Colorectal Cancer: Open Access

Keywords

Colorectal; Screening; Colonoscopy

Introduction

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in men and women in the United States. The lifetime risk of dying from CRC in the USA is 2.5%. [1]. Globally, CRC is the third most common cancer in men and the second most common in women, with mortality paralleling incidence. 1.2 million new CRC cases and 608,700 related deaths were estimated to have occurred worldwide in 2008 [2]. Despite being so common, colorectal malignancies pose a significant early diagnostic problems due to wide variety of reasons which include: lack of awareness about risk factors, avoidance of doctor check-ups, fear of getting tested, perception as “man’s disease”, no symptoms/no problem and lack of proper set-up/colonoscopy especially in remote areas. Numerous international CRC screening programs have been initiated as evidence grows for an impact of CRC screening on mortality [3].

Incidence and mortality rates

The lifetime probability of a colorectal cancer diagnosis is 4.7% in women and 5.0% in men. Incidence and mortality rates are 30% to 40% higher in men than in women overall. Nearly 90% of colon cancer patients are over the age of 50.Other risk factors include: family or personal history of colon cancer or polyps, chronic inflammatory bowel disease, hereditary colorectal syndromes, use of cigarettes and other tobacco products, high-fat/low fiber diet and physical inactivity.

Principles of screening

Cancer prevention may be categorized as primary or secondary. Primary prevention refers to identifying genetic, biological, and environmental factors that are etiologic or pathogenetic and subsequently altering their effects on tumor development. Although several areas of study have been identified that can lead to primary prevention of large bowel cancer, available data do not yet provide a firm basis for the practical application of primary preventive measures. The goal of secondary prevention is to identify existing preneoplastic and early neoplastic lesions and to treat them thoroughly and expeditiously. The assumption is that early detection improves prognosis.

Benefits of screening

Colon Polyp to Cancer takes about 10-15 years. The time taken by a sessile polyp to get converted into pedunculated and frank adenocarcinoma is considered as golden period of time for early detection of colorectal malignancies. Even after devolpment of malignancy in the initial stages when the disease is localized the chances of five year survival go as high as 80% and when it has distant metastasis it goes below10% as shown graphically in Figure 1.

Figure 1: Graphical representation showing high chances of 5 year survival in early i.e., localized disease.

Screening Techniques: (Table 1)

Table 1: Screening Techniques.

• Fecal occult blood testing (FOBT).

• Barium enema.

• Flexible sigmoidoscopy.

• Colonoscopy.

• Virtual Colonoscopy.

• Carcinoembryonic antigen and other tumour markers.

• Fecal DNA and Genetic testing.

Fecal occult blood test

For fecal occult blood test three days before and during testing, patients should avoid the following:

For fecal occult blood test three days before and during testing, patients should avoid the following:

• Rare red meat

• Peroxidase-containing vegetables and fruit (e.g., broccoli, turnip, cantaloupe, cauliflower, radish)

• Certain medications (e.g., iron supplements, vitamin C, aspirin and other NSAIDs)

CRCs and adenomas bleed intermittently. Also Hemoccult testing depends on the degree of blood loss. In general, 2 mL of blood in the stool is necessary to produce a positive result. Sampling multiple stool specimens therefore is likely to result in fewer falsenegative evaluations. Sampling one specimen yields a 40% to 50% false-negative rate, which improves progressively as more stools are sampled. Two samples of each of three consecutive (daily) stools should therefore be tested. It should be remembered that in apositive FOBT only 8% will be neoplastic.

Causes of false-positive results:

• Red meat (nonhuman hemoglobin)

• Uncooked fruits and vegetables (vegetable peroxidase: e.g., broccoli, turnip, cantaloupe, cauliflower, radish)

• Any source of GI blood loss (e.g., epistaxis, gingival bleeding, upper GI tract pathology, hemorrhoids)

• Certain medications (e.g., iron supplements, vitamin C, aspirin and other NSAIDs)

• Exogenous peroxidase activity

Causes of false-negative results:

• Storage of slides for a prolonged period

• Degradation of hemoglobin by colonic bacteria

• Ascorbic acid (vitamin C) ingestion

• Improper sampling or developing

• Non-bleeding lesion at the time of stool collection

Air contrast barium enema (ACBE)

If colonoscopy is unavailable, technically difficult, or refused by the patient, ACBE can be done. ACBE traditionally has been performed following sigmoidoscopy. ACBE has been included as an option in a variety of screening guidelines. No studies, however, have directly addressed the effectiveness of barium enema for CRC screening. Several studies have indicated that the sensitivity of ACBE is less than that of colonoscopy, especially for detecting lesions smaller than 1 cm. A population-based study [4] suggested that if a cancer is present, there is approximately a one in five chance that it will be missed by ACBE.

Colonoscopy

Colonoscopy may well be the most effective tool for CRC screening. colonoscopy is preferable to sigmoidoscopy, because there may be a substantial incidence of proximal colonic cancers and advanced adenomas beyond the reach of the sigmoidoscope. Advantages of colonoscopy include its usefulness in detection of >90% polyps and cancer and provides diagnosis and therapy Howevever its limitations includerisks: (Sedation/bleeding/ perforation/infections), limited availability, patient compliance and incomplete visualisation in approx 12%. A Canadian population-based study compared the risk of developing CRC after a negative colonoscopy in all Ontario residents who had a history of a complete negative colonoscopy with controls that consisted of the Ontario population without a history of colonoscopy [5]. In the negative colonoscopy cohort, the relative risk of distal CRC was significantly lower than the control group in each of the 14 years of follow-up, and the relative risk for proximal CRC was significantly lower, mainly during the last 7 years of follow-up. A second Canadian case-control study demonstrated that complete colonoscopy also was associated with fewer deaths from left-sided CRC but not from right-sided cancer [6]. Several other population-based analyses and analyses of individual screening programs in the USA, Canada, and Europe also suggest that increased use of colonoscopy is associated with mortality reduction from CRC, but that this reduction varies by site of the cancer [7-11].

Newer methods in colonoscopy: They have been suggested as a means of identifying lesions in high-risk groups or as an adjunct to colonoscopy where flat lesions (flat adenomas) are suspected. These include high-contrast endoscopy using dye or stain solutions combined with colonoscopy (chromoendoscopy), highresolution optical methods (e.g., narrow-band imaging, laser confocal endoscopy, endocystoscopy) Evidence suggests that flat or depressed neoplasms are more common than previously appreciated and that they carry a high relative risk of containing in situ or invasive carcinoma [12]. Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection, but its usefulness in routine practice has not been established [13].

Virtual colonoscopy

Virtual colonoscopy uses spiral CT to generate 3D images. It requires cleaning of bowel and distension with air. It is noninvasive procedure. It has a sensitivity of 82% and specificity of around 85% [14-16]. However it is not endorsed for CRC screening. Benefits include lower risk of perforating the colon than conventional colonoscopy. Elderly patients, especially those who are frail or ill, will tolerate CT colonography better than conventional colonoscopy. For large tumours with luminal obstruction where scope cannot be negotiated beyond CT colonography will be better for visualizing proximal lesions. It is well tolerated (Sedation and pain relievers are not needed). CT colonography can detect abnormalities outside of the colon, including early-stage malignancies and potentially dangerous conditions, such as abdominal aortic aneurysms and also help in staging of malignancy, if any. However there is a small risk that inflating the colon with air could injure or perforate the bowel and bowel preparation may lead to dehydration and electrolyte imbalance. Also, there is aslight theoretical risk of developing a cancer secondary to radiation exposure. CT colonography is not recommended for pregnant women.

Several key issues need to be addressed as the use of CT colonography becomes more widespread

• Determination of the acceptable size cut-off of a lesion detected by CT colonography that will necessitate a follow-up colonoscopy.

• Need for bowel preparation,

• Ability to detect flat lesions,

• Non therapeutic

• No biopsy will be available

Carcinoembryonic antigen

CEA, may be useful in the preoperative staging and postoperative follow-up of patients with large bowel cancer, but it has a LOW PREDICTIVE VALUE for diagnosis in asymptomatic patients. The relatively low sensitivity and specificity of CEA combine to make it unsuitable for screening large asymptomatic populations.

Stool DNA: Multi-target DNA stool assay required to achieve adequate sensitivity and detect the various gene mutations stool DNA analysis has been recently cleared by FDA for colorectal screening.

Genetic testing

Genetic testing is now a reality for families with FAP. Testing for altered products of the APC gene allows early and accurate identification of family members at risk who require intensive surveillance. Proper genetic counseling, however, must be incorporated into the screening process.

FAP: It presents more difficulty than screening for FAP, because not all the genes involved have been identified, and the preferred method by which families should be screened has yet to be determined.

HNPCC: A generally accepted approach in persons with suspected HNPCC based on clinical criteria is first to perform MSI testing. Germline mutation testing for hMLH1 and hMSH2 is performed if the tumor is MSI-high, suggesting a mutation in an MMR gene. If testing for hMLH1 and hMSH2 is negative, but HNPCC still is strongly suspected, germline testing for hMSH6 can be performed.

Screening Guidelines (Figure 2, Tables 2-14)

Figure 2: Approach to colon cancer testing.

Table 2: Screening guidelines by American cancer society, U.S. Preventve services and task forces and American college of radiology [17].

Table 3: Risk individuals.

Table 4: Screening guidelines for patients with colorectal cancer.

Table 5: Screening guidelines for FAP.

Table 6: Incidence and screening guidelines of associated malignancies in FAP.

Table 7: Screening guidelines for HNPCC.

Table 8: Incidence and screening guidelines of associated malignancies in HNPCC.

Table 9: Screening guidelines and malignancy risk for IBD.

Table 10: Screening guidelines and malignancy risk for Turcot’s Syndrome.

Table 11: Screening guidelines and malignancy risk for Cowden’s Disease.

Table 12: Screening guidelines, clinical features and malignancy risk for Familial Juvenile Polyposis.

Table 13: Screening guidelines, clinical features and malignancy risk for Puetz jeghers syndrome.

Table 14: Screening guidelines, clinical features and malignancy risk for Ruvalcaba-Myhre-Smith Syndrome (Banayan-Zonana Syndrome).

Average risk individuals

No Symptoms, age< 50. no risk factors (Tables 2-14).

High risk groups (Figure 2)

Factors that put an individual at a higher risk for developing colorectal cancer include: age 60 or older, African, American or eastern European ancestry, a personal history of: colorectal cancer, cancer of the ovary, endometrium, or breast, inflammatory bowel disease (ulcerative colitis or Crohn's disease), a family history of colorectal cancer or polyps, a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC).

Familial adenomatous polyposis and familial cancer

Screening should include genetic testing to detect abnormal APC gene products. Those who test positive should have annual or biennial flexible sigmoidoscopy, beginning at age 10 to 12 years, to assess for emergence of adenomas. If genetic testing is unavailable, annual flexible sigmoidoscopy should begin at age 10 to 12 years. Colorectal surveillance (sigmoidoscopy) should begin at age 18 to 20 years in persons with attenuated FAP (AFAP) and in persons with MUTYH mutations (in whom colonoscopy is recommended).

HNPCC

Patients with a family history of HNPCC must be examined colonoscopically, beginning at age 20 to 25 years, or at an age 10 years younger than that of the index case. A reasonable approach here is to perform colonoscopy every two years, searching for the scattered adenomas that antedate carcinomas in HNPCC; Genetic testing for HNPCC should be offered to first-degree relatives of those with a known MMR gene mutation or to those who meet the modified Bethesda criteria.

Familial CRC

The joint guidelines from the ACS recommend that ifCRC or adenomatous polyps occurred in any first-degree relative before age 60 years, in two or more first-degree relatives at any age, then colonoscopy should be performed every five years, beginning at age 40 years or beginning 10 years before the youngest case in the immediate family.

If either CRC or adenomatous polyps occurred in a first-degree relative 60 years of age or older, or if CRC occurred in two seconddegree relatives, then screening should begin at age 40 years using screening options recommended for average-risk persons. In those with more than two affected first-degree relatives, special care should be taken to exclude HNPCC, and periodic colonoscopy is advised. A recently published guidance statement from the American College of Physicians also recommends that clinicians stop screening for CRC in adults older than age 75 or in adults with a life expectancy of less than 10 years [17].

The European Guidelines for Quality Assurance in Colorectal Screening and Diagnosis is a 386-page document authored by 90 authors from 32 countries that providesan evidence-based review of existing data on CRC screening that stresses quality measures and cost-effectiveness.

HNPCC

Genetic or clinical diagnosis of HNPCC or persons at increased risk of HNPCC Age 20 to 25 yr or 10 yr before the youngest case in the immediate family Colonoscopy every 1 to 2 yr and counseling to consider genetic testing Genetic testing for HNPCC should be offered to first-degree relatives of persons with a known inherited DNA MMR gene mutation. It should also be offered when the family mutation is not known but when 1 or more of the first 3 of the modified Bethesda Criteria is present [18].

Conclusion

We should remember that time taken by a sessile polyp to get converted into pedunculated and frank adenocarcinoma is considered as golden period of time for early detection of colorectal malignancies. Even after development of malignancy in the initial stages when the disease is localized the chances of five year survival go as high as 80% and when it has distant metastasis it goes below 10% Awareness among public regarding risk factors/ symptoms using print/electronic/mass media and through national programmes, allaying discomfort or embarrassment with screening procedures, Proper infrastructure including colonoscopy labs, strategies for engaging and adequately resourcing both primary and secondary care services, proper screening and follow up of diagnosed patients including family members if indicated, are of utmost importance in colorectal screening.

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