SCREESCO - Screening of Swedish Colons
Phase: NA
Conditions: Colorectal Cancer
Sponsor: Uppsala University Hospital

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SCREESCO – Screening of Swedish Colons 
 
Study Protocol Version 3.0 
2025-01-16 
 
 
Principal investigator of SCREESCO and endoscopist: Dr Anna Forsberg, Division 
of Clinical Epidemiology, Department of Medicine K2, Solna, Karolinska 
Institutet, Stockholm, Sweden. Email: anna.forsberg@ki.se   
 
Chair of the SCREESCO scientific committee and epidemiologist: Dr Jonas F. 
Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska 
Institutet, Stockholm, Sweden, and the Department of Pediatrics, Örebro 
University Hospital, Örebro, Sweden. 
 
Medical statistician: Chris Metcalfe, Bristol Medical School: Population Health 
Sciences, University of Bristol, United Kingdom. 
 
Epidemiologist: Ulf Strömberg, School of Public Health and Community Medicine, 
Institute of Medicine, Sahlgrenska Academy at University of Gothenburg. 
 
Research group leader of Cancer prevention and screening, Karolinska Institutet: 
Johannes Blom, Department of Surgery, Södersjukhuset, and Department of 
Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden. 
 
Expertise in microbiome analyses, logistics, storage, DNA extraction and 
metagenome sequencing: Lars Engstrand, Department of Microbiology and 
Department of Tumor and Cell Biology. 
 
Expertise in qualitative research: Kaisa Fritzell, Department of Neurobiology and 
Department of Care Sciences and Society. 
 
Radiology specialist in abdominal imaging, expertise in evaluation of diagnostic 
tests: Mikael Hellström, Department of Radiology, Institute of Clinical Sciences at 
Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. 
 
Specialist in Clinical Chemistry and Laboratory Medicine: Christian Löwbeer, 
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska 
Institutet, Stockholm, Sweden, and Department of Clinical Chemistry, SYNLAB 
Sverige, Täby, Sweden. 
 
Senior scientific advisor, expertise in screening and surgery: Robert Steele, 
Department of Surgery, Population Health and Genomics, School of Medicine, 
University of Dundee, Ninewells Hospital, Dundee DD1 9SY, United Kingdom. 
 
Senior scientific advisor, expertise in screening and surgery: Lars Holmberg, 
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden, and 

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Translational Oncology & Urology Research (TOUR), School of Cancer and 
Pharmaceutical Sciences, King’s College London, London, UK. 
 
Principal Statistician and Data Manager of SCREESCO: Marcus Westerberg, 
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. 
 
 
 

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Summary 
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%. The 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 has 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. Thirteen 
participating counties of Sweden now fund the study to be launched in 2014. 
 
Individuals 60 years of age will be randomized from the population register and 
invited to screening by mail. 31,140 individuals will be invited to primary 
colonoscopy and 60,300 individuals will be invited to high-sensitive FIT (OC 
Sensor) with approximately 10% positivity rate and, if positive, to a 
subsequent follow-up colonoscopy. When test negative a second round of FIT 
will be asked for in two years. In total 186,840 randomized individuals will not 
be invited to screening serve as controls and will be followed in the Swedish 
Cancer Register. The inclusion period is set to five years (five years including the 
second round of FIT) generating approximately    17,000 colonoscopies 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 and colorectal cancer 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of contents 
1. Background ............................................................................................................................... 6 
1.1 Colorectal cancer and screening ............................................................................... 6 
1.2 Evaluation of a screening program .......................................................................... 6 
1.2.1 Effectiveness ............................................................................................................. 6 
1.2.2 The screening test .................................................................................................. 7 
1.2.3 Compliance ................................................................................................................ 8 
1.2.4 Cost-effectiveness ................................................................................................... 8 
1.3 Challenges in colorectal cancer screening ............................................................. 9 
1.3.1 Colonoscopy quality assurance ......................................................................... 9 
1.3.2 Lack of pathologists ............................................................................................... 9 
1.3.3 Compliance and emotional effects ................................................................... 9 
1.4 Colorectal cancer screening in Sweden .................................................................. 9 
1.5 A call for a population-based Swedish CRC-screening study ...................... 10 
2. Study aims .............................................................................................................................. 10 
2.1 Primary endpoints ....................................................................................................... 10 
2.2 Secondary endpoints ....................................................................................................... 10 
3. Material and Methods ........................................................................................................ 11 
3.1 Study population .......................................................................................................... 11 
3.1.1 Inclusion criteria .................................................................................................. 11 
3.1.2 Exclusion criteria ................................................................................................. 11 
3.1.3 Randomization ...................................................................................................... 11 
3.2 Invitation procedures ................................................................................................. 11 
3.2.1 Colonoscopy arm ................................................................................................. 11 
3.2.2 FIT arm .................................................................................................................... 12 
3.2.3 Controls ................................................................................................................... 12 
3.2.4 Undelivered invitations ..................................................................................... 12 
3.3 Interventions ................................................................................................................. 12 
3.3.1 Colonoscopy arm ................................................................................................. 12 
3.3.2. Primary colonoscopy appointment ............................................................. 12 
3.3.3 FIT arm and the positivity rate....................................................................... 12 
3.3.4 Two rounds of FIT ............................................................................................... 13 
3.3.5 Information of FIT-result .................................................................................. 13 
3.3.6 Reminder and default returned FIT ............................................................. 13 
3.3.7 FIT returned after 6 months ............................................................................ 13 

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3.3.8 Follow-up colonoscopy appointment of individuals with positive FIT
................................................................................................................................................ 13 
3.3.9 Bowel preparation for colonoscopy ............................................................. 14 
3.3.10 Medical history taken at telephone confirmation of appointment 14 
3.3.11 Reminder of follow-up colonoscopy .......................................................... 14 
3.3.12 Follow-up after positive FIT follow-up colonoscopy .......................... 14 
3.3.13 Positive FIT and asking for a new FIT replacing colonoscopy ........ 14 
3.3.14 Weight and height measurement and nurse questionnaire ............. 14 
3.3.15 Blood sample at colonoscopy ....................................................................... 14 
3.3.16 Positive finding at colonoscopy ................................................................... 14 
3.3.17 Individuals with positive FIT but negative colonoscopy ................... 15 
3.3.18 Questionnaire after the colonoscopy ........................................................ 15 
3.4 Informed consent ......................................................................................................... 15 
3.5 Quality assurance of colonoscopy ......................................................................... 15 
3.6 Pathology ......................................................................................................................... 16 
3.7 Secondary studies ........................................................................................................ 16 
3.8 Follow-up ........................................................................................................................ 17 
4. Ethical considerations ....................................................................................................... 17 
5. Statistical analyses .............................................................................................................. 17 
6. Data management ............................................................................................................... 18 
7. Head secretariat ................................................................................................................... 18 
8. Participating centers supplement: sites and local PIs ........................................... 19 
9. Main study publications .................................................................................................... 20 
10. Scientific committee ........................................................................................................ 21 
11. Figures ................................................................................................................................... 23 
11.2 Figure 1.......................................................................................................................... 23 
11.1 Figure 2.......................................................................................................................... 24 
12. References ........................................................................................................................... 25 
13. Summary of changes to the SCREESCO study protocol and statistical 
analysis plan 2013-2024 ....................................................................................................... 28 
 
 
 
 
 
 

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1. Background 
1.1 Colorectal cancer and screening 
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 (1), 
colorectal cancer (CRC) is the third most common cancer in Sweden (after 
prostate- and breast cancer) and, hence, a relatively common disease, but it is 
also a major cause of death. There is a 1% risk to develop CRC between the ages 
60-75 years, and the five-year survival rate is close to 60%. The prognosis is 
related to if the cancer is detected at an early or late stage of the disease. When 
detected at an early stage, there is a 90% five-year survival, as compared to only 
a 10% five-year survival if the cancer at detected at a late stage.  
 
CRC is usually detected clinically by patient symptoms, either an alteration in 
bowel habits due to obstruction of the lumen, visual blood in the stool or 
symptoms due to anemia caused by a bleeding from the tumor. Both larger 
precursor stages – the adenomatous polyp (2, 3) – and cancers bleed and could 
be detected by sensitive methods to analyze blood in the stool. All patients 
diagnosed with colorectal cancer need treatment, but there is a significant 
difference in suffers and costs depending on the stage the disease at diagnosis. 
With screening early stages of the disease will be found before they are clinically 
detected. 
 
Removal of adenomatous polyps (adenomas) has a protective effect against 
colorectal cancer development (4, 5, 6) and, consequentially, a colorectal cancer 
screening program also might have the potential of decreasing the future 
incidence of the disease.  
 
1.2 Evaluation of a screening program 
1.2.1 Effectiveness 
The effectiveness of a screening program is the ability of the program to reduce 
the disease specific mortality. Survival is not a valid measure of effectiveness 
because of the possibilities of bias; selection bias (when screened subjects and 
non-screened controls represent different populations), lead time bias (earlier 
diagnosis in screen-detected cancers adds time to the total survival time) and 
length biased sampling (screen-detected tumors often grow slowly and might be 
less malignant). 
 
The most valid measure of effectiveness in screening is a lower mortality in the 
screened group, as compared to the non-screened group evaluated in a 
randomized controlled trial (RCT):  

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1.2.2 The screening test 
A large majority of individuals in the general population using the screening test 
offered will not have colorectal cancer. Therefore the test must be free from 
unwanted side effects, inexpensive, but also simple to take and easy to interpret 
(7). Furthermore, a high sensitivity (to limit the number of missed cancers) and 
specificity (to limit the number of incorrect diagnosed cancers), is a prerequisite 
for a screening test to be used in a program of the average risk population. 
 
There are a number of screening tests and methods to examine the colorectum in 
order to find CRC and/or adenomatous polyps:  
 
Indirect tests: The most commonly used screening test has been the guaiac based 
fecal occult blood test (FOBT) (Hemoccult). Four larger RCTs have 
demonstrated a 16% decreased in CRC mortality with the test in screening (8, 9, 
10, 11). The degree of mortality reduction with Hemoccult depends on the 
compliance with the test and the dietary restrictions, the sensitivity of the test, 
the screening frequency (annual or biennial), the number of screening rounds 
the subjects participate in and, also, the compliance with the diagnostic follow-
up colonoscopy after a positive test. More advanced fecal immunological tests 
(FITs) with higher sensitivity, but only a marginally increase in the false positive 
rate (specificity), are now available. FIT demonstrates presence of human blood 
only, as opposed to the guaiac test that also can be positive due to animal 
hemoglobin. Moreover, no dietary restrictions are needed with FIT. 
 
Direct tests: The main advantages with endoscopy (e.g. colonoscopy and 
sigmoidoscopy) are the direct visualization of the colorectum and the possibility 
of obtaining tissue samples from suspected cancer lesions for histopathology 
and/or removing adenomatous polyps during the procedure. The bowel can be 
examined with sigmoidoscopy and a subsequent colonoscopy in case of 

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pathological finding within the reach of the sigmoidoscope (approximately 60 
cm) or with a complete colonoscopy as primary test (when 1/3 of tumors will 
appear in the right part of the colon). Recently, three randomized controlled 
trials 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% (12, 13, 14).   
 
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.   
 
1.2.3 Compliance 
The proportion of individuals offered a screening test who take the test is 
referred to as compliance (7). The compliance to a screening program is a major 
determinant of the program’s effectiveness and there has to be a rigid 
organization with a call- recall system and quality assurance in a screening 
program to be effective (15).  
 
Instead of number needed to treat (NNT) used to estimate the efficacy in 
interventional RCTs evaluating medication, the number needed to screen (NNS) 
is used in the evaluation of RCTs of screening. The NNS is the number of 
individuals who need to be invited (offered) screening to prevent one death 
(intention-to-screen). The results then reflect the efficacy of the screening 
program to reduce mortality among those invited to screening. With NNS there is 
often an underestimation of the efficacy of the screening test in those people 
who actually participate – are being screened. The NNS for most screening 
programs are usually much higher than the number of people who have to 
participate to prevent one death (16). It is only the participants that can 
contribute to the mortality reduction achieved by the screening program and 
with low compliance the number of deaths prevented will be few, and 
consequently the NNS will be large (16). Therefore, a high participation rate in a 
screening program is important to be able to evaluate its effectiveness on 
mortality. 
 
1.2.4 Cost-effectiveness 
There are a large variety of variables involved when measuring the cost-
effectiveness of a colorectal cancer screening program and focus cannot only be 
on the eventual incidence and mortality reduction of the disease. Firstly, one has 
to make assumptions about the duration of the early, asymptomatic and curable 
stage of the disease. Secondly, one has to estimate the effectiveness and negative 
effects of the screening procedure, such as morbidity due to complications and 
costs. A low compliance in a screening program will both effect the incidence and 
mortality reduction achieved and the cost-effectiveness of the program. 
 
 
 
 
 

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1.3 Challenges in colorectal cancer screening 
1.3.1 Colonoscopy quality assurance 
There are some outstanding challenges in implementing colorectal cancer 
screening for the average risk population. One important issue is the quality 
assurance of the endoscopic examinations and the follow-up of eventual findings. 
If the quality of the examinations is not excellent, but with frequent practical 
mistakes and neglect to find adenomas and or cancers, the positive effect of the 
screening procedure for that particular individual and of the program as a whole 
is both diminished and unethical (17, 18, 19, 20, 21).  
 
Colonoscopy resources and quality will be a key issue in the present study. 
Currently in Sweden, about 65 000 procedures are carried out outside the 
Stockholm area yearly, while approximately 30 000 are carried out in Stockholm. 
A crude estimate is that a future national screening program will need a 
substantial number of colonoscopies, and, thus, much work is needed to both 
increase the number of colonoscopies performed nationally and also increase 
and secure the quality of the investigations.   
 
Adenomatous polyps should be removed in order to prevent the occurrence of 
CRC. The removal of adenomas is a sometimes difficult and dangerous 
procedure, since it may cause bleeding and perforation of the bowel wall. It is 
important that the adenoma is completely removed and correctly diagnosed. 
Thus, both a skillful endoscopists and high-quality histopathology are extremely 
important.  
 
1.3.2 Lack of pathologists 
Another problem when implementing a screening program is the created 
increased burden for pathologists. There is a need for standardization of the use 
of the diagnostic criteria and the possibility to have a group of pathologists to 
evaluate the sections. In order to do so, it would be of great advantage if the 
histological sections could be stained and digitally processed and evaluated 
electronically. 
 
1.3.3 Compliance and emotional effects 
Another important factor, in need of further studies, is the actual adherence rate 
or compliance discussed above and the emotional effects of the inclusion of 
healthy persons from the general population in colorectal cancer screening (22, 
23, 24, 25). 
 
1.4 Colorectal cancer screening in Sweden 
The National Board of Health and Welfare has not been recommending CRC 
screening due to lack of experiences of screening in routine health care and refer 
CRC screening to the Research and Development list waiting for studies outside 
Sweden to generate results. Based on the results from the four RCTs with a net 
CRC-mortality reduction of 16% (8, 9, 10, 11) the Council of the European Union 
in 2003 recommended CRC-screening with guaiac-based fecal occult blood test 
(FOBT) in the average risk population aged 55-74 years old. The 
recommendations have recently been updated in the European Guidelines of 

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Quality Assurance in CRC-screening (26) and as a result, national CRC-screening 
programs with guaiac-based FOBT have started around Europe, e.g. United 
Kingdom, Finland, France, Italy and shortly in Denmark and Norway. In Sweden, 
only the counties of Stockholm/Gotland have an organized colorectal cancer 
screening program of the 60-69 years old general population using guaiac-based 
FOBT as the primary screening test.  
 
1.5 A call for a population-based Swedish CRC-screening study 
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 Swedish Association of 
Local Authorities and Regions (SALAR) organized the task force in cooperation 
with the newly started Regional Cancer Centers of Sweden. A committee was 
formed with one committee member from each national center and professor 
Rolf Hultcrantz, the Principal Investigator of the present study, has been the 
chairman of the committee. The present study was designed based on what data 
was needed to get better outcome of colorectal cancer screening. The study 
design was submitted in January 2012 to the Ministry of Health and Social affairs 
and, since then, a thorough work has been carried out in order to get all counties 
in Sweden to fund the study. Eighteen counties in Sweden achieved the funding 
in March 2013 covering the actual screening procedures. The counties of 
Stockholm and Gotland cannot take part in the study due to the already 
implemented CRC-screening program with Hemoccult. 
 
 
2. Study aims 
2.1 Primary endpoints 
1. To investigate if colorectal cancer screening has an effect on the mortality 
from colorectal cancer in the Swedish population. 
2. To investigate if colorectal cancer screening has an effect on the incidence of 
colorectal cancer in the Swedish population. 
3. To investigate what method should be used in Sweden regarding the effect 
according to 1 and 2. 
 
2.2 Secondary endpoints 
- To study associations of DNA in blood with findings at colonoscopy 
 
- To study the FIT microbiome profile in CRC patients and controls to identify 
microbial biomarkers that are associated with colonoscopy findings 
 
 
 
 

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3. Material and Methods 
3.1 Study population 
In total 278,280 individuals, residents of Sweden will be randomized from the 
population register maintained by Swedish tax agency (Skatteverket) (27). The 
randomized individuals will turn 60-years old the calendar year of 
randomization. 31,140 individuals will be invited to a primary screening 
colonoscopy, 60,300 individuals will be invited to high-sensitive FIT and, if 
positive, to a subsequent colonoscopy and 186,840 persons will serve as controls 
(11. Figure 1 and 2). The inclusion period is set to three years with a repeated 
test after two years in the FIT arm. 
 
3.1.1 Inclusion criteria 
All individuals 60 years old and living in Sweden and randomized and identified 
through the Register of the total population. 
 
3.1.2 Exclusion criteria 
Residents of the counties of Stockholm and Gotland, individuals with a diagnosis 
of colorectal cancer and/or anal cancer in the continuous updated cancer 
registers run by the local Regional Cancer Centers, individuals randomized to be 
included in the ongoing NordICC-trial (28) and individuals living in 
Västernorrland County – the only county (region) in Sweden except for 
Stockholm/Gotland not participating in the study. 
 
3.1.3 Randomization  
From the Swedish tax agency three sets of individuals by random from the 
population register (27) will be asked for, approximately 67 000 individuals each 
born in 1954, 1955 and 1956. The randomization process will then be performed 
at the Head secretariat in the beginning of 2014, 2015 and 2016 and in the 
colonoscopy arm 2017, 2018): 
 
- 
6,700 individuals born 1954, 1955, 1956 will randomized, by county 
(region) in proportion to the population, to be invited to primary 
colonoscopy (3.2.1 Colonoscopy) and 5,250 born in 1957 and1958. 
- 
Three individuals per primary colonoscopy individual will be matched 
according to year of birth, gender and county (region) of residence and 
invited to FIT (3.2.2 FIT).  
- 
Six individuals per primary colonoscopy individual will be matched 
according to year of birth, gender and county (region) of residence and 
serve as controls. 
 
 
3.2 Invitation procedures 
3.2.1 Colonoscopy arm 
All individuals randomized to the colonoscopy arm will receive an invitation 
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 within 8 weeks, sent from the 
endoscopy clinic in their area of residency. 

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3.2.2 FIT arm 
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 for submitting the two tests together 
directly to the analyzing laboratory. The returned FIT will be stored in Bio bank 
after analysis.  
 
3.2.3 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. 
 
3.2.4 Undelivered invitations 
All invitations will be sent by the Regional Cancer Center, Uppsala/Örebro, 
where the Head secretariat of SCREESCO is located. Undelivered and returned 
invitations will be sent out a second time. Since allocation to intervention is by 
random, we believe the number of undelivered invitations will be approximately 
the same in both intervention arms. 
 
3.3 Interventions  
3.3.1 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 performance of the examiners will be investigated. All requirements will 
follow the European guidelines (26).  If the colonoscopy is not complete the 
participant is offered to be examined again with colonoscopy or CT colonoscopy.  
 
3.3.2. Primary colonoscopy appointment 
With the colonoscopy appointment (within 8 weeks) sent after the initial 
invitation letter are instructions to call and confirm the appointment, following 
the same procedure as the participants with a positive FIT (3.3.9 Bowel 
preparation for follow-up colonoscopy). A difference, though, is that in the group 
randomized to primary colonoscopy screening, a reminder will be sent out from 
the CIS-S if no confirmation of the colonoscopy appointment has been performed 
within 8 weeks. The endoscopy site will then send a new colonoscopy 
appointment (within 8 weeks) to be confirmed as previously described. 
 
3.3.3 FIT arm and the positivity rate 
A high-sensitive FIT (OC-Sensor) with about 10% positivity rate will be used. 
The screening method of FIT is well known and established with an adjustable 
positivity rate from about 2% up to almost 10% (with an opposed effect on 

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specificity). Almost all individuals have traces of blood and hereby hemoglobin in 
their feces, why the level of sensitivity of the test is an important balance of not 
missing any lesions, but at the same time minimizing the total number of false 
positive tests. In SCREESCO people are regarded as having a positive test result if 
at least one out of the two test samples are positive, i.e. above the set cut off level 
of 50 µg Hb/L (50 ng Hb/mL). With the used OC-Sensor 1 µg Hb/L buffer = 0,2 
µg Hb/g feces, i.e. 50 µg Hb/L buffer equals 10 µg Hb/g feces. 
 
3.3.4 Two rounds of FIT  
We plan two rounds of FIT – one the first year and one the third year. All 
individuals randomized to the FIT-arm will have new test-kits sent home after 
two years, regardless of compliance with the invitation to the first round. 
Previous studies have been performed with FOBT every second year for ten 
years and 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.  
 
3.3.5 Information of FIT-result 
All participating individuals in the FIT-arm will be informed about their test 
result by mail within 4 weeks after the test was sent in. People with a negative 
test result will in the same mail be informed that a new test-kit will be sent after 
two years. People with positive test will be informed by mail that they within one 
week will get a colonoscopy appointment (within 4 weeks instead of 8 weeks as 
in primary endoscopy arm [3.3.1] due to positive test) by mail sent by the 
endoscopy site in their area of residency.  
 
3.3.6 Reminder and default returned FIT 
People with no tests sent in will get a reminder by mail after 8 weeks and with 
instructions to call to receive new test kits if they are missing. People with 
default FITs sent in will receive new test kits with instructions. 
 
3.3.7 FIT returned after 6 months 
FIT returned after 6 months will be scientifically handled as non-compliers. The 
test results are expected un-valid due to expiring date of the test. 
 
3.3.8 Follow-up colonoscopy appointment of individuals with positive FIT 
The endoscopy site in the participants geographical area of residency will 
electronically within the Central IT-Support System – Study (CIS-S) (6. Data 
management) simultaneously receive the information about the participant who 
needs an appointment for colonoscopy and book one. 
 

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3.3.9 Bowel preparation for colonoscopy 
Instructions to call and confirm the colonoscopy appointment within the 4 weeks 
is included with the mailed colonoscopy appointment and after confirmation the 
participant with a positive FIT will receive bowel preparation (Laxabon®) by 
mail without charge. Split dose is highly recommended (26). 
 
3.3.10 Medical history taken at telephone confirmation of appointment 
At confirmation of the colonoscopy appointment the study nurse will ask a few 
specific questions about the health status of the invitee, including medications 
(e.g. Warfarin®) and check with the responsible physician in doubt of 
colonoscopy risks. The invitee will also at the telephone conversation be able to 
ask questions about the colonoscopy.  
 
3.3.11 Reminder of follow-up colonoscopy 
Without confirmation by telephone a reminder together with a new colonoscopy 
appointment time is sent out from the corresponding endoscopy site, following 
the same confirmation procedure as above.  
 
3.3.12 Follow-up after positive FIT follow-up colonoscopy 
Individuals with no pathological finding at colonoscopy will be invited to a 
second FIT after two years and individuals with a pathological finding will be 
followed regarding to the specific clinical guidelines. 
 
3.3.13 Positive FIT and asking for a new FIT replacing colonoscopy 
Individuals asking for a new FIT instead of a follow-up colonoscopy after a 
positive test will not have this option. In the study, all positive FIT will be 
followed by a colonoscopy. All individuals invited to the FIT-arm will have a 
second round of FIT sent home after two years (except those who had a cancer 
diagnosis or polyp findings requiring surveillance) 
 
3.3.14 Weight and height measurement and nurse questionnaire 
At both primary colonoscopy and follow-up colonoscopy after a positive FIT, the 
nurse will weigh and measure height (not only asked for) and ask up to ten 
health questions regarding e.g. smoking, alcohol and use of non-steroid anti-
inflammatory drugs to be registered in the CIS-S. The questions will be asked 
before the colonoscopy to limit re-call bias.  
 
3.3.15 Blood sample at colonoscopy 
At colonoscopy the participant will be asked to leave two blood samples 
(EDTA®) to be stored in Biobank for future analyses after signing an informed 
consent (3.4 Informed consent). The individual can decline leaving blood 
samples for the study, but participate with colonoscopy. 
 
 
 
3.3.16 Positive finding at colonoscopy 
Individuals with pathological finding at colonoscopy, i.e. colorectal cancer or 
advanced adenomas qualifying to the adenoma surveillance program, will be 

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followed regarding to the specific local clinical guidelines. No further screening 
test will be offered within the study for this category of patients. Patients with 
other findings at colonoscopy, e.g. inflammatory bowel disease, will be taken care 
of by the performing endoscopist, but not excluded from a second round of FIT-
screening within the SCREESCO-study if randomized to the FIT intervention arm.  
 
3.3.17 Individuals with positive FIT but negative colonoscopy 
Individuals with a positive FIT but with a negative colonoscopy (no adenoma or 
colorectal cancer) will not be investigated further within the study, except for a 
second round of FIT after two years if randomized to the FIT intervention arm. 
 
3.3.18 Questionnaire after the colonoscopy 
After the colonoscopy, the participant will receive a short questionnaire about 
their experiences of the invitation to screening, bowel preparation and 
colonoscopy examination, together with a pre-paid return envelope addressed to 
the endoscopy unit. The participant will be asked to fill out and post the 
questionnaire within 24 hours.  
 
3.4 Informed consent 
The SCREESCO-study has approval from the Ethical Review Board (No. 
2012/2058-31/3) Stockholm, Sweden, that a returned FIT-test is to be regarded 
as informed consent to participate in the study. At colonoscopy, an informed 
consent is signed by both the study participant in the primary intervention arm, 
the individuals with a positive FIT and the endoscopist informing about the 
procedure. The informed consents will be stored at the endoscopy site.  
 
3.5 Quality assurance of colonoscopy 
A specific part of the study will be aimed at studying the outcome of the 
estimated 17 000 colonoscopies. The patients will be subjected to colonoscopy in 
33 different centers throughout Sweden in the 18 participating regions 
(counties). Previous work in this field has demonstrated that a good quality 
endoscopist should perform more than 100 procedures/year and be able to 
detect adenomas in more than 20 % of the examinations. Moreover, following 
intubation of the instrument to the caecum, the withdrawal time should be more 
than six minutes.  
 
There will be a thorough evaluation endoscopist performance according to set 
guidelines. This will be carried out by using a specific quality register in the CIS-
S, 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 (29) and the Swedish Causes of Death register (30) in 
order to find severe adverse events.  
 
The colonoscopy performance register will contain a unique set of data, which 
could be used for both colonoscopy development as well as the follow-up of the 
safety and success in a screening setting – enabling correlation of the 

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performance regarding findings and adverse events of each endoscopist and the 
previous described quality indicators. The results will be stratified by different 
categories of endoscopists, those with high and medium numbers of procedures 
annually, with special focus on nurses performing endoscopies since involving 
nurses in the endoscopies may be an important step and a key to a successful 
CRC-screening program in the country.  
 
An internet-based on-line system to connect one endoscopist with a set of 
experts will be developed within the study to deliver immediate second opinion 
of findings during a procedure. Criteria for the identification of adenomatous 
polyps as opposed to hyperplastic polyps (31) during the endoscopy will also be 
developed in the study. Hyperplastic polyps are unlikely to develop dysplasia 
and, hence, do not have to be removed. If they can be identified in the endoscope 
much work is saved and patient safety is improved. 
 
Moreover, both primary screening colonoscopies and follow-up colonoscopies 
after a positive FIT test will be evaluated with a participant questionnaire (3.3.18 
Questionnaire after the colonoscopy). 
 
3.6 Pathology 
All removed adenomatous polyps will be sent for histopathology and stored in a 
biobank (Biobank of the Karolinska Institute) for further analyses. 
Approximately 11 000 adenomas will be removed during the study. A new 
technique for digitalization of sections from adenomas larger than 10 mm will be 
developed. Digital images will be made in Aperio machines from sections of 
adenomas and stored. These images will be used for quality studies to develop 
processes for diagnostic procedures in pathology in colorectal screening. 
Secondary studies on correlation of evaluation between various pathologists will 
be performed in order to create kappa-values in collaboration with Swedish 
gastrointestinal pathologists in the KVAST (Kvalitets- och 
standardiseringskommittén [in Swedish]) Study Group of the Swedish Society 
for Pathology (32). The data will be used to demonstrate which type of 
adenomas need to be extra carefully resected and which of them are especially at 
risk to develop new adenomas. The purpose is to combine these results with the 
results from the colonoscopy investigation in order to possibly reduce the 
number of polyps needed to be resected generating a decreased risk for 
perforation of the colonic wall by the procedure and also a reduced work-load 
for both endoscopists and pathologists (31).   
 
3.7 Secondary studies 
The following secondary studies are planned:  
 
 Complier and non-complier experiences  
 Health-economy: intervention arms versus control arms 
 Quality assurance of primary and secondary screening tests 
 DNA in blood and advanced colorectal neoplasia 
 Microbiome in feces 

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 Socio-economical inequities in screening participation and in screening-
detected colorectal findings  
 
3.8 Follow-up 
Follow-up time is set at 15 years after inclusion and invitation for the primary 
endpoint colorectal cancer mortality and incidence. The previous versions of the 
Study Protocol did not however specify when in calendar time the analysis 
should be performed. The Scientific Committee assessed in 2024 the impact of 
choice of date for the end of follow-up on the statistical precision for comparing 
colorectal cancer specific mortality between each of the two active screening 
arms and the control arm and decided the last date of follow-up is 2030-12-31 
(see the Statistical Analysis Plan 3.0 for details). The Scientific Committee also 
decided, in contrast to what was initially specified, that no interim analyses will 
be performed for the primary endpoint. 
 
Data of all  278,280 individuals randomized from the population register (FIT-, 
primary colonoscopy- or control arm) will be obtained from the Causes of Death 
register (30) and the Cancer register (1) managed by the Swedish National 
Board of Health and Welfare. Regarding secondary outcomes, e.g. quality control 
of performed colonoscopies and non-steroid anti-inflammatory drugs and 
adenoma development, information will be retrieved from registries such as The 
Swedish National Patient Register (29) and The Swedish Prescribed Drug 
register (33). 
 
 
4. Ethical considerations 
To randomize people from the Total Population Register and invite them to 
screening colonoscopy (or not when control) is an ethical challenge. Primarily, 
we do have to consider possible risks for the participants, i.e. side effects of the 
primary and follow-up colonoscopies, but secondarily, we also have to consider 
the stress a false positive test could generate. Furthermore, we will cross link 
register information of individuals randomized as controls without their 
informed consent and the information generated must be treated rigorously and 
that is why the controls are de-identified and the register information gathered 
aggregated at group level. On a population level, it is of utter most importance 
that the study is performed. Most certainly, due to the increasing frequency of 
opportunistic screening, we only have one chance to get a solid answer to our 
primary endpoint - to investigate if colorectal cancer screening has an effect on 
the mortality from colorectal cancer in the Swedish population. The study has 
been processed and approved by the regional Ethics Review Board at Karolinska 
Institutet, Stockholm, Sweden (No. 2012/2058-31/3).   
       
                                                                                                                              
5. Statistical analyses 
All individuals will be randomized and allocated to one of three arms; 
colonoscopy, FIT or control. Disease specific mortality is the variable used for 

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power analysis. Individuals registered in the national Register of the total 
population will be the bases for the intention to screen analysis.  
 
Study planning including the sample size target were based on the following 
power calculation. 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 
20,100 persons in the colonoscopy arm, 60,186 in the FIT arm and 120,372 in 
the control arm.  
 
Based on previous studies, we estimate that the reduction in mortality will be 
about 30% for those examined with FIT and a subsequent colonoscopy if the FIT 
is positive and approximately 50% for individuals who are examined with a 
primary screening 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 low 
contamination from opportunistic screening.  
 
In 2016 we prolonged the colonoscopy arm due to a lower-than-expected 
compliance, 35% instead of 50% and added 10, 500 participants.  
 
See the Statistical Analysis Plan for further details regarding the power 
calculations and rationale for setting the last date of follow-up to 2030-12-31. 
 
6. Data management 
The Central IT-Support System – Study (CIS-S) platform will be located at the 
Head secretariat. All information generated by the invitation routines, laboratory 
tests and findings at colonoscopy, as well as individual questionnaire 
information, will be automatically registered in the system prospectively and 
available with explicit restriction to guarantee discretion of personal information 
of individuals.  
 
7. Head secretariat 
The Head secretariat of the study is situated at the Regional Cancer Centre in the 
Uppsala/Örebro region (now called Mellansverige), Uppsala, Sweden.  
 
https://cancercentrum.se/samverkan/vara-uppdrag/prevention-och-tidig-
upptackt/screening-tjock-och-andtarmscancer/screesco-studien/ 
 
https://cancercentrum.se/samverkan/regional-cancer-centres/ 
 
 
 

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8. Participating centers supplement: sites and local PIs 
There are 33 participating endoscopy sites distributed nationally and in the 
areas of residency of the invitees (and controls) of the study. 
SCREESCO Principal investigators per site 
Stefan Spinnell  
Bengt Sundbaum
Sunderby hospital 
Leif-Göran Carlsson
Skellefteå hospital
Lars Almersson
Lycksele hospital
Tomas Koczkas
Östersund hospital
Åke Öberg
University hospital of Umeå
Michael Wagner
Uppsala University hospital
Lech Rademacher
Avesta hospital
Stefan Willmarsson
Karlstad hospital
Lars Strandberg
Falun hospital
Verena Voss 
Jörn Holm 
Torbjörn Sakari
Gävle hospital 
Laszlo Kosztyu
Hudiksvall hospital
Gunilla von Schoultz 
Karin Nyborg
Lindesberg hospital 
Karlskoga hospital
Gunter Häselbarth
Mora hospital
Märit Larsson
Eskilstuna hospital
Daniel Nordström
Nyköping hospital
Ronald Malcher 
Josip Kujundzic
Västerås hospital 
Rikard Svernlöv
University hospital of Linköping
Eva Adauktusson 
Ahmad Kassem
Värnamo hospital 
Mats Persborn 
Jörgen Tolstrup Rasmussen 
Bengt Druvefors
Eksjö hospital 
Roland Persson
Kalmar hospital
Hjalmar Åselius
Västervik hospital
Otto Űberbacher 
Cyrus Dyarmand
Varberg hospital 
Joakim Holmin 
Robert Kunz
Halmstad hospital 
Dietrich Ahlhausen
Northern Älvsborg County hospital
Anders Lasson
Southern Älvsborg County hospital
Andreas Pischel
Sahlgrenska University hospital Gothenburg
Morteza Shafazand
Sahlgrenska University hospital /East (Eastern hospital) Gothenburg
Birgit Edin 
Fotios Chalkidis
Falköping hospital 
Ervin Toth
University hospital of Malmö
Jörgen Torp
Kristianstad hospital
Matthias Hoeschen
Helsingborg hospital
Björn Ohlsson
Karlshamn hospital
Peter Andersson 
Staffan Jangmalm
Växjö hospital 
 
 

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9. Main study publications 
Planned and published main studies of SCREESCO: 
 
 Compliance, findings and negative effects of the screening initiative (34)  
 Emotional impact of screening on participants and non-participants (35) 
 Quality assurance of screening colonoscopy (36) 
 Study of intervention compared to control: adverse events and incident 
colorectal cancers during the intervention phase 
 Health economy of colorectal cancer screening implementation  
 Main analysis of the primary end-point (mortality) 
 
See Section 3.7 for a list of secondary studies. 
 
 

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10. Scientific committee 
 
Original list of members of the Scientific Committee 
Name  
 
 
Country 
 
 
Area of expertise  
Rolf Hultcrantz 
 
Sweden 
 
 
Gastroenterology 
 
Lars Holmberg 
 
Sweden 
 
 
Screening, surgery 
Anders Ekbom 
 
Sweden 
 
 
Epidemiology 
Anna Forsberg 
 
Sweden 
 
 
Gastroenterology,  
endoscopy 
Robert Steele  
 
United Kingdom 
 
Screening, Surgery 
Richard Palmqvist 
 
Sweden 
 
 
Pathology 
Mef Nilbert 
 
 
Sweden 
 
 
Molecular oncology 
Andreas Pischel 
 
Sweden 
 
 
Endoscopy 
Marc Buyse 
 
 
Belgium 
 
 
Biostatistics 
Yvonne Wengström  
Sweden 
 
 
Qualitative research 
Per Carlsson  
 
Sweden 
 
 
Health economy 
Lars Engstrand 
 
Sweden 
 
 
Microbiota 
 
Johannes Blom 
 
Sweden 
 
 
Screening, surgery 
 
 
 
Updated list of members of the Scientific Committee (May 06, 2021) 
 
Name  
 
 
Country 
 
 
Area of expertise  
Rolf Hultcrantz 
 
Sweden 
 
 
Gastroenterology 
 
Lars Holmberg 
 
Sweden 
 
 
Screening, surgery 
Anders Ekbom 
 
Sweden 
 
 
Epidemiology 
Anna Forsberg 
 
Sweden 
 
 
Gastroenterology,  
endoscopy 
Robert Steele  
 
United Kingdom 
 
Screening, Surgery  
Chris Metcalfe 
 
United Kingdom 
 
Medical Statistics 
Christian Löwbeer 
 
Sweden 
 
 
Laboratory medicine,  
 
 
 
 
 
 
 
 
clinical chemistry 
Andreas Pischel 
 
Sweden 
 
 
Endoscopy 
Yvonne Wengström  
Sweden 
 
 
Qualitative research 
Lars-Åke Levin 
 
Sweden 
 
 
Health economy 
Lars Engstrand 
 
Sweden 
 
 
Microbiota 
 
Johannes Blom 
 
Sweden 
 
 
Screening, surgery 
 
Mikael Hellström 
 
Sweden 
 
 
Radiology 
Kaisa Fritzell  
 
Sweden 
 
 
Qualitative research 
Ulf Strömberg 
 
Sweden 
 
 
Epidemiology 
 
 
 
 

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Updated list of members of the Scientific Committee (Nov 26, 2024) 
 
Name  
 
 
Country 
 
 
Area of expertise  
Lars Holmberg 
 
Sweden 
 
 
Screening, surgery 
Anna Forsberg 
 
Sweden 
 
 
Gastroenterology,  
endoscopy 
Marcus Westerberg  
Sweden 
 
 
Medical Statistics 
Jonas F Ludvigsson  
Sweden 
 
 
Epidemiology 
Robert Steele  
 
United Kingdom 
 
Screening, Surgery  
Chris Metcalfe 
 
United Kingdom 
 
Medical Statistics 
Christian Löwbeer 
 
Sweden 
 
 
Lab medicine, clinical     
chemistry 
Lars Engstrand 
 
Sweden 
 
 
Microbiota 
 
Johannes Blom 
 
Sweden 
 
 
Screening, surgery 
 
Mikael Hellström 
 
Sweden 
 
 
Radiology 
Kaisa Fritzell  
 
Sweden 
 
 
Qualitative research 
Ulf Strömberg 
 
Sweden 
 
 
Epidemiology 
 
 

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11. Figures 
 
11.2 Figure 1. Flow chart of invitation procedure of individuals 
randomized to intervention primary colonoscopy 
 

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11.1 Figure 2. Flow chart of invitation procedure of individuals randomized 
to intervention FIT 
 
 
 
 
 
 

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12. References 
 
1. 
The Swedish Cancer Register 
http://www.socialstyrelsen.se/register/halsodataregister/cancerregistret/inen
glish: National Board of Health and Welfare; [cited 2013 December] 
2. 
Muto T, Bussey HJ, Morson BC. The evolution of cancer of the colon and 
rectum. Cancer. 1975;36(6):2251-70. 
3. 
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, 
et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 
1988;319(9):525-32. 
4. 
Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et 
al. Prevention of colorectal cancer by colonoscopic polypectomy. The National 
Polyp Study Workgroup. N Engl J Med. 1993;329(27):1977-81. 
5. 
Muller AD, Sonnenberg A. Prevention of colorectal cancer by flexible 
endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern 
Med. 1995;123(12):904-10. 
6. 
Thiis-Evensen E, Hoff GS, Sauar J, Langmark F, Majak BM, Vatn MH. 
Population-based surveillance by colonoscopy: effect on the incidence of 
colorectal cancer. Telemark Polyp Study I. Scand J Gastroenterol. 
1999;34(4):414-20. 
7. 
Armitage N. Screening for cancer. In: Morris D, Kearsley, J, Williams, C, 
editor. Cancer: a comprehensive clnical guide. pp 9-20. U.K.: Taylor and Francis 
Ltd 1997. 
8. 
Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, et 
al. Reducing mortality from colorectal cancer by screening for fecal occult blood. 
Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328(19):1365-71. 
9. 
Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised 
study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 
1996;348(9040):1467-71. 
10. 
Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour 
TW, et al. Randomised controlled trial of faecal-occult-blood screening for 
colorectal cancer. Lancet. 1996;348(9040):1472-7. 
11. 
Lindholm E, Brevinge H, Haglind E. Survival benefit in a randomized 
clinical trial of faecal occult blood screening for colorectal cancer. Br J Surg. 
2008;95(8):1029-36. 
12. 
Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, 
et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal 
cancer: a multicentre randomised controlled trial. Lancet. 
2010;375(9726):1624-33. 
13. 
Segnan N, Armaroli P, Bonelli L, Risio M, Sciallero S, Zappa M, et al. Once-
only sigmoidoscopy in colorectal cancer screening: follow-up findings of the 
Italian Randomized Controlled Trial--SCORE. J Natl Cancer Inst. 
2011;103(17):1310-22. 
14. 
Schoen RE, Pinsky PF, Weissfeld JL, Yokochi LA, Church T, Laiyemo AO, et 
al. Colorectal-cancer incidence and mortality with screening flexible 
sigmoidoscopy. N Engl J Med. 2012;366(25):2345-57. 
15. 
Faivre J, Bouvier AM, Bonithon-Kopp C. Epidemiology and screening of 
colorectal cancer. Best Pract Res Clin Gastroenterol. 2002;16(2):187-99. 

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16. 
Richardson A. Screening and the number needed to treat. J Med Screen. 
2001;8(3):125-7. 
17. 
Bretthauer M. Colorectal cancer screening. J Intern Med. 2011;270(2):87-
98. 
18. 
Brouwers MC, De Vito C, Bahirathan L, Carol A, Carroll JC, Cotterchio M, et 
al. What implementation interventions increase cancer screening rates? a 
systematic review. Implementation science : IS. 2011;6:111. 
19. 
Tinmouth J, Ritvo P, McGregor SE, Claus D, Pasut G, Myers RE, et al. A 
qualitative evaluation of strategies to increase colorectal cancer screening 
uptake. Can Fam Physician. 2011;57(1):e7-15. 
20. 
Blom J, Liden A, Jeppsson B, Holmberg L, Pahlman L. Compliance and 
findings in a Swedish population screened for colorectal cancer with 
sigmoidoscopy. Eur J Surg Oncol. 2002;28(8):827-31. 
21. 
Blom J, Liden A, Nilsson J, Pahlman L, Nyren O, Holmberg L. Colorectal 
cancer screening with flexible sigmoidoscopy-participants' experiences and 
technical feasibility. Eur J Surg Oncol. 2004;30(4):362-9. 
22. 
Collins RE, Lopez LM, Marteau TM. Emotional impact of screening: a 
systematic review and meta-analysis. BMC Public Health. 2011;11:603. 
23. 
Tornberg S, Lundstrom V, Gustafsson S, Hultkrantz R. [The first year with 
colorectal cancer screening in Stockholm. Careful monitoring and quality control 
of the whole process is necessary]. Lakartidningen. 2010;107(26-28):1709-11. 
24. 
Foss C, Ellefsen B. The value of combining qualitative and quantitative 
approaches in nursing research by means of method triangulation. J Adv Nurs. 
2002;40(2):242-8. 
25. 
Ostlund U, Kidd L, Wengstrom Y, Rowa-Dewar N. Combining qualitative 
and quantitative research within mixed method research designs: a 
methodological review. Int J Nurs Stud. 2011;48(3):369-83. 
26. 
von Karsa L, Patnick J, Segnan N. European guidelines for quality 
assurance in colorectal cancer screening and diagnosis. First Edition--Executive 
summary. Endoscopy. 2012;44 Suppl 3:SE1-8. 
27. 
Register of the total population 
https://www.skatteverket.se/download/18.2b543913a42158acf80003761/138
6594730871/AllmänBeskrivning.pdf: Swedish tax agency;  [ 
28. 
Kaminski MF, Bretthauer M, Zauber AG, Kuipers EJ, Adami HO, van 
Ballegooijen M, et al. The NordICC Study: rationale and design of a randomized 
trial on colonoscopy screening for colorectal cancer. Endoscopy. 
2012;44(7):695-702. 
29. 
Patient register 
http://www.socialstyrelsen.se/register/halsodataregister/patientregistret/inen
glish: National Board of Health and Welfare;  [ 
30. 
Causes of Death register 
http://www.socialstyrelsen.se/register/dodsorsaksregistret: National Board of 
Health and Welfare;  [ 
31. 
Wallace MB, Kiesslich R. Advances in endoscopic imaging of colorectal 
neoplasia. Gastroenterology. 2010;138(6):2140-50. 
32. 
Hamilton SR AL. Pathology and Genetics. Tumours of the Digestive 
System, WHO Classification of tumours, vol. 2. IARC WHO, Classification of 
tumours, No 2; 20. 

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33. 
Wallerstedt SM, Wettermark B, Hoffmann M. The first decade with the 
Swedish prescribed drug register–a systematic review of the output in the 
scientific literature. Basic & clinical pharmacology & toxicology. 
2016;119(5):464-9. 
34. 
Forsberg A, Westerberg M, Metcalfe C, Steele R, Blom J, Engstrand L, et al. 
Once-only colonoscopy or two rounds of faecal immunochemical testing 2 years 
apart for colorectal cancer screening (SCREESCO): preliminary report of a 
randomised controlled trial. Lancet Gastroenterol Hepatol. 2022;7(6):513-21. 
35. 
Fritzell K, Forsberg A, Wangmar J, Wengström Y, Bottai M, Hultcrantz R. 
Gender, having a positive FIT and type of hospital are important factors for 
colonoscopy experience in colorectal cancer screening–findings from the 
SCREESCO study. Scandinavian Journal of Gastroenterology. 2020;55(11):1354-
62. 
36. 
Sekiguchi M, Westerberg M, Ekbom A, Hultcrantz R, Forsberg A. 
Endoscopist Characteristics and Polyp Detection in Colonoscopy: Cross-Sectional 
Analyses of Screening of Swedish Colons. Gastroenterology. 2023;164(2):293-5 
e4. 
 
 
 

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13. Summary of changes to the SCREESCO study protocol and 
statistical analysis plan 2013-2024 
 
 
Changes in the study protocol version 2.0 
Study protocol was amended after new power-calculation due to anticipated 
35% participation in the colonoscopy arm. In Swedish 2017-03-10, translated to 
English 2021-04-29. List of members Scientific Committee was updated. 
 
Changes in the study protocol version 3.0 
Study protocol was amended after the Scientific Committee decided on a last 
date of follow-up based on new power calculations. It was also decided that the 
previously described interim analysis will not be performed. The list of main 
publications was updated, and so was the list of members of the Scientific 
Committee. A summary of changes of the protocol and statistical analysis plan 
was added. Weblinks under Head Secretariat were updated. 
 
Changes in the statistical analysis plan 2.0 
Statistical analysis plan was amended after new power-calculation due to 
anticipated 35% participation in the colonoscopy arm.  
 
Changes in the statistical analysis plan 3.0 
Statistical analysis plan was amended on 2024-11-04 after the Scientific 
Committee decided on a last date of follow-up based on new power calculations. 
It was also decided that the previously described interim analysis will not be 
performed. Details and clarifications regarding the initial and modified power 
calculations were added. The analysis of incidence of colorectal cancer was 
changed and is now based on cumulative incidence curves instead of the log-
rank test.