Prevention of colorectal cancer
Primary prevention of colorectal cancer could be possible by eliminating risk factors associated with development of the disease and is directed towards individuals in whom the malignant transformation has not yet occurred. By changing diet, from red meat and fat in favor of fruits, vegetables and fibers, the risk of colorectal cancer could be reduced. In secondary prevention such as screening, the attempts are instead to find the disease in an early stage with the aim of limiting mortality.
Moreover, removal of adenomatous polyps (adenomas), a precursor stage of the disease, has a documented protective effect. Consequentially, population based screening programs also have the potential of decreasing the incidence of colorectal cancer in the future. Colorectal cancer screening is recommended in the United States since 2001 and by the European Union since 2003
Evaluation of a screening program
The only valid measure of effectiveness of a screening program is the ability to reduce the disease specific mortality. The comparison of survival in colorectal cancer among screen-detected and clinically detected cases is difficult due to the possibility of bias. For example, the is a selection bias when screened and non-screened individuals represent different populations with different risks of the disease or in case-control evaluations when the dying cases and surviving controls do not represent the same source population. Lead time bias occurs when investigators do not recognize that earlier diagnosis with screening adds time to the total survival time even if there is no change in the time of death (Figure 1).
Another pitfall is the so-called length biased sampling. Slowly growing (and possibly less malignant) tumours are more likely than aggressive tumours to be picked up by screening programs when they take longer time to pass the stage between being detectable with screening instruments and becoming clinically evident (Figure 2).
The only valid measure of success of a screening program is lower mortality within the screened population. So far, a 16% reduction in colorectal cancer mortality has only been demonstrated in randomised controlled trials (RCT’s) using fecal occult blood test (FOBT) as screening test (see below).
With compliance is meant the proportion of individuals offered a screening test that actually completes it. Since only participants can contribute to the mortality reduction achieved by the program, compliance is a major determinant of the effectiveness. With low participation the number of deaths prevented will be few and, consequently, the number of people that needs to be invited to screening to prevent one death (number needed to screen) has to be very large. Therefore, low compliance in a screening program will not only hamper the mortality reduction achieved, but also the cost-effectiveness of the program. Moreover, with a self-selection of healthier people that participate and higher-risk people that do not, population-based screening programs could become very cost-inefficient.
The screening test
The screening test that is used in the program also affects the cost-effectiveness. Since the test will be used by people in the general population who – in the main – do not have colorectal cancer, it must be simple to take, easy to interpret, have limited side effects and also be inexpensive. Moreover, a high sensitivity and specificity is essential to limit the number of people who have colorectal cancer but are missed (false negative) as well as those who are incorrectly diagnosed as having the disease (false positive). In population based screening programs a low specificity is not feasible since many people without the disease will have a positive test. This depends on the relatively low prevalence of the curable preclinical phase of colorectal cancer (in “the zone of detection”) in the average-risk population. The prevalence of colorectal cancer increases in older age groups and quite dramatically if one would consider the detection of adenomas. The false positive results generate unnecessary anxiety, costs due to follow-up with different diagnostic or therapeutic measures, and even morbidity or mortality due to complications.
Different screening tests
There are many different colorectal cancer screening tests suggested. The test offered in different screening programs depends on a variety of factors, such as economy and the availability of endoscopy. Still, “the best screening test is the test that is taken”.
Fecal Occult Blood Test (FOBT)
FOBT tests the stool for invisible (occult) blood and has the advantages of being simple, safe and also inexpensive. Older FOBT (based on the guaiac-peroxidase reaction or tests that detect heme porphyrine) are frequently reimbursed by more advanced immunological tests (FITs) with higher sensitivity, but only with a marginally decrease in specificity (more false positives). Annual screening is recommended in the United States, although biennial screening is mostly adopted in Europe. A positive test must be followed by a diagnostic examination of the entire colon. Only larger lesions (>2 cm) bleed consistently and, consequently, small lesions can be missed. Another pitfall is false positive tests after eating red meat and, therefore, dietary restrictions are often recommended for the more sensitive guaiac-based test. The sensitivity of a single FOBT is low (30-50%) but higher with repeated testing within a screening program. Despite a specificity of 95%, less than 20% of people in the target population with a positive test have colorectal cancer. Compliance in the older RCT’s was in the range of 60-78%, but, unfortunately, is a lower in national screening programs so far.
The main advantages of colonoscopy are the direct visualization of the colorectum and, more importantly, the possibility of obtaining tissue samples and removing adenomas during the procedure. This minimizes the need of a secondary investigation and, hereby, there is a reduction in the indirect costs by decreasing the time needed away from work in order to participate. Moreover, colonoscopy is recommended as screening test only every 10 years. Colonoscopy, however, is relatively expensive, uncomfortable, and carries a small risk of severe complications such as bleeding and perforation. Colonoscopy is most often used as “gold standard” in the evaluation of new screening tests. Still, the accuracy of colonoscopy is dependent on both the experience of the endoscopist and the thoroughness of the bowel preparation. A sensitivity of 97% for cancer and 91% for polyps ≥1 cm has been reported. Unfortunately, compliance with colonoscopy screening is low (~30%).
Sigmoidoscopy shares many of the benefits of colonoscopy, but only regarding the approximately 60 cm of the most aboral colorectum. It is easier to perform, routinely in less than 10 minutes, cheaper, and a rectal enema is often sufficient bowel preparation. Sigmoidoscopy is recommended as screening instrument every five years due to the lower sensitivity (~75%). Pilot screening programs have reported of compliance in the wide range of 25-80%.
Double Contrast Barium Enema (DCBE)
DCBE is a radiological method when first, after bowel preparation, barium-containing contrast is administered into the rectum and, secondly, air is insufflated. DCBE is in the first place recommended as additional examination to sigmoidoscopy to cover the entire colon, but has as well been proposed as screening instrument every 5 years at a lower cost and risk than colonoscopy, but with lower sensitivity (~80%). In case of a positive finding, a diagnostic endoscopy must still be performed. Another drawback is that DCBE is associated with relatively high doses of radiation.
The normal colorectal mucosa can develop into cancer by a series of genetic events, for example mutations in the K-ras gene resulting in an adenoma. While testing stool for occult blood is rather unspecific, the identification of tumour-specific DNA, stool-based DNA (SB-DNA), is an interesting concept, but not yet recommended as screening test. The DNA is also shed continuously and not intermittently as seen with blood and no dietary restrictions are needed. Colorectal cancers, though, are genetically heterogeneous and multiple DNA markers are needed. Despite promising pilot studies, the sensitivity and specificity were ~50% and ~95%, respectively, when screening in the average-risk population.
At capsule endoscopy the participant swallows a small camera-containing capsule. During the passage through the gastrointestinal tract, the capsule transmits data to a receiver attached to the participant’s waist. As of today, capsule endoscopy is only used ruinously to examine the small bowel in case of obscure gastrointestinal bleeding, although it could hypothetically be used as a screening test since colonic tumours also can be visualized. The diagnostic accuracy of colonic tumours needs to be developed when approximately every third positive case is false.
Computed Tomography Colonography (CTC) and Magnetic Resonance Colonography (MRC) are novel techniques where data from a spiral CT scanner or magnetic resonance images are three-dimensionally reproduced to simulate the endoluminal views of colonoscopy; “virtual colonoscopy“. Standard bowel preparation is most frequently used. The actual examination is rapid, well tolerated, and does not cause any major complications. Another positive aspect is the possibility of finding extra-colonic pathology. The benefit of MRC, as compared to CTC, is that no ionizing radiation is used, with the drawback that the patients cannot have metallic implants.
In small populations referred for diagnostic colonoscopy the sensitivity in virtual colonoscopy was >90% and the specificity ~75-99%. As with DCBE, people with positive findings still need a diagnostic follow-up endoscopy. Virtual colonoscopy is not yet recommended for screening outside research settings or for other than people who cannot take conventional tests. There is a lack of clinical studies in the average-risk population and understanding of its costs.
Screening programs across Europe
National colorectal cancer screening programs starting from 50-60 years of age are currently running with FOBT in Finland, Latvia, U.K. and the Czech Republic and with colonoscopy in Germany, Poland and Italy. The reason colonoscopy has become accepted as screening test in the average-risk population – even without randomised controlled trials demonstrating effectiveness, complications or costs – are probably the attractive colorectal cancer incidence reduction demonstrated with up to 75%. Also, colonoscopy has gained large mass medial attention with advocates such as the deceased pope John Paul II and Senator Hillary Clinton.
Even with the demonstrated reduction in colorectal cancer mortality under ideal conditions in randomised controlled trials, the effectiveness of screening to reduce mortality in the average-risk population in routine screening has to be evaluated continuously. In screening with FOBT, the degree of mortality reduction depends on the compliance, screening frequency (annual or biennial), the number of screening rounds the subjects participate in, and compliance with the diagnostic follow-up colonoscopy in case of a positive test. This is why, as opposed to opportunistic screening, rigid organizations with formal invitations, reminding systems and quality assurance are to prefer. There are still many questions unanswered, for example the effectiveness of screening colonoscopy and how individuals with screening detected adenomas are to be follow-up. Future research co-operation is very welcome.