Finnish FIT test for more efficient screening of colorectal cancer

Kari Syrjänen, MD, PhD, FIAC
Chief Medical Director, Biohit Oyj
Visiting Professor, Barretos Cancer Hospital, SP, Brazil 

A new, more sensitive and specific test for screening of colorectal cancer (CRC) has been developed in Finland, the efficacy of which will be evaluated in a comparative clinical trial in Brazil.

Cancer of the colon and rectum (colorectal cancer) continues to be one of the leading causes of cancer morbidity and mortality worldwide, more than 1.2 million new cases and 609.000 annual deaths (1).  In Finland, CRC is the third most common cancer second only to prostate and breast cancer, and the incidence has been steadily increasing during the past several decades.

According to the latest statistics of 2011, over 2.800 new CRC cases were detected in our country, being almost equally common among men and women; 1.310 and 1.499 cases, respectively. The reasons for the steady increase of CRC are not entirely clear, but the prime suspects are the changes in lifestyle and, consequently, increased exposure to various risk factors.

Colorectal cancer develops through precursor lesions

CRC refers to all malignant tumors that develop in the region of colon and rectum. Tumors that are located in the caecum, ascending- and the transverse colon are called proximal cancers, and those located in the descending colon, rectum and sigma are known as  distal cancers. According to this definition, CRCs do not include bowel cancers that are located in the small intestines or in the anal region. 

The majority of CRC cases are classified as sporadic, and 75% of them are estimated to develop in people who are considered to be at moderate risk of developing this disease. Only about 20% of CRC cases are found among people known to be have some degree of family history. The remaining 80% occur in patients with a predisposing inflammatory bowel disease (ulcerative colitis), or any of the known gene mutations (FAP, familial adenomatous polyposis, or HNPCC, hereditary, non-polyposis colorectal cancer)(2,3). Already the early case-control studies showed that the risk of developing CRC is more than double among the subjects with their first-degree relatives having the same disease (4)

It is currently estimated that at least 95% of all CRC cases develop from clearly identifiable precursors, such adenomatous polyps and flat adenomas (5). This progressive adenoma-to-cancer pathogenesis is based on extensive population studies, according to which the bowel cancer risk is many times higher in people who suffer from hereditary polyposis syndromes, as well as on follow-up studies, indicating that the development of CRC was reduced by 60 to 90% among individuals who had undergone an endoscopic removal of their polyps (polypectomy)(6).  Well-designed case-control studies also show conclusively that the removal of polyps in sigmoideoscopy resulted in reduction of CRC mortality by more than 60% during 10 years of follow-up, as compared to the respective control subjects (7)

In their microscopic structure, adenomas are benign tumors, which, however, are considered as CRC precursors, due to the reasons described above. On the basis of their microscopic structure, three main types od adenoma are distinguished: tubular, tubulo-villous and villous adenoma, listed in the order of their increasing tendency for malignant transformation.  Adenomas are accompanied by precancerous lesions of different degree of severity, known as dysplastic changes, of which the most severe forms represent local cancer (carcinoma in situ, CIS). Only when the malignant tissue grows through the mucosal muscle layer, it is referred to as an invasive adenocarcinoma.

Another concept gained popularity in the recent literature is an entity called advanced neoplasia (AN), which includes cancers, adenomas >10mm in diameter, adenomas with severe dysplasia, or with <25% of their volume composed of villous morphology (8).

Colorectal cancer is well suited for population-based screening 

Among the few human malignant tumors, CRC is suitable for population-based screening. To be eligible for screening, the tumor must be common enough to represent a major disease burden, and it develops during a sufficiently long period of time through well-defined precursor lesions. CRC meets both these requirements which makes it suitable for both prevention (primary prevention) and early detection (secondary prevention). The development of cancer is preventable by finding and treating the precursors (polyps, adenomas), whereas early detection aims to find cancers at an early stage that are curable by effective treatment.

In Finland, all population-based cancer screening is based on the Governmental Statute from 2006. CRC screening started in Finland in the autumn of 2004, initially in 23 municipalities, but over the years the program has expanded, so that in 2012, already 153 municipalities were involved (9). At the beginning, the screening targeted to age groups 60 to 64 years, but soon extended to cover the 60-69-year age groups. During the first two years of the program, only about 15% of these age groups were screened, but the original intention was to gradually expand the screening, so as to cover the entire age group  within 10 years. This approach has been designed to ensure, on one hand, the evaluation of the program, and on the other hand, the adequacy of the health care resources mobilized. The screening tests are repeated on the same target group every second year (9).

Based on the 2011 statistics, it is obvious that the original plans have not been fully realized. At that time, 147 municipalities completed screening of a total of 73 608 people, with the participation rate of all invited being 67.9%. Within the organized screening, a total of 46 CRCs and 417 precursors (adenomas) were detected (9). This means that the vast majority of the annually diagnosed >2 800 CRC cases in Finland are found outside the organized CRC screening program. The same applies also to the other types of cancer (breast cancer, cervical cancer) screened in Finland, and in this respect, CRC screening does not differ from other cancer screening in our country.   

Traditional methods of CRC screening

In countries where implemented, CRC screening has been conducted mainly by three different methods: 1) demonstration of fecal occult blood by FOB (fecal occult blood) tests, 2) sigmoidoscopy, and 3) colonoscopy (10,11). Of these three, the most suitable for population-based screening is the FOB test, which is also used in Finland. On global market, a large number of FOB tests are available with different proprietary names, all of which are so-called guaiac-based tests, based on the same principle. They detect fecal occult blood on the basis of hemoglobin (Hb)-derived heme groups, because of its peroxidase activity (10,11).

Unfortunately, these guaiac-based FOB tests are not specific for human blood, but also react with animal blood derived from the dietary intake of meat. In addition, also peroxidases derived from other sources, e.g. ingestion of fresh vegetables, can cause a false positive reaction. Such false positive results lead to unnecessary colonoscopies. Furthermore, these tests are relatively insensitive, which may also lead to false-negative results.

Given these shortcomings, the effectiveness of CRC screening carried out by FOB tests on the long-term mortality is questionable (10,11). Although in a relatively recent Cochrane-type meta-analysis, CRC screening carried out by FOB test repeated at 2-year intervals was shown to reduce mortality by 15% (RR=0.85, 95% CI 0.78 to 0.92)(12), one crucial longitudinal study was missing, and when added, the impact of FOB-based screening on CRC mortality during 17 years of follow-up lost its statistical significance (13). When critically evaluated, traditional CRC screening using the FOB test does not seem to lead to a statistically significant decrease in mortality in the long term (10,11).

New tests for colorectal cancer screening 

Japan is considered as the pioneering country in CRC screening, and already in the 1990’s, the first new-generation tests for CRC were developed in that country (14). However, this development has its origin in Finland since the 1970’s, when Labsystems Oyj established by Osmo Suovaniemi developed Fecatwin/EIA test for screening and diagnosis of colorectal cancer. This test is specific for human blood, and it was patented e.g. in USA (21,22,23). This invention is the basis for the technology of ColonView. All FIT-tests are based on demonstration of faecal occult blood by immunochemical reaction,  and consequently, these tests are known as FIT (fecal Immunochemical test) tests. A recent review listed more than 20 different trade names of FIT tests, the comparison of which, however, proved to be impossible due to the different characteristics of these tests as well as due to many weaknesses in the study designs (10,11)

Similar problems have been encountered in a number of studies attempting to compare the traditional FOB tests with the new FIT tests (15,16,17,18).  Although the results are somewhat contradictory, it seems clear that the sensitivity of FIT tests is much better than that of the FOB tests. In some studies, the specificity of both tests was of the same magnitude, but also in many other studies, the specificity of  FIT test was significantly better than of the FOB tests. In the only randomized controlled trial (18), FIT tests proved to be superior to the FOB tests in both sensitivity and specificity in detecting any intestinal tumors (cancer, adenoma, polyp). However, this is an area where more randomized controlled trials are needed, in which the best available FOB tests are compared to the new generation of FIT tests in a screening setting.

ColonView test, an innovation from Finland

One of the new generation FIT tests is ColonView, developed by a Finnish biotechnology company Biohit Oyj. The new refined version of the test is launched in 2014.

ColonView Hb and Hb / Hp Fecal Occult Blood Test (simply ColonView) is a visual and qualitative rapid test based on an immunochromatographic method for the detection of human blood hemoglobin (Hb) and hemoglobin/haptoglobin (Hb/Hp) complexes in stool samples. The human blood hemoglobin molecule is composed of two pairs of peptide chains (α – and β-globin) and four heme groups, each of which has one iron atom. Free Hb can be split into α – and β-molecules that bind to haptoglobin protein.

These Hb/Hp complexes play an important role in the recovery of Hb from the degraded red blood cells, particularly because they are relatively resistant to proteolysis and poorly biodegradable. These Hb/Hp complexes are still detectable in the feces after passing through a long distance in the intestines, which improves the chances of finding the sources of bleeding in the upper gastrointestinal tract (the proximal colon polyps, adenomas and cancers). Studies have provided evidence that it is the Hb/Hp complexes in feces that can clearly improve the detection of colorectal adenomas and cancers as compared with the tests detecting only Hb (19,20)

ColonView is based on immunochromatographic method in which both Hb and Hb/Hp complexes are detected by specific antibody reactions. The test (T) area of the strip in the cartridge is coated with human Hb and Hb/Hp antibodies, while the control region (C) of the strip is devoid of these specific antibodies. 

The Hb/Hp- complexes in the stool sample, together with the marker (colloidal gold conjugate) are moving by chromatographic capillary forces along the test strip. In positive test, these tracer-loaded Hb/Hp complexes bind with the antibody in the T zone, and the resulting reaction is visualized as a color change from colorless to pink or red. When the test sample is negative, i.e., the sample does not contain Hb/Hp complexes, there is no binding to antibodies in the T-zone, and no color reaction will develop. ColonView test is technically simple to perform in any laboratory, and it gives a reliable result, as long as the samples are correctly collected and properly delivered to the laboratory.


CRC develops over a long period through well-defined precursor lesions which can be  detected e.g. on colonoscopy and removed before their progression to cancer. CRC is one of the few human malignancies which is amenable to population-based screening. In Finland, CRC screening was initiated by 23 municipalities in 2004, and the program has been expanded to cover at best 190 municipalities.

The impact of cancer screening is determined by its coverage at the population level, the participation rate of the invited people in the screening, as well as the sensitivity and specificity of the screening test. 

The best screening method is the one having the highest positive predictive value (PPV), because the test detects only the true cancers and their precursor lesions, with few false-positive results that would necessitate triage testing by expensive additional investigations. In Finland, only a small fraction of the >2 800 annual new CRC cases are detected by organized screening, which is roughly in line with the screening coverage.

The problem is that the FOB test gives too many false positive results, and the high number of expensive colonoscopies needed to confirm those has a major negative impact on the cost-effectiveness of CRC screening. For example, in the 2011 screening, only 46 cancers and 417 adenomas were found among the 1 739 subjects who were examined by colonoscopy due to positive FOB test. Thus, the PPV of the used FOB test was alarmingly low: 2.6% for the cancers and 23.9% for the adenomas.

 In addition to refined traditional tests, the recent years have witnessed the development of  new tests for faecal occult blood, based on completely different technology, i.e., the  FIT tests. One of these new-generation FIT tests is ColonView, developed in Finland. ColonView is particularly suitable for CRC screening, because of its higher sensitivity and specificity as compared with the traditional FOB tests, it is easy to use, and inexpensive in price. 

In laboratory tests, ColonView has proven to perform as expected. To establish the final value and usefulness of the test as a CRC screening tool, however, necessitates well-designed, controlled clinical trials, in which ColonView test is compared with the best available FOB tests. Such studies are about to start in different clinics, among the few first, at Barretos Cancer Hospital in Brazil.


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22. Aggressive innovation and patenting strategy

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