by: W. Alan Harmon, M.D., F.A.C.P.
In 2009, there were an estimated 147,000 new cases of colorectal cancer (CRC) in the United States and 50,000 related deaths. Colorectal cancer (CRC) is the third leading cause of cancer in the United States and is second only to lung cancer as a cause of cancer death in the United States (1,2). It accounts for 9% of all new cancer diagnoses and 11% of all cancer deaths. Not all individuals are at equal risk. A person with a first degree relative with CRC has an 8% lifetime CRC risk, but with two first-degree relatives the risk increases to 17%. Various racial and geographic factors also contribute to the risk. African Americans have the highest incidence of CRC of any racial or ethnic group (3-7). The reasons for higher rates of CRC in African Americans are unclear, however, nutritional factors and an increased incidence of obesity may contribute (8-13). Also implicated are higher rates of smoking and lower rates of access to healthcare.
Removal of adenomas has been demonstrated to be associated with a 76 to 90% reduction in the number of expected CRC cases. Five year CRC survival is 90% if the disease is diagnosed while still localized to the bowel wall, but decreases to 68% if lymph nodes are involved and is only 10% in cases of distant metastasis (14). Still a majority of US adults are not receiving regular age and risk appropriate colon cancer screening or have never been screened (15,16).
This review presents the available colon cancer screening strategies available based in part on the 2008 joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (1). It also references the 2008 American College of Gastroenterology colon cancer screening guidelines.
Screening tests for the detection of CRC
Stool based tests for fecal occult blood fall into two primary categories: guaiac based fecal occult blood test (gFOBT) and fecal immunochemical testing (FIT). Blood in the stool is a nonspecific finding but may originate from advanced polyps or CRC. As advanced polyps and CRC may bleed intermittently it is recommended to obtain 2-3 samples depending on the product used. In all cases of a positive gFOBT or FIT a diagnostic workup with a colonoscopy would be required to rule out the presence of an advanced polyp or CRC (17,18,19). The gFOBT detects blood in the stool through pseudoperoxidase activity of heme or hemoglobin while immunochemical tests react with human globin. In most cases it is recommended to avoid aspirin, nonsteroidal anti-inflammatory drugs and red meat for a 3 day period as these may result in false positive results. On the other hand, the ingestion of vitamin C may result in false negative results on gFOBT. Three large, randomized controlled trials with gFOBT demonstrated that screened patients had CRC detected at an earlier and more curable stage than unscreened patients with CRC mortality rate reductions from 15-33% (20-22). There is also variation in the sensitivity of gFOBT with hemoccult II having lower sensitivity than hemoccult SENSA which has higher sensitivity. In office screening using a digital rectal exam had a sensitivity of 4.9% for advanced adenoma and 9% for cancer and thus is NOT recommended as a screening method. FIT detects human globin so is more specific for human blood than gFOBT. It does not require any dietary restrictions and is less demanding on patients as many types require only two samples.
A new method of CRC screening known as stool based DNA (sDNA) relies on known DNA alterations in the adenoma-carcinoma sequence to detect CRC at an earlier stage. No single gene mutation is present in all cells shed by advanced adenomas or CRC. For that reason a multitarget stool assay has been developed which checks for 21 point mutations in K-ras, APC, P53 genes with a probe for BAT-26 (marker for microsatellite instability) (24,25). The currently available sDNA (version 1.1) test requires an entire stool specimen 30 gram minimum weight. In one recent study, the sensitivity for CRC was reported to be 70% using sDNA version 1.1 (24). Several limitations exist with sDNA testing. It is significantly more expansive than existing forms of stool based testing. The exact interval of sDNA testing has not been established, however, the American College of Gastroenterology in their 2008 guideline for colorectal cancer screening recommended performing sDNA every 3 years if that was the chosen method of CRC screening (26). Other concerns with sDNA testing include what should be done in cases in which the sDNA test is abnormal, however, colonoscopy does not reveal either a CRC or advanced adenoma in the colon. It is possible that the sDNA may be detecting supracolonic aerodigestive cancers (esophagus, stomach, pancreatic, biliary, small bowel) (26) and that some form of further testing, such as upper endoscopy or potentially abdominal imaging would be needed.
Tests for the detection of adenomas and CRC
Flexible Sigmoidoscopy (FSIG) is an endoscopic procedure that examines the lower half of the colon with a satisifactory exam defined in part as one that reaches at least to 40 cm proximal to the anal verge (1). In two case control studies, FSIG was associated with a 60-80% reduction in CRC mortality for the area of the colon within its reach with a protective affect extending out to 10 years or more (28,29). The detection of an adenomatous polyp on FSIG mandates that a full colonoscopy be performed to screen the proximal colon and rule out other synchronous lesions. Potential advantages of FSIG over colonoscopy include the ability to perform the exam in an office setting without sedation and a lower risk of colon perforation. Concerns exist about the possibility of missed lesions on the right side of the colon particularly in populations that have been reported to have a higher incidence of right sided advanced adenomas such as women and African Americans (30-32). Current guidelines recommend that FSIG be performed every 5 years (26).
Double Contrast Barium Enema (DCBE) evaluates the colon in its entirety by coating the mucosal surface with high-density barium and distending the colon with air. DCBE will detect most cancers and a majority of advanced polyps (1) with a perforation rate that is lower compared with colonoscopy (1:25,000 versus 1: 1,000-2,000) (34). It’s limitations include an extensive colon preparation with some discomfort as air is insufflated in the colon. The is no opportunity to perform either polypectomy or mucosal biopsy. The National Polyp Study suggested that DCBE finds fewer than 50% of the polyps detected by colonoscopy and that specificity of DCBE is poor with 18% false-positives (33). It is recommended that any patient with a polyp > 6 mm on DCBE should undergo colonoscopy. Current guidelines recommend that DCBE be performed every 5 years (1).
CT colonography (CTC) or Virtual Colonoscopy is a promising new tool. It uses a helical CT scanner with a special software package to construct 2-dimensional and 3-dimensional images of the colon. Adequate bowel preparation and gaseous distention of the colon are essential to a successful exam. Typically the preparation is similar to optical colonoscopy with the addition of barium to tag residual stool. The colon is insufflated using CO2 and a small caliber rectal catheter. CTC has the advantage of having no required sedation nor is a chaperone required. Currently 47 states offer medicare reimbursement for diagnostic CTC where the indication is incomplete optical colonoscopy (35). There remains concerns about the ability of CTC to detect flat lesions or lesions <6 mm in size. There also is a concern about the cumulative effect of ionizing radiation with repeated CT colonography (still it should be noted that CT colonography involves significantly less radiation exposure than would a traditional CT of the abdomen and pelvis). Finally, it is unclear how the affects of extracolonic findings will impact patients and the ultimate cost effectiveness of the technology.
Colonoscopy is one of the most commonly performed medical procedures in the United States and allows for direct mucosal inspection of the entire length of the colon including the terminal ileum in selected cases. One of the most attractive features of colonoscopy is the ability to have same session biopsy sampling, polypectomy and in some cases definitive therapy of early colon cancers that are contained within polyps (malignant polyp). The colon preparation is often difficult for patients but critical to the ability of the endoscopist to find and remove polyps or identify other mucosal abnormalities. In most cases it is not necessary to stop aspirin, or non-steroidal anti-inflammatory medications prior to the procedure. In the National Polyp Study, the incidence of CRC after a clearing colonoscopy was reduced by 76-90% compared with three reference populations (36). Colonoscopy does have several limitations. The performance of the procedure is operator-skill dependent. The current reimbursement system for colonoscopy does not reward careful examination but tends to reward rapidly performed exams that may be at unnecessarily short intervals (37). Colonoscopy is not infallible. Controlled studies have shown colonoscopy miss rates for 10 mm adenomas to be 6%-12% and colonoscopy miss rates for CRC to be 5% (38-40). Harms of colonoscopy include post-polypectomy bleeding which is more common in large polyps and those located in the proximal colon. There is also a reported risk of perforation (increases with age and the presence of diverticular disease) estimated to be 1:500 in the medicare population and 1:1000 in screened patients overall (41). Cardiopulmonary complications of colonoscopy include cardiac arrhythmias, hypotension and oxygen desaturation. These complications represent about half of all complications during colonoscopy and most are related to sedation (42).
Today’s Screening Guidelines
Death from CRC is largely preventable with age and risk appropriate colon cancer screening. In those who elect colonoscopy as their screening method, asymptomatic individuals with no risk factors for colon cancer should undergo colonoscopy starting at age 50 years and have the exam repeated every 10 years. In the African American population, screening for CRC should begin at the age of 45 years due to increased rates of CRC and advanced polyps at earlier ages (26). For those found to have small hyperplastic polyps, patients should be screened at intervals identical to those considered average risk. In the case of one or two adenomas <10 mm in size with low grade dysplasia (no high grade dysplasia or villous histology) colonoscopy should be repeated in 5-10 years (43). If 3-10 adenomas are present or one adenoma > 1 cm in size or with villous features or high grade dysplasia is present then colonoscopy should be performed 3 years after the initial polypectomy (43). If there are greater than 10 adenomas on a single exam, colonoscopy should be repeated <3 years after the initial polypectomy (43). In the case of sessile adenomas that are removed piecemeal, a repeat colonoscopy should be done in 2 to 6 months to verify complete resection (43).
In the case of a patient who develops colon or rectal cancer, a high quality perioperative clearing colonoscopy should be performed 3 to 6 months after cancer resection as long as no unresectable metastasis are found during surgery; alternatively colonoscopy can be performed intraoperatively (44). In patients who have undergone a clearing colonoscopy during the perioperative period with curative resection for colon or rectal cancer, colonoscopy should be performed 1 year after resection (14). If the colonoscopy performed at one year is normal, then the interval before the next examination should be 3 years. If the colonoscopy at 3 years is normal, the patient should have the subsequent exam performed in 5 years repeating every 5 years thereafter. If there is evidence of hereditary non-polyposis colon cancer syndrome or if there are adenomas detected during interval colonoscopy, the interval between colonoscopy may need to be more frequent (14).
In patients with a family history of colorectal cancer or adenomatous polyps in a first-degree relative prior to the age of 60 years or in 2 first degree relatives of any age, colonoscopy should begin at age 40 (or 10 years younger than the earliest case noted in a first degree relative) and be repeated every 5 years (18) . In patients with a family history of colorectal cancer or adenomatous polyps in a first degree relative > 60 or in 2 second degree relatives with colorectal cancer, colonoscopy should begin at age 40 and be repeated every 10 years (18).
Conclusion
There is compelling evidence to support screening average-risk individuals over age 50 years to detect and prevent CRC (1). Screening of average-risk individuals can reduce CRC mortality by detecting cancer at an early, more curable stage and by detecting and removing clinically significant adenomas. Each of the recommended forms of CRC screening discussed above has unique advantages and limitations and each is believed to be cost-effective (45-48). Patient preferences and availability of resources play an important role in the selection of screening tests.
In the future, based on different incidence rates and different patterns of polyp and cancer distribution in the elderly, women, and African Americans it is possible that different screening recommendations will be made for each group (49,50). Already the American College of Gastroenterology recommends screening average risk African Americans at the age of 45 years. Future research is likely to address whether CRC incidence and mortality in these higher risk groups would be positively impacted by tailored screening recommendations.
American College of Gastroenterology 2008 CRC screening recommendations (summary)
Average Risk: The preferred CRC prevention test is colonoscopy every 10 years, beginning at age 50. Screening should begin at age 45 years in African Americans.
High Risk:
- Personal history of Adenomatous Polyps
- Personal history of Colon Cancer
- Family history of Colon Cancer (1st degree relative)
The preferred interval for colonoscopy for High Risk patients is every 3- 5 years once there is a normal colonoscopy examination.
Alternative CRC prevention tests:
- Flexible sigmoidoscopy every 5 - 10 years
- CT colonography every 5 years
- The preferred cancer detection test is the annual FIT for blood. FIT annual fecal immunochemical testing for human globin (no dietary restrictions, requires 2 samples).
- Annual Hemoccult Sensa, requires 3 samples.
- Fecal DNA testing every 3 years
Colon Cancer Screening Programs as currently recommended still fail to detect Colon cancer development in approximately one per 1,000 patients. For that reason suspicious symptoms or signs of bleeding should be investigated immediately regardless of last screening interval.
Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, Pickhardt P, Rex DK, Thorson A, Winawer SJ; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008 May-Jun;58(3):130-60
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