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Colon Cancer Screening Tests
Screening tests are used to detect the asymptomatic course of the disease in apparently healthy people. To some extent, these tests are designed to increase a person’s life expectancy and improve its quality. An effective test should have sensitivity (optimal detection of patients), specificity (give a minimum of false positive results) and be accessible to a wide range of patients. Currently, there are two main screening tests for colon cancer - fecal occult blood testing and endoscopic bowel examination. Both tests are effective in reducing cancer mortality, but have their limitations.
Examination of stool for occult blood
Colon tumors are believed to bleed in the early stages of the disease. Hemoglobin has peroxidase activity, which can be detected using a guaiac test. Guaiac glue, a colorless indicator, can oxidize to form colored quinone in the presence of peroxidase and hydrogen peroxide. Typically, during this test, feces are applied to the filter paper, then a guaiac reagent, acetic acid and hydrogen peroxide are added to them. This method is very sensitive to detect peroxidase activity, but it is poorly standardized and overly sensitive. Therefore, a test has now been developed in which the guaiac reagent is pre-coated on a plastic strip. In this case, the test is less sensitive, but more standardized. The guaiac test is able to detect the content of hemoglobin in feces, starting from 0.12 mg / ml. It is believed that 1 mg of hemoglobin contained in 1 g of feces corresponds to the ingestion of 1 ml of blood in the stool. Thus, even small bleeding is very easy to detect.
Normally, up to 1 ml of blood per day is lost through the gastrointestinal tract. As it moves through the intestines, blood is distributed in the feces and is decomposed by digestive and bacterial enzymes. Moreover, peroxidase inhibitors are present in feces. A standardized guaiac test yields a negative result in the control group with the appropriate diet, and even with a diet with a low peroxidase content, false-positive results are only 1%. In the case of using moistened feces (to increase sensitivity when analyzing stool dried as a result of storage), its results will be unreliable.
To determine the diagnostic value of the occult blood test in early cancer diagnosis, you need to know how much bleeding from the tumors is. On average, blood loss from tumors of the cecum and the ascending transverse colon is 9.3 ml / day (2 to 28 ml / day). With localization distal to the hepatic bend of the intestine, blood loss is much less and amounts to 2 ml / day. This difference is probably due to the large size of the proximal colon tumors. The percentage of positive guaiac test results depends on the amount of blood in the stool. The test usually gives negative results when the concentration of hemoglobin in feces is less than 2 mg per 1 g and becomes positive with an increase in its concentration. This test also helps in the diagnosis of colon polyps, but blood loss from polyps is much less, and the test may not be sensitive enough. On average, blood loss from an adenomatous polyp is 1.3 ml / day, regardless of its location. Polyps of the distal part of the colon (the descending part of the transverse colon, sigmoid and rectum) give positive results in 54% of cases, in contrast to the proximal part of the intestine, where positive results are recorded only in 17% of cases.
Colorectal tumors usually bleed slightly, so they are difficult to detect with a hidden blood test. When it enters the feces, the blood mixes with them and undergoes degradation, which makes it even more difficult to identify it with the help of a guaiac test. Lesions of the distal part of the intestine are easier to identify, because in this case the blood is on the surface of the feces, and its mixing is limited. The concentration of hemoglobin on the surface of the dense stool is usually sufficient and gives positive test results, even taking into account the drying of feces and the degradation of hemoglobin during transportation of the analysis. Techniques aimed at increasing the sensitivity of the test, such as wetting the stool, increase the frequency of false-positive results. A guaya test on plastic plates reveals cases of colon cancer and, to a lesser extent, the presence of adenomatous polyps. Identification is affected by the size of the formations and their localization. Since guaiac oxidation is the basis of this test, the presence of strong antioxidants in the stool prevents the test. For example, the use of 1-2 g per day of ascorbic acid leads to false negative results.
Many attempts have been made to develop a more effective occult blood test. A plate test called "Hemoccult SENSA" (Smith Kline Diagnostics, San Rose, CA) was developed. This sensitivity test is similar to the guaiac test with additional wetting. An immunochemical test was developed to detect hemoglobin in feces - HemeSelect. It used specific antibodies to human hemoglobin. But this test can only be carried out in a special laboratory, it is not applicable at home. An important advantage of the immunological test is the absence of a cross-reaction with other types of hemoglobin (for example, contained in meat). This test does not detect bleeding from the upper gastrointestinal tract. Hemoccult SENSA and HemeSelect are more sensitive than Hemoccult II, and 94% and 97% of cases of symptomatic colon cancer are detected in a single study, respectively, compared with 89% when using Hemoccult II. But the sensitivity in the asymptomatic course of cancer turned out to be low (in this case, indeed, it is extremely difficult to identify the lesion sites). New tests are more sensitive when detecting adenomatous polyps with sizes of 1 cm or more: Hemoccult SENSA and HemeSelect are positive in 76% and 60% of cases, respectively, in contrast to 42% when using Hemoccult II. In a screening study - in 5% and 3% of cases - these tests were positive in the absence of neoplasm in the colon. Therefore, the negative point with increasing sensitivity is the need for a large number of colonoscopies.
HemoQuantTecr quantifies hemoglobin in the stool. This study allows you to quantify the hidden bleeding from the gastrointestinal tract and identify minimal blood loss (for example, with colon cancer). The test results do not depend on the content of peroxidase in food, and it exceeds the information content of the Hemoccult test. Unfortunately, bleeding from other sources of the gastrointestinal tract may exceed blood loss from colon tumors. Stool analysis must be sent to the laboratory, so this test cannot be called simple. Moreover, it is less sensitive than the tests described above. Several studies have been carried out that have revealed the possibilities and limitations of methods for screening for colon cancer. Controlled studies have shown that occult blood tests are effective in detecting asymptomatic colon cancer, as well as for risk groups. In the group of subjects without complaints, positive test results are observed in 1-2.4% of cases. Usually, if positive results are found in 1–2% of cases, this indicates a non-compliance with the diet or additional wetting of the stool to increase the sensitivity of the test. A few days before the test, it is recommended to avoid eating meat. It is also forbidden to use non-steroidal anti-inflammatory drugs, antioxidants such as vitamin C. After taking the test, it is necessary to test as soon as possible, avoiding additional wetting of the plates.
In patients taking iron preparations, false-positive results are possible. These measures allow you to minimize the number of false positive results and, therefore, avoid the cost of research. However, a decrease in the sensitivity of the test leads to the fact that prior to the Uz, no cases of colorectal cancer are detected.
With the help of tests for occult blood, it is possible to detect cancer in the early stages of development. The widespread use of this method has led to a reduction in mortality from colon cancer. A study by the Oakland Kaiser-Permanente medical organization found a 25% reduction in cancer deaths in people who had been screened for occult blood for 5 years. The most significant study was conducted at the University of Minnesota. It included examination of 46 thousand patients for 13 years, in 83% of which the test for occult blood was performed after additional wetting of the feces. The study showed that an annual occult blood test reduces the incidence of colon cancer mortality by 33%. This is achieved by detecting cancer at an early stage of development. The subjects showed a 50% decrease in cases of detection of cancer at the last stage of development. Therefore, an annual fecal occult blood test is needed to reduce colon cancer mortality. As the intervals between tests increase, the effectiveness of screening decreases.
Use of endoscopic methods for colon cancer screening
Currently, endoscopic examination methods can detect up to two-thirds of colon tumors. Therefore, these methods are recommended to be widely used in screening examinations. The ability of flexible endoscopes to reach the cecum has dramatically increased the capabilities of this method.
Two studies have been carried out confirming the effect of screening sigmoidoscopy on reducing mortality from colon cancer. As part of the Oakland Kaiser-Permanente program, a so-called casecontrol study was conducted. The study analyzed the medical history of 261 people who died from colorectal cancer and other parts of the distal colon. Among them, only 8.8% performed endoscopic sigmoidoscopy, in contrast to 24.2% in the control group. As a result, it was concluded that the risk of mortality from cancer of the rectum and distal part of the colon in the examined patients was only 30% of the risk of mortality in the unexplored. Moreover, it was proved that endoscopic examination reduces the likelihood of illness by up to 10 years. The frequency of cancer development at such a localization, which cannot be achieved with sigmoidoscopy, was the same in both groups (this proves that initially both groups had the same degree of risk of the disease). These findings were confirmed by another study in Wisconsin. Among the examined at least once in a 10-year follow-up period, mortality from colon cancer was 10% (for comparison, in the control group without examination, 30%). Thus, even after a single examination, the risk of cancer mortality is reduced by 79%. In those who underwent only a digital rectal examination or testing for occult blood in the feces, such a decrease was not observed.
At the time of this writing, the authors have not found published data to compare the effectiveness of sigmoidoscopy and fibrocolonoscopy. But the usefulness of sigmoidoscopy has already been proven, the so-called "protective" effect of which lasts much longer than a hidden blood test (must be repeated annually). When using endoscopic examination methods, the risk of mortality is reduced more than when using tests for occult blood. In addition, it must be borne in mind that during endoscopic examination, precancerous lesions can be removed, thereby interrupting the neoplastic process in the early stages of development.
According to the recommendations of the American Cancer Society, the National Cancer Institute and some other similar organizations, in the usual group of patients (the average risk of cancer), screening tests for colon cancer should be started from the age of 50. Tests for occult blood must be carried out annually, and endoscopic examination - once every 3-5 years. Patients undergoing screening tests are less likely to die from colon cancer. They also have less postoperative mortality. Moreover, endoscopic methods are more effective in the prevention of cancer than hidden blood tests, both in terms of reducing mortality and in the duration of the period between studies. More in-depth screening studies reduce cancer mortality to a greater extent, but also cost more. Thus, the question arises of how much to conduct screening studies.
Colon Cancer Screening Capabilities in the 21st Century — Genetic Approach
A better understanding of the genetic basis of the pathogenesis of gastrointestinal cancer gives the doctor new opportunities for the early detection of this disease. Great progress has been made in genetic studies of colon cancer. And probably the same thing will happen soon in relation to the study of cancer of other organs of the gastrointestinal tract.
Hereditary mutations. By examining blood samples for hereditary mutations, hereditary colon cancer syndromes can be diagnosed: mutation of the APC gene (causes fibroadenomatous polyposis); mutation of hMSH2, hMLH1 and some other genes that cause non-polypous hereditary (colon) cancer of the colon. This is very important, because it shows that two families that are not related by kinship, suffering from these diseases, have their own mutations that are different from others. Members of the same family have a mutation that is characteristic only for them, which facilitates their examination. Carriers of the same mutation may have phenotypic differences, for example, different ages at the onset of the disease, different degrees of malignancy of the process, and different extraintestinal localizations of the cancer. Identification of possible diseases associated with this mutation helps the doctor to predict the development of cancer. For example, it is now known that mutations at the 5'-end of the APC gene DNA chain (the first 3-4 exons) lead to a “soft” form of fibroadenomatous polyposis, and mutations in an isolated part of the APC gene (capturing about 150 codons) lead to early onset and most malignant course of fibroadenomatous polyposis.
In families with hereditary non-polypous colon cancer, the genetic information site responsible for the occurrence of the disease is located on chromosomes 2p and 3p. But there are cases when, with the same course of the disease, genetic defects are not associated with the locus of chromosomes 2p and 3p. Tests for screening for fibroadenomatous polyposis are being intensively developed, and hereditary non-polypous colon cancer is next in line.
Detection of oncogen in feces. Mutations of the K-RAS2 gene. usually not found in various precancerous diseases, small adenomas. This mutation is detected in approximately 50% of cases of large adenomas, colon and rectal cancer. It is proved that the RAS gene can be detected in the feces using the polymerase chain reaction, even taking into account the fact that the mutated gene makes up only a small part of the DNA found in the feces. Therefore, the definition of this gene in feces is used for screening for cancer of the colon and rectum. The study of this test was carried out only on a very small group, and therefore it cannot yet be said whether this method is suitable for screening studies. Given the limitations when using endoscopic methods, tests for determining hidden blood, further study of the method for determining "cancer" genes in the feces is necessary, followed by its use for screening.
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Colon Cancer Screening Tests
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