It has been established that CRC mortality could be reduced by screening with periodic fecal occult blood tests (FOBTs), followed by colonoscopy when the results were positive. A systematic review published in 2008, which included 4 clinical controlled trials involving over 300000 participants, found that screening with FOBT reduced the relative risk (RR) of CRC mortality by 16%, without adjustment, and by 25% after adjusting for screening attendance[12]. The follow-up of those patients showed that the effect of screening was reduced CRC-mortality, and this effect persisted for over 30 years[13]. A reduction in the RR of CRC incidence was also detected in follow-up, mainly due to the removal of adenomatous polyps. This effect was greater among individuals that received annual screenings (20% RR) than among those that received biennial (17%) screenings[14].

Currently, there are two different tests available: the FIT and the guaiac fecal occult blood test (G-FOBT). The FIT achieved significantly higher detection rates for advanced adenomas and CRC than the G-FOBT. Although the FIT was more sensitive than the G-FOBT (61% vs 23.8%, respectively), its specificity was slightly lower (95.1% vs 97.7%, respectively)[15,16]. Participation rates appeared to be higher in screening programs that used FIT compared to those that used G-FOBT[15]. This issue is probably related to the facts that FIT does not require dietary restrictions (due to its specificity to human hemoglobin [Hb]) and that only one sample is needed in most screening programs[16]. Additionally, FIT offers quantitative results (ng Hb per mL buffer or μg Hb per gram feces) and an automated reading of the results. The cut-off value for the amount of Hb detected can be predetermined by the investigator. Several cut-off values have been used with different sensitivity and specificity rates. The investigator can adjust the cut-off value to limit the number of colonoscopies required, and thus, avoid overextending the available endoscopic resources. An optimum cut-off value has not been established; therefore, the choice should be based on the availability of endoscopic resources, the epidemiology of CRC in the study population, and the expected participation in the program[17]. Values between 20 and 30 μg/g are recommended when the Health Care System can accommodate colonoscopies for approximately 5% (expected FIT positivity rate) of the population study (aged 50-74 years)[18].

Based on current evidence, the FIT has been recommended as the first option for detecting fecal occult blood in CRC screening[19]. Most European countries with an organized screening program are currently using the FIT. This test has replaced the G-FOBT in screening programs in the United Kingdom since 2014 and in France since 2015[4].

Other non-invasive techniques are available, such as the fecal DNA analysis. These tests identify molecular alterations in adenomas and CRC cells. However, these tests are currently underused, due to the high cost and relatively low cost-effectiveness[20].

Flexible sigmoidoscopy screening was shown to be effective in reducing the incidence and mortality rates of CRC[21,22]. It should be taken into account that, when a distal adenomatous polyp is detected in a sigmoidoscopy, a colonoscopy is required. This is necessary, because the characteristics of adenomas found in the rectum and sigma are correlated with the probability of presenting a proximal CRC[23,24].

Colonoscopy screening is used in several programs. Data are scarce from randomized clinical trials that have attested to its effectiveness. However, several observational studies have reported that colonoscopy screening reduced CRC mortality and incidence, mainly due to its great capacity for detecting neoplasias and adenomas. In a case-control study, performing a colonoscopy, regardless of its indication, was associated with a large reduction in the risk of CRC in the following 10 years after the test. This effect was greater when the colonoscopy had been used as a screening test[25]. Several cohort studies have confirmed this finding. One study showed that, in an average-risk population, performing a colonoscopy was associated with a 67% reduction in CRC incidence after an 8-year follow-up[26]. Another study demonstrated the long-term protective effect of a polypectomy. When a colonoscopy was performed with a polypectomy of at least one adenoma > 5 mm, the CRC incidence was reduced by 80% after a 10-year follow-up[27].

Colonoscopy quality has varied in reports from different endoscopists. For this reason, over the last decade, a series of quality indicators for colonoscopy have been described. However, application of these indicators has not become well established in endoscopic practice[28]. Currently, the main quality indicator among endoscopists is the adenoma detection rate (ADR). The ADR is defined as the proportion of screening colonoscopies performed by a physician that detected at least one histologically confirmed colorectal adenoma or adenocarcinoma. The recommended ADR is ≥ 25% (men ≥ 30%, women ≥ 20%)[29]. Several studies have demonstrated a strong correlation between the ADR record of an endoscopist and the probability of diagnosing CRC within a given number of months of a colonoscopy (an interval CRC) [24]. Despite the clinical importance of this measure, large variations remain among endoscopists.

One study analyzed the results of colonoscopies performed in the US through an integrated health services organization, over a 12-year period. The association between the ADR and the risk of diagnosing CRC within 6 mo to 10 years after the first colonoscopy was evaluated, and the risk of death from cancer was calculated. They studied a total of 314872 colonoscopies performed by 136 gastroenterologists, with ADRs that ranged from 7.4% to 52.5%. They identified 712 interval colorectal adenocarcinomas and 147 associated deaths. The gastroenterologists were placed into quintiles, based on their ADRs (lowest ADR quintile ≤ 19.06% and highest ADR quintile ≥ 33.51%). They found that patients examined by gastroenterologists in the lowest ADR quintile had almost double the risk of being diagnosed with an interval cancer compared to patients examined by gastroenterologists in the highest quintile. In addition, the risk of a fatal interval cancer was reduced by 62% among patients examined by gastroenterologists in the highest quintile. Each 1% increase in the ADR was associated with a 5% decrease in the risk of a fatal interval colorectal cancer[30].

Although the colonoscopy is more effective than the FOBT for detecting neoplasias and adenomas, the FOBT is more readily accepted by participants in population screening programs. Thus, the higher FOBT participation rates may counteract its lower detection capacity[31]. The COLONPREV study hypothesized that biennial FIT screening would be non-inferior to a one-time colonoscopy, for reducing CRC-related mortality among subjects with average risk. They recruited more than 50000 asymptomatic participants between ages 50 and 69 years, and randomly assigned them to undergo either a one-time colonoscopy or the biennial FIT. After the first round of FIT screening, they confirmed a similar CRC detection rate with both methods. However, advanced adenomas and other adenomas were detected at a higher rate in the colonoscopy than in the FIT groups. This result confirmed, once again, the superiority of the colonoscopy for detecting this type of lesion. Therefore, the colonoscopy has higher potential than the FIT for reducing the CRC incidence. Nevertheless, the higher participation rate in the FIT group (34.2% vs 24.6%), and the biennial periodicity of this test may reduce the apparent advantage of colonoscopy over the long term[32]. Final results from that study are expected in the next few years.

In 2003, based on compelling evidence, the Council of the European Union recommended that all Member States should establish early detection programs with CRC screening for men and women aged 50 to 74 years, with annual or biennial FOBTs, followed by colonoscopy, when the results were positive[33]. Following this recommendation, several CRC screening programs were launched in Europe, with wide variations in screening practices, probably due to different preexisting screening programs (pilots, opportunity-based, or organized) in several countries. Variations among different countries also arose due to differences in financial resources available for research and differences in colonoscopy capacities.

In 2015, 24 countries in the European Union had established or were preparing to organize country-wide CRC screening programs. For example, Finland, France, Slovenia, and the United Kingdom had completely implemented organized programs. In Belgium, the Netherlands, Denmark, Ireland, Italy, Malta, Poland, and Spain, programs were being launched. Norway, Portugal, and Sweden were in the pilot phase. In contrast, other countries, including Slovakia, with the highest CRC rate in Europe[1], did not have a national screening program. Similarly, no screening programs existed in Bulgaria, Albania, Bosnia, Herzegovina, Kosovo, Macedonia, Montenegro, Romania, Serbia, and Russia[4].

An analysis of different programs in several European countries showed that Croatia and the Czech Republic had the lowest participation rates (< 25%), and both countries reported high ASRms (18.7% and 15.4%, respectively), followed by France (participation rate 34.3%). The other countries achieved better participation rates (over 45%); the highest participation was observed in the Netherlands, followed by Slovenia. The Netherlands had the highest positive test rate (test positivity, 12.2%), but the lowest cut-off value for the FIT test: 15 μg/g. The second highest test positivity was found in Ireland (10% test positivity, with a cut-off value 20 μg/g). In Italy, with the same cut-off value, test positivity was 5.8%, and in Slovenia, it was 5.9%. The lowest test positivity rates were found in England and France (2% and 2.8%, respectively), where the G-FOBT was used. In Croatia, Lithuania, and the Netherlands, the proportion of colonoscopies performed did not exceed 75%; but in the Czech Republic and Slovenia, the proportions were above 95%. In England, a very high CRC percentage was detected (10.1% of patients a with positive G-FOBT result), but only 2% of all patients had a positive G-FOBT. Ireland had a similar CRC percentage (9%), but also a greater number of patients had positive FIT results (10%). The highest detection rate was found in the Netherlands (5.9 per 1000 screenings), followed by Ireland (3.3 per 1000 screenings). More detailed results are described below and in Table 2.

Spain: Different screening programs have been implemented in all areas of Spain for the population aged 50-69 years. These programs mostly use the FIT. In 2014, participation rates varied among the regions, but the average was 49.2%. More women than men participated (51.41% vs 47.01%). On average, 6.56% of test results were positive, with a higher percentage found in men (8.2%) than in women (5.17%). The positive predictive value (PPV) for cancer was 4.70%. The CRC detection rate was 2.75 per 1000 screenings[34].

The Netherlands: In 2011, the Netherlands decided to implement a national population screening program for CRC. The program began in 2014, with the FIT test and a cut-off value of 15 μg/g. This program achieved a 68.2% participation rate. Initially, it was necessary to increase the cut-off value (from 15 μg/g to 47 μg/g ), because the proportion of individuals with positive tests was higher than expected (12%). This proportion exceeded the number of false positives, and it surpassed the capacity to perform colonoscopies. With the first cut-off value, test positivity was 10.1% in women and 14.5% in men. Colonoscopies were performed in 74.3% of these patients; among these, CRC was detected in 763 (6.7%) and advanced adenoma was detected in 33.5%. The CRC detection rate was 5.9 per 1000 inhabitants and the PPV was 6.7%[35].

Ireland: The first pilot program in Ireland was the Adelaide and Meath Hospital/Trinity College Dublin Colorectal Cancer Screening Program (TTC-CRC-SP). It included a population aged 50 to 74 years, and it applied the FIT (OC Sensor, cut-off value 20 μg/g). The participation rate was 51% (58% women and 42% men). The proportion of individuals with positive test results was 10%. Of the colonoscopies performed (87%), advanced adenomas were detected in 99 patients (24%) and CRC was detected in 38 (9%). The PPVs for CRC and advanced adenoma were 4% and 5%, respectively, and the CRC detection rate was 0.33%[36]. A second round was conducted, where they excluded patients that had changed residence, had been diagnosed with cancer, and had died. The participation rate was 48%, and 375 patients had positive test results (8%). Of the patients with a positive test, 87% underwent a colonoscopy. The PPV for CRC was similar to that of the first round (4%), and the CRC detection rate was 0.12%[37].

Italy: Lombardy is a densely populated northern region of Italy with the highest incidence of CRC. The screening program began with the population aged 50-69 years, in 2005-2006. They applied the FIT with a cut-off value of 20 μg/g. The second round of the program had been completed in 2009. The PPVs for advanced adenoma were 29% in the first round, and 30.2% in the second round. The PPVs for CRC were 4% and 3%, respectively. The PPVs for advanced adenoma and CRC were higher in people aged 60-69 years and in males. The CRC detection rates in the first and second rounds were 2.5 and 1.6 per 1000 screened, respectively[38].

Croatia: The Croatian screening program was implemented in 2007 for the population aged 50-74 years. They implemented the G-FOBT. Participation was low, reaching 19.9%. Positive tests were found in 6.9% cases, and of these, only 66% received a colonoscopy. CRC was identified in 472 patients (3.8%)[39].

Lithuania: The Lithuanian National Screening Program began in 2009, for the population aged 50 to 74 years. The FIT was applied. The participation rate for 3 years was 46% (271396). A positive FIT was observed in 19455 participants (7.2%). Of these, 66.1% underwent a colonoscopy. High-grade neoplasia was detected in 3.9% of cases, and the rate of CRC was 3.1% among all colonoscopies. The rate of CRC detected with the program was 0.2%[40].

Slovenia: The Slovenian National Screening Program (SVIT program) started in 2009. This program performed a biennial FIT for the population aged 50 to 69 years during 2014. The participation rate was 57.8% (53.2% men, 62.3% women). In this population, 6% had positive test results (7.6% men and 4.7% women). The colonoscopies detected 159 (2.12%) patients with CRC and 1887 (25.16%) patients with advanced adenomas[41].

England: The English National Screening Program began in 2006 for the population aged 60 to 69 years. This program performed a biennial G-FOBT. The first round was completed in 2010. Of the 2 million invitations sent, 49.6% of men and 54.4% of women responded. The overall participation rate was 52%. Positive test results were found in 2% (2.5% men, 1.5% women). Among the colonoscopies performed (83%), CRC was detected in 10.1% (n = 1772; detection rates of 11.6% in men and 7.8% in women). High risk adenomas were detected in 9.8% (n = 1721; detection rates of 12.2% in men and 6.2% in women)[42].

Czech Republic: The Czech National Screening Program started in 2000 for individuals older than 50 years. They applied a biennial G-FOBT. By 2009, the FIT was introduced. The coverage of CRC screening in 2010 was 22.7%[43]. The results of the program from 2001 to 2011 are shown in Table 3.

France: The French National screening program started in 2008 for the population aged 50-74 years. They applied the G-FOBT. The participation rate was 34.3%. Positive test results were found in 2.8%. Of these, 88% underwent a colonoscopy. CRC was detected in 7.5% (detection was 9% in men and 5.8% in women). The advanced adenoma detection rate was 4.9 per 1000 screened; the CRC detection rate was 1.9‰[44].

United States: Currently in the US, screening programs have been established on an opportunistic basis. The average-risk population (50-75 years) are encouraged to undergo screening at 50 years of age, and participants choose among several options. The available options are: (1) annual G-FOBT or FIT, according to the manufacturer’s recommendations for specimen collection; (2) multi-target stool DNA test every 3 years; (3) flexible sigmoidoscopy every 5 years; (4) colonoscopy every 10 years; (5) double-contrast barium enema every 5 years; or (6) CT colonography every 5 years. In about 90% of cases, colonoscopy is the preferred option[28].

On the other hand, screening program evaluations have been conducted in several regions of the country. For example, the Kaiser Permanente Northern and Southern California program conducted 4 screening rounds in a population of 50 to 70 years. They used the annual FIT (cut-off value 20 μg/g). They achieved a 48.2% participation rate in the first round. A positive FIT result was found in 5% of participants and the PPVs were 51.5% for adenomas and 3.4% for CRC[45].

Canada: Canada organized a CRC screening program for average-risk individuals, aged 50-74 years, from January 2009 to December 2011. Five provincial programs were included (British Columbia, Saskatchewan, Manitoba, Nova Scotia, and Prince Edward Island). The results of the first round showed very low participation rates (16.1%)[46]. The test positivity rate was 4.4% (4.8% with FIT and 3.7% with G-FOBT). Positive test results were more frequent in men (5.9%) than in women (3.4%), and the frequency increased with age: positive tests were found in 5.7% of the 70-74 age group and 3.4% of the 50-54 age group. Compliance with a follow-up colonoscopy was 80.5%. The detection rates were 16.9 per 1000 screened for adenomas, and 1.8 per 1000 screened for CRC. The PPVs for adenoma were 35.9% with the G-FOBT and 50.6% with the FIT. The PPV for CRC was 4.4% in both tests.

Chile: In Chile, an organized screening program was launched between 2007 and 2009 in asymptomatic subjects, aged 50 years or older without risk factors. They applied the FIT test with a cutoff of 20 μg/g. The participation rate was 77%. Of 4938 participants, positive test results were found in 9.6%. Of these, a colonoscopy was performed in 58.6%. CRC detection rates were 2 per 1000 screenings[47].

The Asian Pacific Colorectal Cancer Working Group has recommended organized screening in regions with the highest CRC incidence (> 30 per 100000)[48]. The programs target average-risk individuals, aged 50-75 years, and they preferably apply the FIT test. Several studies have investigated the barriers to CRC detection in different cultural and socio-political contexts in the Asia-Pacific region. These barriers included poor understanding of the characteristics of screening and testing, lack of financial support, and lack of health insurance[49]. Several countries in East Asia have ongoing organized screening programs, including Japan, Korea, China, Hong Kong, Taiwan, and Bangkok[50]. The results for several of these CRC Screening Programs are described below and in Table 4.

Japan: In Japan, a CRC screening program has been in place since 1992 for beneficiaries of health insurance, aged 40-69 years. The program applies the FIT. In 2013, participation rates were 41.4% in men and 34.5% in women[51].

South Korea: The South Korean National Screening Program was introduced in 2004. It targets the National Health Insurance population, aged over 50 years. They employ an annual FIT (qualitative or quantitative). Participation increased from 10.5% in 2004 to 21.1% in 2008 and to 25% in 2012[52]. In 2008, the FIT positivity rate was 7.5% (8.8% in men and 6.4% in women). A colonoscopy was performed in 31.4% of those with positive test results. The CRC detection rate was 1.2%[53].

Taiwan: The Taiwanese National program began in 2004. They performed biennial FITs in individuals aged 50 to 69 years. In the first round, 1160895 individuals (21.4%) participated. The test positivity rate was 4%. Subsequent colonoscopies detected 4284 advanced adenomas (detection rate 4.6 per 1000) and 2304 CRCs (detection rate 2.5 per 1000). The PPVs of FITs were 11.7% for advanced adenoma, and 6.1% for CRC[54].

Thailand: A Thai pilot screening program was implemented in 2011. The FIT was performed in the population aged 50-65 years in Lampang Province. The participation rate (62.9%) was higher among women (67.8%) than men (57.8%). The test was positive in 1.1% (1.2% men, 1.0% women). Colonoscopy was performed in 72% of those with positive tests. Detection rates were 3.7% for CRC and 30.6% for adenomas[55].

Australia: An Australian pilot program was conducted from 2002 to 2006 with the biennial FIT in the population aged 55-74 years. The participation rate was 45.4% (women 47.4%, men 43.4%). Positive FIT results were found in 9% of participants. Colonoscopy was performed in 54.8% of the individuals with positive FITs. Adenomas were found in 19.8% (13.9% advanced) and CRC was found in 5.3%[56]. In 2006, The National Bowel Cancer Screening Program was initiated with a biennial FIT for the population aged 55-65 years. The program will continue to expand until 2020. The program aims to apply biennial screening to the entire population aged 50-74 years[4].