Higher Quality Screening Colonoscopies Associated With Lower Risk of Colorectal Cancer Death, Without Higher Overall Costs

JAMA: An analysis that included information from more than 57,000 screening colonoscopies suggests that higher adenoma detection rates may be associated with up to 50 percent to 60 percent lower lifetime colorectal cancer incidence and death without higher overall costs, despite a higher number of colonoscopies and potential complications, according to a study in the June 16 issue of JAMA.

Virtual colonoscopy not recommended by US experts

Berkeley: You may have heard of “virtual” (or CT) colonoscopy. Many people are attracted to the idea because they dread the invasiveness of being “scoped.” With virtual colonoscopy, no colonoscope is inserted. Instead, the colon is visualized by a CT scan. It may sound like a great alternative, but it really isn’t.
Studies on virtual colonoscopy have had some promising results. One in the New England Journal of Medicine in 2008, for instance, found that the test is good at identifying larger polyps and cancer in people at average risk.

Normal colonoscopy (video)

Author: Dr Brian Fennerty Oregon Health and Science University 2008-03-13

Normal colonoscopy: a couple of small diverticuli (small cave like holes) are seen on the way in

Colonoscopy with diverticulosis and a polyp (video)

 Author: Dr Brian Fennerty Oregon Health and Science University 2008-03-13

Colonoscopy with diverticulosis and a polyp: Small colon polyp (redish bump) and many diverticuli (small outpouches in wall of the colon).

Virtual colonoscopy

Author : Dr Don Rockey Duke University Medical Center Durham

2008-07-28

Polyp with virtual colonoscopy. Source: National Cancer Institute

Introduction

    Colon cancer is one of the most common cancers in the U.S. and the world; in the U.S. colon cancer accounts for approximately 150,000 new cases and 50,000 deaths/year.  Colon cancer is largely preventable, since it goes through predictable progression from early polyp to invasive cancer.  Therefore, screening is essential.  A number of screening strategies have been proposed (see the “Colon Cancer Screening” knoll).  Each of the screening strategies currently in use has advantages and disadvantages.  For example, screening stool for occult blood (“Fecal occult blood testing”) is noninvasive and inexpensive, but is not as accurate as colonoscopy, which on the other hand is more invasive and expensive. Because of these kinds of issues, there has been tremendous interest in finding alternatives methods to screen the colon.

    Among these potential alternatives, the one that has gained the most favor is computed tomographic colonography, (also CT colonography or virtual colonoscopy).  This Knol will describe the technique of virtual colonoscopy and some of the advantages and disadvantages of it.   Whatever method that patients choose for screening, the most important issue is that tens of thousands of lives are lost unnecessarily each year because people who could benefit from screening fail to receive it.

What is CT colonography (also virtual colonoscopy)?

    This technique was first proposed as a method to evaluate the colon for polyps in the 1980s, but the field remained quiet until the mid-1990s.  However, over the last decade the field has expanded remarkably.  Fundamentally, CT colonography involves performing an abdominal CT scan of the colon – with several caveats.  A typical CT scan of the abdomen (see http://www.mayoclinic.com/health/ct-scan/FL00065 for general information about CT scans) is usually performed with contrast (both oral and IV) and provides excellent detail of the abdominal organs.  In comparison, CT colonography consists of a non-contrasted  exam focused on the colon. 

    As of 2008, CT colonography requires a full bowel preparation; patients must cleanse the colon in a process that is essentially the same as that used prior to a colonoscopy.  Next, air is blown into the colon, the CT scan is performed, and then the images are reformatted so that the reading physician can interpret them.  Thus, it is not a “virtual test” at all.  Rather, the preparation is very real, (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).

    In more detail, after the bowel preparation, the colon is filled with air, and then CT scanning of the abdomen and pelvis, typically during a single breath hold, is performed.  This is typically done in both the prone (face down) and supine (face up) positions and two-dimensional axial images are captured.  There are many variations in the way the CT is performed (variations in collimation (alignment), slice thickness, reconstruction interval, table speed, acquisition time, and radiation dose).  Regardless of the variation, captured images are then downloaded to a workstation that is equipped with software programs that allow a range of data manipulations, including multiplanar reformation, two- and three-dimensional rendering, virtual dissection, and computer aided diagnosis.  An example of the kinds of abnormalities that can be identified by CT colonography is shown in Figure 1.  Although variations in hardware, software, and general technique abound, efforts are being made to standardize the methodology.

    A major attraction of CT colonography is that it is relatively non-invasive and safe (although there are growing concerns about radiation exposure) and is relatively simple for patients to do.  Nevertheless, most patients complain about the preparation, and the filling of the colon with air.  One of the major drawbacks of CT colonography is that if a polyp or other problem is identified, then the patient will have to undergo a definitive test, namely colonoscopy, to take biopsies or to remove polyps.  Nonetheless, CT colonography is less invasive than colonoscopy and represents an important consideration when considering the large number of patients that are currently not being offered or avoid a colon cancer screening test.

    As the medical community considers incorporating CT colonography as a regular item on the menu of screening options, a variety of issues are of critical importance, including the sensitivity and specificity of the test, the patient experience, management of extracolonic lesions, and advances in colon preparation.  There are also many new issues related to training.  It is clear that CT colonography has great promise, but also that many questions about its use remain. 

How accurate is CT colonography?

    Since the introduction of CT colonography, a major endeavor in the field has been to investigate its sensitivity.  Early reports typically involved smaller populations at high risk for colorectal pathology and used comparatively slow technology (single-row scanners).  Later studies generally demonstrated improved detection sensitivity for polyps, but continued to have wide variation in results.  A number of single center studies demonstrated extremely high sensitivities that were in fact too good to be true. Subsequently, a series of large and well conducted (and well-publicized multicenter trials) reported variable results. 

    As of 2008, several facts about CT colonography have become apparent.  First, the technology has advanced considerably and could be considered “mature.”  Further refinements are expected, although these are not expected to change the general conduct of the procedure.

    Second, the ability of CT colonography to detect abnormalities appears to be proportional to their size.  A major goal of CT colonography is to detect polyps (believed to be precursors of colon cancer), and CT colonography is best at identifying large polyps (those greater than 10 mm in size).  The reported sensitivity for detecting polyps at this size is from 50% to above 90%.  Recent studies suggest that the accuracy is likely closer to the 90% figure. CT colonography is not as good as at detecting polyps that are smaller; in the 6-9 mm size range, it will likely detect approximately 70% of polyps.  At 5 mm or less, the data indicate that CT colonography is not very accurate, and the sensitivity for polyp detection is likely to be below 50%.  By comparison, colonoscopy appears to be more sensitive at detecting polyps, particularly the smaller ones. 
Third, not everyone who reads CT colonography is equal.  This is perhaps not surprising, since in essentially all walks of life, there is variability in skill with which people perform (see below under “training”).  Thus, it is essential that any practioner recommending this test or any patient having it done understand how much training and experience their physician has in reading the test.

Bowel preparation

    A major drawback of the current modalities used to examine the colon is the requirement for cathartic cleansing of the bowel.  This is true not only for CT colonography, but also for colonoscopy, and air contrast barium enema.  In several studies of CT colonography, this has been identified as one of the most poorly tolerated aspects of the test.  Thus, any test that would allow a high quality examination of the colon without this type of preparation would be highly attractive.  With CT colonography, it may be possible to use a minimal preparation that does not require full bowel catharsis.

Extracolonic lesions

    Because the entire abdomen and pelvis are scanned during a CT colonography examination, the test can readily detect lesions outside the colon, which may be a major advantage to the test.  Many studies have reported the identification of calcifications, gallstones, hernias, bone lesions, abdominal aortic aneurysms, benign, and even malignant tumors.  It has been suggested that CT colonography may be most beneficial in elderly patients who are at greatest risk for cancers or other more prominent abnormalities.  While it is clear that CT colonography is able to detect many lesions outside of the colon, further research is needed in order to understand which of these findings should be further evaluated, as well as how much cost is added to the evaluation when these are pursued. 

Patient experience and acceptability

    Several studies have examined patient experience with and preference for colon imaging procedures.  The most unpleasant aspects of all colon imaging tests include the preparation for the test, which usually involves cleansing or purging the colon, and the act of performing the test, which usually involves distension of the colon.  With CT colonography, air (or CO2) is typically blown into the colon to allow better visualization of structures.  This causes discomfort.  Some programs use CO2, which is more rapidly dissolved than air, and thus may be less uncomfortable.  One difference between CT colonography and colonoscopy is that during the latter patients typically have moderate sedation, which involves administration of sedative, amnestic, and pain-relieving medications; patients undergoing CT colonography do not require any medication (although some physicians prefer to give anti-spasmodic agents).

    In studies comparing colonoscopy and CT colonography, the data are mixed.  Some studies have demonstrated that patients have a strong preference for CT colonography, while others indicate that the majority of patients prefer colonoscopy (the preferences are usually related to the degree of discomfort caused by the test).  Interestingly, patients appear to prefer either CT colonography or colonoscopy over other examinations of the colon such as air contrast barium enema or flexible sigmoidoscopy.  Notwithstanding, how CT colonography is perceived and tolerated by patients will clearly play an important role in its use for follow-up examinations.

Safety

    It appears that CT colonography is relatively safe.  There is a small risk of perforation of the bowel (due to colon distension); the reported risk in large series of patients appears to be somewhere in the range of one in 1,000 to one in 2,000.  Importantly, perforations have typically been seen in patients with underlying colon abnormalities.  For example, patients with inflammatory bowel disease affecting the colon may have friable mucosa or ulcerations, either of which could tear if stressed.  The other situation in which perforation may be more common is after colonoscopy with polypectomy is performed, because the polypectomy may cause small defect in the colon mucosa. 

    A further important safety concern centers on the risk of radiation (see Table 1).  A routine CT scan of the abdomen delivers in the neighborhood of 10-15 millisieverts (mSv) - with an average of two CT scans per study.  Estimating risk to the individual based on this radiation dose, however, is difficult. Most of the quantitative estimates of the radiation-induced cancer risk come from analyses of atomic-bomb survivors, who are thought to have received a dose of radiation in the area of 40 mSv (the risk of cancer is clearly elevated in these subjects).  Other data about radiation risk comes from study of radiation workers in the nuclear industry.  The radiation dose in these subjects has been estimated to be approximately 20 mSv, again in the range of a routine CT scan.  Again, these radiation workers are at increased risk for developing radiation related malignancy. 

    Whether these risk scenarios are applicable to the radiation dose for CT colonography remains open given obvious differences in total dose, the timing interval over which radiation is administered, life-time accrual of radiation risk (in an adult older than 50 years old vs. in younger age), physical area of radiation exposure (abdomen only vs. full body or bone marrow, lungs), and other factors.  At this time, it is not clear that the radiation dose received with a standard CT colonography exam will be associated with an increased risk of cancer.  Moving forward, it is clear that a major area of investigation will be lowering radiation doses (and this appears to be highly feasible). 

New technology

    New technology in the CT colonography field is exploding.  CT scanners have now reached a level at which the exam can be performed rapidly and protocols are being developed that may allow relatively low radiation doses.  New image display techniques are evolving.  The addition of computer-aided diagnosis (CAD) is of particular interest, but there are many other areas of importance, including integration of differing types of data input into single reader platforms (i.e. an “all in one” platform).

Training

    It is becoming clearer that specific training is required in order for readers to accurately read CT colonography.  The exam is not necessarily easy to interpret and reading the exam appears to be more intuitive for some than others.  Data continue to emerge about how much training is required, and whether individuals with different types of backgrounds can be adequately trained to read CT colonography.  For example, while formally trained radiology experts have taken the lead in reading and training of CT colonography, it is likely that other groups will be able to adequately read the study.  Regardless of who reads the test, it will be essential that they have had adequate training.  Finally, regardless of who could or should read the exams, currently there is a general consensus that there is a lack of adequately trained readers. 

Implementation

    One of the most important areas of concern is that if it is agreed that CT colonography is a viable option for mass colon cancer screening, then how will it be implemented in clinical practice?  For example, although it represents an attractive alternative method for colon cancer screening, it is unknown whether offering CT colonography in a menu of “competing screening strategies” will truly enhance compliance. It is not known whether patients will embrace the technology and procedure, or whether concerns about radiation safety may make it unpopular.  Additionally, CT scanners are prevalent in the US, but are there enough to carry out large numbers of CT colonographic exams?

     Another major issue has to do with whether and how to report lesions identified at the time of CT colonography.  Some have advocated that small lesions (less than 5 or 6 mm) are not clinically meaningful, and that they should not be reported.  From a scientific standpoint, this may be reasonable, but there are problems with this approach.  First, it is unclear whether patients (or their physicians for that matter) will accept this approach.  We also don’t know enough about the natural history of polyps to understand whether we can really leave polyps in place and simply observe them – as would be required in a scheme in which smaller polyps might be ignored.

    Another important issue is whether there are enough skilled readers to perform enough CT colonography exams to help screen a large fraction of the population at risk (generally asymptomatic patients over the age of 50; patients with specific symptoms or those with additional risk factors should likely undergo expedited colonoscopy).  If enough readers can be trained, and CT colonography is able to incrementally increase the number of patients screened, then it would represent a very important tool in the effort to screen the population for colon cancer.  

How important are polyps?

    Since an objective of CT colonography is to detect polyps, an important consideration is: exactly how important are polyps?  Current thinking is that cancer arises through a sequential growth sequence in which a small polyp forms in the mucosa of the bowel, and this grows into a larger polyp, which ultimately grows into a cancer of the colon.  Most experts believe that the recent reduction in colon cancer deaths in the U.S. is due to an overall increase in the detection and removal of polyps (by colonoscopy) before they have had the opportunity to become cancers.

Who should have it?

    As of 2008, agreed upon indications for CT colonography are for completion of the colon exam in patients who have had a colonoscopy that failed to examine the entire colon.  This usually occurs when the colon is so difficult to move the scope through that the colonoscopist cannot examine the entire colon or when the patient is not able to tolerate the colonoscopy exam due to discomfort. CT colonography is being used to screen the colon for cancer in some patients, though as of 2008, most insurance plans do not cover the test.  It is expected that this will likely change as new data emerge about how the test is best performed.  Risks and benefits of CT colonography are summarized in Table 2.

Summary

CT colonography is a powerful new adjunct in the field of colon imaging.  It appears to be safe and reasonably well tolerated by patients.  Radiation exposure is an important consideration that must be assessed further before the test is widely implemented.   Whether CT colonography is ready for a regular place at the table in the colon cancer screening menu is unclear as of 2008, but it appears that major national societies are poised to make recommendations that take CT colonography into consideration.  For those physicians and patients willing to embrace this new and exciting technology, it is imperative to understand the multiple issues surrounding its use.  

Selected References

1.    Coin CG, Wollett FC, Coin JT, Rowland M, DeRamos RK, Dandrea R. Computerized radiology of the colon: a potential screening technique. Comput Radiol 1983;7:215-21.
2.    Vining DJ. Virtual endoscopy flies viewer through the body. Diagn Imaging (San Franc) 1996;18:127-9.
3.    Johnson CD, Hara AK, Reed JE. Computed tomographic colonography (Virtual colonoscopy): a new method for detecting colorectal neoplasms. Endoscopy 1997;29:454-61.
4.    Dachman AH, Kuniyoshi JK, Boyle CM, Samara Y, Hoffmann KR, Rubin DT, Hanan I. CT colonography with three-dimensional problem solving for detection of colonic polyps. AJR Am J Roentgenol 1998;171:989-95.
5.    Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003;349:2191-200.
6.    Cotton PB, Durkalski VL, Pineau BC, Palesch YY, Mauldin PD, Hoffman B, Vining DJ, Small WC, Affronti J, Rex D, Kopecky KK, Ackerman S, Burdick JS, Brewington C, Turner MA, Zfass A, Wright AR, Iyer RB, Lynch P, Sivak MV, Butler H. Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia. Jama 2004;291:1713-9.
7.    Hur C, Gazelle GS, Zalis ME, Podolsky DK. An analysis of the potential impact of computed tomographic colonography (virtual colonoscopy) on colonoscopy demand. Gastroenterology 2004;127:1312-21.
8.    Iannaccone R, Laghi A, Catalano C, Mangiapane F, Lamazza A, Schillaci A, et al. Computed tomographic colonography without cathartic preparation for the detection of colorectal polyps. Gastroenterology 2004;127:1300-11.
9.    Brenner DJ, Georgsson MA. Mass screening with CT colonography: should the radiation exposure be of concern? Gastroenterology 2005;129:328-37.
10.    Rockey DC, Paulson E, Niedzwiecki D, Davis W, Bosworth HB, Sanders L, et al. Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison. Lancet 2005;365:305-11.
11.    Zalis ME, Perumpillichira JJ, Magee C, Kohlberg G, Hahn PF. Tagging-based, electronically cleansed CT colonography: evaluation of patient comfort and image readability. Radiology 2006;239:149-59.
12.    Burling D, Halligan S, Atchley J, Dhingsar R, Guest P, Hayward S, Higginson A, Jobling C, Kay C, Lilford R, Maskell G, McCafferty I, McGregor J, Morton D, Kumar Neelala M, Noakes M, Philips A, Riley P, Taylor A, Bassett P, Wardle J, Atkin W, Taylor SA. CT colonography: interpretative performance in a non-academic environment. Clin Radiol 2007;62:424-9; discussion 430-1.
13.    Rockey DC, Barish M, Brill JV, Cash BD, Fletcher JG, Sharma P, Wani S, Wiersema MJ, Peterson LE, Conte J. Standards for gastroenterologists for performing and interpreting diagnostic computed tomographic colonography. Gastroenterology 2007;133:1005-24.
14.    Schwartz DC, Dasher KJ, Said A, Gopal DV, Reichelderfer M, Kim DH, Pickhardt PJ, Taylor AJ, Pfau PR. Impact of a CT Colonography Screening Program on Endoscopic Colonoscopy in Clinical Practice. Am J Gastroenterol 2007.

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 American Cancer Society - http://www.cancer.org (Your other reference was the American Chemical Society)

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/

References

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