Colorectal cancer screening

Author : Dr Don Rockey Duke University Medical Center Durham

2008-07-28

Overview

Anatomy of colon and rectum. Source: National Cancer Institute

Colorectal cancer is currently the second leading cause of cancer death in the U.S., but is believed to be a highly preventable cancer.  Currently, it is recommended that all (asymptomatic) persons over the age of 50 undergo screening of the colon (and rectum).  Despite the fact that excellent tests for screening are available, the rate of screening varies between 35-65 percent, depending on a multitude of factors.  It is currently believed that the most accurate method of screening is by colonoscopy.  However, this is also the most risky method. New methodologies, including virtual colonoscopy (also known as CT colonography), capsule endoscopy, novel endoscopic methods, and fecal DNA testing offer promise that new approaches will be attractive enough to entice a larger proportion of people to undergo screening. 

Pathogenesis of Colorectal Cancer: How it Develops

Colorectal cancer is believed to develop over many years.  It is currently thought dogma that colorectal cancers develop from a precancerous lesion to full blown cancer.  This generally consists of a scenario in which an abnormal growth of cells develops into a recognizable “polyp.” This small growth then develops into a larger polyp, and eventually a cancer.  In addition, some polyps may develop into flat lesions or growths.  Importantly, there are different types of polyps and their histology varies from hyperplastic to adenomatous (or adenoma).  There are three types of colorectal adenomas: tubular, villous, and tuberovillous.  Hyperplastic polyps have no increased risk of cancer, while adenomas are the precursors of cancer.  The likelihood of malignancy in an adenomatous polyp and the likelihood that it will develop into a cancer depend on its size, histologic type, and degree of dysplasia.  Pictures of polyps are shown in Figure 1.  It is noteworthy that the prevalence of polyps in the general population varies from just several percent to as high as 50% (if hyperplastic polyps are considered), but is usually in the 15-25% range (if only adenomas are considered).  Such variation depends on a multitude of factors, including gender (usually higher in men), cigarette smoking (increases the risk), family history of polyps or colon cancer (increases the risk), diet (a high fiber likely reduces the risk); finally, other unknown factors may be important.

Cancers exist in several stages, depending on their size and whether they have spread (Figure 2).  Extensive research is focused on understanding the basis for the development of cancer, and thus understanding on factors that might affect its prevention.  An extensive body of literature has addressed many variables thought to be important in development of cancer (Table 1).  For example, it is commonly accepted that diets high in fiber protect against colorectal cancer, and that high residue – “Western diets” – predispose to colorectal cancer.  Other variables such as ethnic background (Eastern European descent), race (African Americans have the highest risk of all racial groups in the U.S.), physical inactivity, obesity, cigarette smoking, and diabetes mellitus also are important in risk assessment.  A variety of other factors have been implicated (dietary calcium, etc…) and may also be important.  Some factors, such as physical activity, aspirin, and others may protect against the development of colorectal cancer.

Colorectal Cancer Screening - Getting Started

The bulk of the material found in this knol will deal with people who are at average risk for developing colorectal cancer, though certain categories of people who are at higher risk are described below.
A series of general principles underlying screening of patients for colorectal cancer can be found in Table 2 (adapted from a panel and of the U.S. Multi-society Task Force on Colorectal Cancer, and experts from the American College of Gastroenterology, the American Society of Gastrointestinal Endoscopy, the American Gastroenterological Association, and the American College of Physicians/Society of Internal Medicine). In general, screening programs should begin by considering each person’s level of risk.

Risk Factors

A variety of risk factors for colorectal cancer exists, and these factors are related to individual and familial (hereditary) variables.

For the individual, it is important to realize that underlying disease, particularly inflammatory disease, affecting the colon and rectum consistently increases the risk for development of colorectal cancer. Patients with inflammatory bowel disease that affects the colon and/or rectum (whether ulcerative colitis or Crohn’s disease) substantially increases the risk of cancer. Individuals with these diseases must undergo colorectal cancer screening with colonoscopy within a defined time period after they are found to have inflammatory bowel disease. In patients with pancolitis or after 15 years in those with left-sided colitis, screening surveillance is recommended every one to two years eight years after the disease presents. At the time of surveillance examinations, biopsies are performed, and are usually extensive. Management of patients after biopsy depends on histologic findings, and should be handled on an individual basis, with the assistance of an expert in inflammatory bowel disease.

Another critical individual factor in assessing colorectal cancer risk is whether a person has had a previous cancer or an adenomatous polyp. Either of these increases the risk that the patient will have a subsequent cancer and therefore, specific guidelines have been developed for follow-up of those with either of these previous disorders (see below). The strongest risk factor among those patients who do not have a genetic predisposition to colorectal cancer (see below) is most likely to be age; the older the patient, the greater the risk. A variety of other environmental factors may also play a role (see above and Table 1).

Others at higher risk of colorectal cancer include those with symptoms or signs that are consistent with the presence of colorectal cancer (or polyps). For example, warning symptoms include rectal bleeding (“bright red blood per rectum” or hematochezia), “change in stool habit” (for example a change in stools from their usual size to thinner or abnormally colored stools), weight loss, iron deficiency anemia (see Google knoll site on occult gastrointestinal bleeding), or abdominal pain. These people should immediately have a definitive diagnostic colorectal exam (preferably colonoscopy). Further, any patient who has already had a positive screening test such as a fecal occult blood test is at greater risk for colorectal cancer and should also have a diagnostic colon examination.

Familial Risk Factors

There is now excellent evidence telling us that if a person has a family member who has had colorectal cancer or an adenomatous polyp, then his or her own risk of developing colorectal cancer is increased. This depends in part on what kind of relative had the cancer. For example, in a meta-analysis of 27 studies that assessed familial colon cancer risk, when one first-degree relative was affected with colon cancer, the relative risk (of colon cancer in the index person) was increased to 2.4, meaning that all other factors being equal, that in someone in whom one first-degree relative was affected with colon cancer, that patient is slightly more than twice as likely to be affected with colon cancer. The risk was 4.2 if more than one relative was affected. The risk was 3.8 for relatives if colon cancer was diagnosed before age 45 years, 2.2 if it was diagnosed between ages 45 and 59 years, and 1.8 if the cancer was diagnosed at 59 years or more. Importantly, the risk was also elevated in the setting of a familial member with an adenomatous polyp; the relative risk for colon cancer if the first-degree relative had an adenomatous polyp was 1.9, with age effects similar to those observed for cancer.

Known familial genetic disorders

There are several known familial genetic disorders that raise the risk of colorectal cancer. These include familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). These are each special situations. FAP is an autosomal dominant syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. The average age at which adenomas appear in these patients is 16 years, and the average age at which colorectal cancer is clinically evident is 39 years. These individuals develop multiple adenomas, generally greater than 100. There is also an attenuated (weaker) variant of FAP, termed attenuated APC (AAPC). This syndrome is associated with the development of 20-100 polyps and the onset is approximately 10 years later than classic FAP.

Sigmoidoscopy (see below) is satisfactory to screen most family members with FAP, generally starting in the teens, depending on the age at which the syndrome presented in other family members, but colonoscopy should be used for those with AAPC to be sure the entire large bowel is examined. Screening intervals are extremely abbreviated in patients with FAP or AAPC, and surgical removal of all or part of the colon (colectomy) is considered when polyps are first identified. When someone has FAP, genetic testing is often performed in family members and relatives. This should usually be carried out only by experts and as part of a comprehensive program. It should also be emphasized that patients with FAP are at increased risk of developing adenomatous polyps in other areas of the GI tract (particularly the upper small intestine), and screening of these areas should be considered. A summary of familial risk factors and recommendations for those with increased risk is shown in Table 3.

HNPCC (also called Lynch syndrome) is a familial cancer syndrome inherited in an autosomal dominant pattern. This cancer affects the entire digestive tract, but particularly the colon and rectum. People with HNPCC have an increased risk of cancers not only of the colon and rectum, but also of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women with this disorder also have a greatly increased risk of endometrial and ovarian cancer. Shown in Table 4 are diagnostic criteria for HNPCC. The term “nonpolyposis” is a misnomer because people with HNPCC clearly have an increased risk for development of colon polyps and, as with FAP, they occur at an earlier age than do colon polyps in the general population. Although the polyps do not occur in greater numbers than in the general population, they are more prone to become cancerous. People with HNPCC (either a genetic or clinical diagnosis) or who are at increased risk for HNPCC should have colonoscopy every one to two years beginning at age 20–25 years, or 10 years earlier than the youngest age of colon cancer diagnosis in the family, whichever comes first. As with FAP, genetic testing for HNPCC should be offered to first-degree relatives of persons with a known HNPCC and this should be carried out only by experts and as part of a comprehensive program.

The Average Risk Person - Who Should be Screened?

Patients who are not at increased risk for colon cancer as described above are considered to be of average risk for development of colorectal cancer once they reach the age of 50. Thus, current guidelines are that any individual above the age of 50 be offered screening for colorectal cancer. There are, of course caveats to this recommendation. For example, patients with underlying serious life-threatening diseases may not be good candidates for screening, not only because the screening test itself could harm the patient (such as with colonoscopy), but also because the patient’s outcome may not be affected by the finding of a cancer should it be identified by screening. Thus, it is imperative that patients and physicians discuss screening risks and benefits. The average, otherwise healthy individual should always undergo screening.

Is their an upper age limit for screening?
This has been a specific area of controversy and is reflected by the fact that current guidelines do not provide absolute cutoff values for age. The reason for this is that even though cancer risk increases with age (in fact, age itself is one of the most important risk factors for colon cancer), the decision to recommend screening should be individualized. For example, a healthy 80-year-old patient would be a good candidate for screening, but a 70-year with severe comorbidities may not be. The pros and cons of screening in the elderly must be discussed between the patient and his/her care providers.
 

Screening modalities

A number of professional societies have emphasized the importance of screening for colorectal cancer. As of 2003, the Multi-society Task Force on Colorectal Cancer recommends the following for the average risk individual:

• Fecal occult blood testing (FOBT) annually

• Flexible sigmoidoscopy every 5 years

• FOBT annually plus flexible sigmoidoscopy every 5 years

• Air contrast barium enema every 5 years

• Colonoscopy every 10 years

In 2008, the Multi-society Task Force on Colorectal Cancer revised their recommendations and included the following new tests as screening tests that may be considered effective:

• CT colonography (or virtual colonoscopy)

• Fecal DNA testing

• They considered guaiac based, and immunochemical tests separately

Specific tests are highlighted below.
Fecal occult blood tests (FOBT) annuallyA FOBT is designed to detect blood in the stool by placing a stool sample on a chemically treated pad, card, or wipe. A FOBT may be either guaiac based or immunochemical based (see also the knol on occult gastrointestinal bleeding). The evidence supporting the use of guaiac based FOBTs for colorectal cancer screening is strong. Three large, prospective, very high quality, trials have each demonstrated that screening using FOBTs (guaiac based tests were used in the studies) reduces mortality from colorectal cancer 2-4. Thus, there should be no question that this modality is effective.

Nevertheless, there are a number of important issues to bear in mind. First, in order for any FOBT to be positive, the index lesion must bleed at least enough to be detected by the stool blood test. Thus, the sensitivity of FOBTs varies depending not only on the kind of test used (there are a variety currently available on the market), but also on intrinsic features of the lesion it is meant to detect. In general, the larger the lesion in the colon/rectum, the more sensitive is fecal occult blood testing for detecting the lesion. Thus, FOBTs are better at detecting cancers than detecting polyps. In all primary programs using FOBT, it is recommended that the FOBT testing be performed annually. The other important issue to consider is that the false positive rate of FOBTs is relatively high, meaning many patients with a positive FOBT will not be found to have cancer (or polyps). There are a number of other considerations with FOBTs, including that stool specimens must be collected properly and processed appropriately, and the fact that for guaiac based tests, patients should be on a specific diet.

Recent evidence suggests that immunochemical FOBTs may be highly sensitive and more specific than guaiac-based tests – and these very well may replace guaiac-based tests. It is recommended that patients with a positive FOBT undergo colonoscopy to evaluate the entire colon and rectum.
Flexible sigmoidoscopy

In flexible sigmoidoscopy, the operator inserts a short, flexible, lighted tube into the rectum and slowly guides it into the colon. Typically only the lower half (or descending) colon is viewed. The available evidence supports the position that flexible sigmoidoscopy is effective. At least four case-control studies have reported that flexible sigmoidoscopy was associated with reduced mortality for colorectal cancer.

There are several issues that must be considered with flexible sigmoidoscopy. First, this examination requires a full bowel preparation (cleansing of the bowel prior to the test), similar to that required for colonoscopy (or CT colonography). Second this exam is typically performed without sedation, and thus, it may be uncomfortable. Additionally, it is usually only possible to examine the left side of the colon (and rectum) with this test, and some evidence suggests that flexible sigmoidoscopy may be less accurate than colonoscopy. This is because the quality of the bowel preparation may be suboptimal (often not as good as with colonoscopy), the experience of the examiner may be variable (many different kinds of practioners perform flexible sigmoidoscopy, compared to colonoscopy in which most practioners have been highly trained), and patient discomfort may limit the exam (as above, this exam may be uncomfortable, and thus the endoscopist may not be able to insert the sigmoidoscopy so as to visualize the entire left colon). Finally, patients who are found to have a polyp identified during flexible sigmoidoscopy generally require some form of follow-up. This is because the finding of a polyp on the left side of the colon is thought to identify the patient as someone with an increased risk for a lesion proximally (the transverse and/or right colon). Factors associated with an increased risk of advanced proximal neoplasia (growths) include age over 65 years, villous histology (on analysis of distal polyps), an adenoma greater than 1 cm in size, and multiple distal adenomas. These patients should generally undergo full colonoscopy. An area of controversy exists for polyps less than 1 cm in size identified at the time of flexible sigmoidoscopy. This is because biopsy may or may not be performed. Biopsy is recommended, because it will distinguish hyperplastic from adenomatous polyps. If villous elements or high grade dysplasia (abnormal development) are identified, full colonoscopy is recommended. If histology is hyperplastic, current evidence suggests that the risk of advanced proximal neoplasia in persons with only hyperplastic polyps in the distal colon is comparable to the risk in persons with no distal polyp.
Combined FOBT and flexible sigmoidoscopy

The combination of FOBT and flexible sigmoidoscopy has not been as rigorously studied as the effect of either test alone, but is recommended given the evidence for each individually. Some evidence supports the combination. First, the combination appears to detect a higher frequency of colon cancers than the FOBT alone. Further, large adenomatous polyps are more commonly identified if the combination of the two tests is used than for FOBT alone. When both tests are used to screen for colorectal cancer, FOBT should be performed first because a positive result is an indication for colonoscopy. This would eliminate the need for the flexible sigmoidoscopy examination. A disadvantage of the combined FOBT/flexible sigmoidoscopy strategy is that people incur the inconvenience, cost, and complications of both tests but we do not know definitively the gain in effectiveness.

Air contrast barium enema (ACBE)

An air contrast barium enema is an imaging test, in which x-rays are taken while a barium sulfate contrast solution is infused into the colon. There are little data with which to assess the utility of ACBE as a colorectal cancer screening tool. Nonetheless, we know that the sensitivity of ACBE for polyps (both large and small) is limited. There is good evidence now indicating that CT colonography is more sensitive than ACBE, suggesting that this noninvasive modality might replace ACBE. ACBE does not permit removal of polyps or biopsy of cancers and patients with an abnormal ACBE require subsequent colonoscopy.

Colonoscopy every 10 years

A colonoscopy enables a trained operator to view the entire colon through a long, flexible, lighted tube called a colonoscope or endoscope that is inserted through the rectum and slowly guided into the colon. Although there are no studies that have directly examined whether primary screening colonoscopy reduces the incidence or mortality from colorectal cancer (in average risk persons), some data support the effectiveness of screening colonoscopy. For example, colonoscopy was used in the clinical trials of FOBT screening that showed that screening reduced colorectal cancer mortality. Further, since detection of polyps and colorectal cancer by colonoscopy is as good, if not better than flexible sigmoidoscopy, it is likely that the data from the flexible sigmoidoscopy screening studies is applicable (and of course assumes that the risk from colonoscopy does not far surpass that from flexible sigmoidoscopy). Finally, colonoscopy appears to reduce the incidence of colorectal cancer in people with previous adenomatous polyps. Although colonoscopy permits detection and removal of polyps and biopsy of cancer throughout the colon, it clearly involves greater cost, risk, and inconvenience to the patient than other screening tests, and not all examinations visualize the entire colon. There have also been recent questions about quality of colonoscopy; it is clear that not all colonoscopies are performed equally.

The appropriate interval between screening examinations for average-risk people (if the preceding examination is negative) remains an area of controversy. The current 10-year recommendation has been based on the presumed sensitivity of colonoscopy and the rate at which advanced adenomas develop. Unfortunately, natural history data on not only the development of adenomatous polyps, but also the time required for them to transform into cancer is sorely lacking. The 10-year estimate is just that, an estimate.

Virtual Colonoscopy (see also the Google knol site on this topic)

Virtual colonoscopy, also known as computed tomographic (CT) colonography or CT colography, is one of the newest modalities proposed as a method to screen the colon for cancer. As of 2008, the test requires a cleansing preparation of the colon, followed by the blowing of air into the colon, performing a non-contrasted CT scan, and then reformatting the images so that the reading physician can interpret them. Thus, it is not a virtual test at all. Rather, the preparation is very real, essentially the same at that used for colonoscopy (in fact, CT colonography is probably best done in the screening setting with the ability for the patient to proceed to a colonoscopy should any abnormal findings be identified by the CT colonography). CT colonography is noninvasive and does not appear to cause major complications. However, a limitation of the exam is that if abnormalities are identified, subjects will require (therapeutic) colonoscopy. Additionally, the appropriate interval to use CT colonography as a screening test is unknown.

Fecal DNA

Colorectal cancer is associated with several acquired genetic abnormalities that may be responsible for the transition from normal mucosa to polyp to cancer sequence. Since it is possible to recover analyzable human DNA from the stool, abnormalities can be detected. Several studies have now demonstrated that neoplastic polyps and cancers can be detected by obtaining DNA samples from the stool (the sensitivity appears to be much greater for cancers than polyps). Although in principle, fecal DNA testing makes excellent sense, practical implementation of this test will require further research. Finally, as with CT colonography, the appropriate interval to use fecal DNA testing as a screening test is unknown.

Can a cancer (or polyp) be missed by a screening test?

No method of colorectal cancer screening is infallible. Some tests appear to be more accurate than others and there are many variables that play into misses of polyps or cancers by a screening test. For example, FOBTs may miss a lesion if it happens not to be bleeding at the time the stool sample for testing is collected. Sigmoidoscopy will only detect lesions in the left colon, so right colon lesions can be missed. Even the most accurate test, colonoscopy, may miss polyps and cancers.

Follow-up Testing (surveillance)

Since a personal history of colon cancer and/or adenomatous polyps represents one of the most important risk factors for development of colorectal cancer, it is imperative that once a patient has been found to have a colon cancer or adenomatous polyp, they should undergo ongoing surveillance.

Patients with a history of adenomatous polyps

People with only one or two small adenomas at index (baseline) colonoscopy appear to be at low risk for future development of advanced adenomas. Those with large adenomas (greater than 1 cm), villous features, or multiple adenomas are at increased risk for future development of advanced adenomas and colorectal cancer. Follow-up colonoscopy after polypectomy (polyp removal) in patients with adenomatous polyps has been shown to reduce subsequent cancer incidence. Having said that, the rate of developing adenomas after index colonoscopy and polypectomy is low. The detection rate appears to be similar when colonoscopy is performed one or three years subsequent to index colonoscopy. Follow-up examinations accomplish two major goals. First, they detect and remove adenomas missed on the initial examination. Second, they help determine whether the patient has a tendency to form new adenomas. Interestingly, it is believed that the major benefit of colonoscopy is the index polypectomy; the follow-up colonoscopy may be beneficial primarily in those at highest risk for future advanced adenomas. Thus, there is a critical need for stratification of risk based on index lesions.

A number of special surveillance circumstances exist. One has to do with patients who have poor preparation, which means that the bowel has not been thoroughly cleansed at the time of the colonoscopic examination. These patients should be handled on an individual basis and require judgment on the part of the colonoscopist. For example, if the colonoscopist cannot rule out the possibility of a large adenoma, then a repeat study is warranted sooner (for example within one year). If on the other hand, lesions larger than five mm can be excluded, it is reasonable for the patient to return to a standard surveillance program. The other is the patient with a large adenoma that may not have been removed entirely. These patients generally require a repeat exam within three to six months, particularly if the adenoma has advanced features. Finally, patients with a remote history of adenomatous polyps with an interval normal colonoscopy can usually have a repeat colonoscopic surveillance at a longer interval (five to10 years).

A summary of recommendations for follow-up by the U.S. Multi-society Task Force is shown in Table 5.

Patients with a history of colon cancerThe incidence of colorectal cancer is increased after the index diagnosis (not including recurrence of the original cancer). Since these cancers presumably develop as a result of the polyp-cancer sequence, surveillance should theoretically detect new polyps. It is recommended that patients with a colon cancer that is planned to be resected (removed) for cure should have a colonoscopy at the time of initial diagnosis to rule out synchronous neoplasms. If the colon is obstructed preoperatively, colonoscopy can be performed approximately six months after surgery. In those who have undergone a curative cancer resection, follow-up colonoscopy should be offered after three years and then, if normal, every five years.

New colon cancer screening modalities

A number of new techniques to detect colon cancer are evolving, and will likely change the way we screen for this disease in the future.

Capsule Endoscopy

A small, capsule can be ingested and programmed to examine the colon. The capsule has dual cameras, with a total operating time of approximately 10 hours (including a delay mode of two hours to allow passage through small bowel), wide-angle optics, sensor array, and standard data recorder connected to the patient. It is capable of obtaining high quality images from within the colon (Figure 3), and can detect polyps. Patients must have a colon purge, but the technique is safe and well tolerated. A limitation of the capsule is that if abnormalities are identified, subjects will require (therapeutic) colonoscopy.

Self-propelled endoscope

A self-propelled, self-navigating endoscope (“Aer-O-Scope”; GI View Ltd, Ramat Gan, Israel) has been developed and used to examine humans in pilot studies (Figure 4). This endoscope uses three automated, independent, pressure regulators (computer-controlled) to self propel a balloon tipped endoscope through the colon. At the distal (far) tip of the instrument is a digital camera. Once inserted into the rectum by the operator, the device propels itself proximally to the cecum (a pouch connected to the ascending colon). The exam appears to be comfortable and can be carried out with little or no sedation in a short period of time (average of 14 minutes) and has been shown to reach the cecum in a high proportion of cases. An operator is then able to withdraw the device, capturing images, which are displayed in real time on a monitor (similar to colonoscopy). This technique appears to be safe and well tolerated. A drawback is that it does not allow therapeutic maneuvers (polyp removal) the way a colonoscopy does.

Web Sites

The American Gastroenterological Association - http://www.gastro.org
The National Institute of Diabetes and Digestive and Kidney Diseases -  http://digestive.niddk.nih.gov/ddiseases/a-z.asp
The NIH -- Hereditary nonpolyposis colorectal cancer - http://ghr.nlm.nih.gov/condition=hereditarynonpolyposiscolorectalcancer
The American Cancer society - http://www.cancer.org/docroot/lrn/lrn_0.asp
The Centers for Disease Control - http://www.cdc.gov/cancer/colorectal/

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