extent to which cancer has spread from its original site to other parts of the body, is usually determined after surgical treatment and laboratory analysis of the tissue sample removed during surgery. Stage 0 has the best prognosis or outcome, whereas stage IV (4) is the most advanced and thus has a poor prognosis.

The Tumor, Node, Metastasis (TNM) Staging System of Colorectal Cancer
TNM definitions (from the American Joint Committee on Cancer (AJCC) 1977): T = Tumor, N = Node, M = Metastasis (Yarbro JW et al 1999).

T: Primary tumor
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ, 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 tissues
T4: Tumor directly invades other organs or structures and/or perforates visceral peritoneum**

*Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.
**Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa (e.g., invasion of the sigmoid colon by a carcinoma of the cecum).

Regional lymph nodes (N) – at least 12 lymph nodes should be analyzed

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in 1 to 3 regional lymph nodes
N2: Metastasis in 4 or more regional lymph nodes
Distant metastasis (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

Stage 0
Tis, N0, M0

Stage I
T1, N0, M0
T2, N0, M0

Stage II
T3, N0, M0
T4, N0, M0

Stage III
Any T, N1, M0
Any T, N2, M0

Stage IV
Any T, Any N, M1



Tumor Markers
Tumor markers are substances produced by the tumor itself or by the body in response to the presence of cancer, and can be detected in higher-than-normal amounts in the blood of colorectal cancer patients.

Serum tumor markers, including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), alpha-fetoprotein (AFP), and tissue polypeptide-specific antigen (TPS), may be helpful in the early diagnosis of colorectal cancer, in the initial assessment of the extent of the disease (aggressiveness, metastases), and in monitoring tumor growth or regression during treatment (Nakagoe T et al 2003; Yachida S et al 2003; Krauss H et al 2002; Lawicki S et al 2002; Griesenberg D et al 1999). The measurement of CA 125 in patients with normal CEA levels is useful in managing colorectal carcinoma (Mavligit GM et al 2000). Blood tests (complete blood count, or CBC) should be performed to evaluate the presence of anemia or liver dysfunction, both of which can be consequences of the patient’s underlying cancer.

CEA is the most reliable colorectal tumor marker. If a patient’s CEA level is raised prior to surgery and does not decrease to normal levels following surgery, it is an indication that the cancer may recur (Belluco C et al 2000). For patients with stage II or III colorectal cancer who may be candidates for liver resection, and for stage IV advanced cancer patients, CEA levels should be measured every two to three months for at least three years after diagnosis (Duffy MJ et al 2003; Palmqvist R et al 2003). Patients with a CEA level of greater than 5.0 nanograms/ml before surgery have an almost fourfold higher relative risk of recurrence (Carriquiry LA et al 1999).