Colorectal cancer (CRC) is a major cause of death in Sweden. There are approximately 6000 new cases each year in Sweden and the disease specific mortality is more than 40%. There risk is about 1% to develop CRC between 60-70 years of age making 60-year olds a suitable target population for colorectal cancer screening.

The Swedish ministry of health and social affairs proposed a national study on the efficiency of colorectal cancer screening in the Swedish population regarding mortality, but also what screening method to be used. Eighteen participating counties of Sweden now fund the study to be launched in 2014.

From the Register of the total population individuals 59-62 years of age will be randomized and invited by mail to screening. Thirty- thousand five hundred individuals will be invited to primary colonoscopy and 60 000 individuals will be invited to high sensitive FIT (approximately 10% positive) and if positive to a subsequent follow-up colonoscopy. If test negative a second round of FIT will be asked for in two years. In total 183 000 randomized individuals will not be invited to screening, but followed in the Swedish Cancer register and serve as controls. The inclusion period I set to five years (five years with the second round of FIT) generating approximately 5 000 colonoscopies yearly the first three years and 1200 year four and five at a compliance rate of 35% in the colonoscopy arm and 50% in the FIT arm.

Follow-up time is set to 15 years with the primary endpoint disease specific mortality, but also incidence. Secondary outcomes by others to be studied are in short quality assurance variables of colonoscopy, participants and non-participants experiences of the invitation and the screening procedure, health economy measures of the CRC-screening study and when implemented in clinical care.

Background: The primary purpose of cancer screening is to reduce mortality from the disease in the population by finding the cancer at an early and treatable stage. The cancer has to be an important health problem to be a suitable target for screening. With approximately 6 000 new cases each year in Sweden (Cancer register), colorectal cancer (CRC) is the third most common cancer in Sweden and the five-year survival rate is close to 60%, but when detected at an early stage the rate is 90%.

Both larger precursor stages - the adenomatous polyp (Muto, Vogelstein) - and cancers could be detected by sensitive methods to analyze blood in the stool. Removal of adenomas has a protective effect against colorectal cancer development (Winawer, Muller, Thiis-Evensen) and, consequentially, a colorectal cancer screening program also have the potential of decreasing the future incidence of the disease.

The screening test must be free from unwanted side effects, inexpensive, but also simple to take and easy to interpret (Armitage). Furthermore, a high sensitivity and specificity is a prerequisite for a screening test to be used in a program of the average risk population.

Indirect tests: The most commonly used screening test has been the guaiac based fecal occult blood test (Hemoccult®). Four larger RCTs have demonstrated a 16% decreased in CRC mortality with the test in screening (Mandel, Kronborg, Hardcastle, Lindholm). More advanced fecal immunological tests (FITs) with higher sensitivity, but only a marginally increase in specificity, are now available. FIT demonstrates presence of human blood only and no dietary restrictions are needed.

Direct tests: The main advantages with endoscopy are the direct visualization of the colorectum and the possibility of obtaining tissue samples from suspected cancer lesions for histopathology and removing adenomatous polyps. Recently, three RCTs with sigmoidoscopy as the primary screening test have demonstrated both a reduced disease specific mortality of around 30%, but also a reduced incidence of CRC of as much as 40% (Atkin, Segnan, Schoen).

Up to now, there are no larger randomized controlled studies of the average risk population published demonstrating a disease specific mortality reduction with colonoscopy as the primary screening test.

Compliance: compliance is the proportion of individuals offered a screening test and actually take the test (Armitage). The compliance to a screening program is a major determinant of the programs effectiveness - only those who participate can contribute to the mortality reduction achieved by the screening program and with low participation the number of deaths prevented will be few.

A call for a Swedish study of colorectal cancer screening: The Swedish minister of Health and Social affairs, Göran Hägglund, funded a task force in 2011 in order to design a study of the effectiveness of colorectal cancer screening of the average risk population of Sweden. The present study was designed based on what data was needed to get better outcome of colorectal cancer screening in Sweden. All counties participate except for Stockholm and Gotland, due to the already implemented CRC-screening program with Hemoccult®, and the county of Västernorrland.

Material and Methods - study population: In total 200 000 individuals and residents of Sweden will be randomized from the Register of the total population (Register of the total population). The randomized individuals will turn 60-years old the calendar year of randomization. Thirty thousand five hundred individuals will be invited to a primary screening colonoscopy, 60 000 individuals will be invited to high sensitive FIT and, if positive, to a subsequent colonoscopy and 183 000 persons will serve as controls. The inclusion period is set to five years with a repeated test after two years in the FIT arm.

Invitation procedures - FIT: All individuals randomized to FIT as primary screening test will by regular mail receive an invitation to participate in the study. The invitation includes a brochure with information about the incentives of the study and the need for a follow-up colonoscopy in case of a positive test. The invitation contains a FIT-kit for two separate test samples and instructions on how to take the test. With the invitation is a pre-paid return-envelope.

Colonoscopy: All individuals randomized to the colonoscopy arm will receive an invitational letter by regular mail including the brochure with information about the incentives of the study. The invitee will be informed that they shortly by mail will receive an appointment for colonoscopy, sent from the endoscopy clinic in their area of residency.

Controls: The individuals randomized to the control arm will not be contacted and informed about participation as controls in the study. If any individuals would contact the Head secretariat to ask about if they are controls, information will be given.

Interventions - FIT-arm: We plan two rounds of FIT, one the first year and one the third year. We will follow the findings and perform interim analyses and suggest that further rounds of FIT are carried out if the scientific committee deems it necessary. Two tests per round will be asked for without dietary restrictions. If 50% of the invitees comply and send their FIT test to the laboratory (experiences from the ongoing screening program in the counties of Stockholm and Gotland) and 10% are positive, this will generate approximately 1 200 colonoscopies for each year in the FIT-arm except for year four when the number of generated colonoscopies is estimated to 2 400 due to the second round re-testing.

Colonoscopy-arm: A primary screening colonoscopy will be carried out once and with an estimated adherence of about 35%, approximately 10 000 colonoscopies will be carried out. The examination will be performed with or without sedation following a standard bowel cleaning preparation. The endoscopy centers will be accredited and the quality of the examiners will be investigated. The preparations of the bowel will be standardized. All details will follow the European guidelines (von Karsa, Rembacken).

There will be a thorough evaluation of each endoscopist from a quality aspect according to set guidelines. This will be carried out by using a specific quality register in the IT-system where data on the success rate of the colonoscopist, findings and side effects will be entered from all the estimated 17 000 colonoscopies. In the study registry, adverse advents such as pain, bleeding and perforations will also be collected. The register data will continuously be cross-linked with data from the National Patient register (Patient register) and the Swedish Causes of Death register (Cause of death register) in order to find severe adverse events.

Follow-up: Follow-up time is set at 15 years after inclusion and invitation for the primary endpoints colorectal cancer mortality and incidence with interim analysis at 5 and 10 years. Data of all 200.000 individuals randomized from the population register will be obtained from the Causes of Death register (19) and the Cancer register (1). Regarding secondary outcomes, information will be retrieved from other national registries such as the Patient register (18).

Ethical considerations: The study has been processed and approved by the regional Ethics Review Board at Karolinska Institutet, Stockholm, Sweden (No. 2012/2058-31/3).

Statistical analyses: The lifetime cumulative mortality in colorectal cancer in Sweden is about 1% after 15 years. With a 80% power and a 2.5% significance level according to the Bonferroni method the present study need to randomize 30 500 persons in the colonoscopy arm, 60 186 in the FIT arm and 183 372 in the control arm. Based on previous studies, we estimate that the reduction in mortality to about 30% for those examined with FIT and a subsequent colonoscopy and approximately 35% for individuals who are examined with a primary colonoscopy. The compliance is estimated to about 50% in the FIT-arm and approximately 10% of them will have a positive test and invited to follow-up colonoscopy with 80-90% adherence rate. Compliance with primary colonoscopy is estimated to 50% and there is supposed to be a very low contamination from opportunistic screening.

Inclusion Criteria:

• People 59-62 years old living in Sweden randomized and identified through the Register of the total population.

Exclusion Criteria:

• Residents of the counties of Stockholm, Gotland and Västernorrland, individuals with diagnosed with colorectal cancer and/or anal cancer, and individuals randomized to be included in the ongoing NordICC-trial.