Colorectal Cancer Screening in Average-risk Population: a Multicenter, Randomized Control Trial Comparing Immunochemical Fecal Occult Blood Testing Versus Colonoscopy.
Phase: NA
Conditions: Colorectal Cancer, Colorectal Neoplasm
Sponsor: Hospital Clinic of Barcelona

 
 
 
 
 
 
Colorectal cancer screening in the average-risk 
population: a pragmatic, multicentre, randomised, 
controlled trial comparing colonoscopy and faecal 
immunochemical testing (COLONPREV Study) 
 
ClinicalTrials.gov NCT00906997 
 
 
Grupo Cooperativo para el Cribado del Cáncer 
Colorrectal en España 
 
 
Study Protocol 
 
 
Date: January 24th, 2024  
 
 
 
 

 
2
INDEX 
1. EXECUTIVE SUMMARY 
3 
2. BACKGROUND AND CURRENT STATUS OF THE ISSUE  
4 
3. OBJECTIVES 
 
7 
3.1. Primary objective 
7 
3.2. Secondary objectives 
7 
3.3. Additional objectives  
7 
4. STUDY METHODOLOGY 
8 
4.1. Study type 
8 
4.2. Scope 
8 
4.3. Target population 
8 
4.4. Study groups, randomisation, and stratification 
9 
4.5. Sample size calculation 
9 
4.6. Processes of selecting and inviting the population to be screened 
10 
4.7. Determination of faecal occult blood 
11 
4.8. Technical characteristics of colonoscopies 
11 
4.9. Quality assurance program 
12 
5. DEVELOPMENT OF THE STUDY 
14 
5.1. Screening phases 
15 
5.2. Organisation and management of the project 
16 
6. DEFINITIONS 
17 
6.1. Classification of colorectal polyps 
17 
6.2. Treatment of malignant polyps 
18 
6.3. Classification of colorectal cancer 
18 
7. STATISTICAL ANALYSIS PLAN 
20 
8. CHRONOGRAM 
22 
9. ETHICAL QUESTIONS 
23 
10. RESEARCH PROJECT TEAM 
24 
11. REFERENCES 
25 
 
 

 
3
1. EXECUTIVE SUMMARY 
Introduction 
Colorectal cancer (CRC) is one of the most common malignancies in Western nations, 
and the second most common in Spain after lung cancer in men and breast cancer in 
women. Its incidence is estimated at 25,000 new cases per year, and it is the second 
leading cause of cancer death.  
Although the efficacy of CRC screening in the prevention of this cancer is well 
established, the most appropriate procedure for screening has not yet been 
identified.  
Primary objective  
To measure CRC-specific mortality at 10 years after screening using biennial faecal 
immunochemical testing (FIT) compared to screening by one-time colonoscopy in an 
average-risk population (asymptomatic individuals aged 50-69 years with no personal 
or family history of CRC). 
Study design 
A pragmatic, non-inferiority, multicentre, randomised, controlled trial in eight 
Autonomous Regions of Spain (Aragon, Canary Islands, Catalonia, Galicia, Madrid, 
Murcia, Basque Country, and Valencia). 
Methodology 
Inclusion criteria: Asymptomatic men and women between the ages of 50 and 69.  
Exclusion criteria: 1) Having previously undergone CRC screening within the 
prescribed period; 2) Belonging to high-risk groups due to family history (hereditary 
nonpolyposis colorectal cancer, familial adenomatous polyposis, other hereditary 
polyposis syndromes, first-degree relatives with CRC) or personal history 
(inflammatory bowel disease, adenoma, or prior CRC); 3) Symptoms suggestive of 
colorectal disease; 4) Having undergone a total colectomy; or 5) Individuals suffering 
from a serious illness.  
Study groups 
Group 1: Screening using biennial FIT (latex agglutination, OC-Sensor®, cut-off point: 
75 ng Hb/ml), and performance of colonoscopy in patients with a positive result. 
Group 2: Screening using one-time colonoscopy.  
The study design allowed for cross-over between both screening strategies. 
Sample size calculation 
With an alpha risk of 0.025 and a beta risk of 0.20, using one-sided test of 
proportions, 27,749 subjects are required in each trial arm (total: 55,498) accepting 
a non-inferiority condition if the absolute difference was below 1.6‰ in the CRC-
specific mortality rate at 10 years according to the intention to screen analysis 
(primary objective of the study). 
 

 
4
2. BACKGROUND AND CURRENT STATUS OF THE ISSUE 
Colorectal cancer (CRC) is the second most common cause of cancer death in Spain, 
accounting for more than 11,000 deaths annually. Its rate of incidence makes it the 
second most common cancer after lung cancer in men and breast cancer in women, 
but it is the most common cancer if figures for both genders are combined, with 
more than 25,000 new cases detected each year (1). 
The mean survival rate for CRC in Spain is only 48% at 5 years after diagnosis (2). This 
may be because diagnosis is made late, in most cases as a result of a lack of 
screening programmes.  
Several prestigious medical societies and clinical guidelines based on scientific 
evidence recommend screening for all individuals over the age of 50 even if no 
additional risk factors are present, as well as for members of high-risk population 
groups (hereditary CRC syndromes, individuals with first-degree relatives with CRC, 
and patients suffering from inflammatory bowel disease) (3-12). For screening in 
high-risk populations, the strategy of choice is colonoscopy, performed at various 
intervals depending on the clinical situation (6,12). However, it is not known which 
screening method (annual or biennial faecal occult blood testing [FOBT], 
sigmoidoscopy every 5 years, or colonoscopy every 10 years) is the most suitable for 
the average-risk population.  
Of all the possible strategies, the most evaluated to date is annual or biennial FOBT 
screening. Several randomised controlled trials have shown that FOBT screening with 
a chemical test (guaiac) reduced mortality from CRC by approximately 15-30% (13-15) 
and also reduced its incidence (16).However, this method has been disputed because 
of its low sensitivity, with a detection rate of 30-50% in a single round of screening 
for CRC (15.17), and of less than 20% for advanced adenoma (18,19). Other 
disadvantages of screening with the guaiac-based FOBT method are that it needs to 
be repeated every 1-2 years, that it requires dietary restrictions to ensure the 
reliability of the test, and that three consecutive samples must be collected, thereby 
greatly reducing compliance. On the other hand, there are faecal immunochemical 
tests (FIT) that are more sensitive than chemical methods (20). Such methods 
specifically detect human haemoglobin, and therefore do not require dietary 
restrictions and only need a single sample to be taken. However, they have been 
insufficiently tested in Western countries, and there are no studies on the cost-
effectiveness of CRC screening using this procedure. 
In the past 15 years several pilot studies have been carried out in Spain for early 
detection of CRC in average-risk populations (21-25). Most of them used the chemical 
FOBT method as a screening test, followed by colonoscopy in individuals with a 
positive result. In total, these studies included more than 12,000 participants, with 
an average participation rate of 56% and an average detection rate of early stage 
CRC of 80%. Although these studies are not comparable from the methodological 
point of view, and were performed at different times, the results suggest an 
acceptable level of participation in the Spanish population, and high efficacy in the 
early detection of CRC. However, no studies have been conducted in Spain assessing 
the efficacy of screening in terms of mortality or incidence over the long-term. 
In a recent study conducted in Tenerife (25), the acceptance, efficacy, and cost-
effectiveness of a new FIT (latex agglutination, OC-Light®) was compared to the 
hemoFEC® chemical test for the detection of advanced adenoma and CRC. The study 
showed that the immunological method is more sensitive than the chemical test for 
detection of advanced adenoma (51% vs. 18%), CRC (100% vs. 52%) or both (57% 
vs. 22%). Specificity with the immunological method was 97% for advanced 
adenoma, 93% for CRC, and 95% for both, while with the chemical test it was 97% for 

 
5
either advanced adenoma or CRC, and 98% for both. This study also showed that the 
probability of detecting advanced cancers (advanced adenoma or CRC) in individuals 
with a positive immunological test (OR: 13; 95% CI: 6.1-27.7) was four times higher 
than that for those in whom the chemical test was positive (OR: 3.17; 95% CI: 1.98-
5.07). The immunological method was also more cost-effective than the chemical 
test in the detection of CRC or advanced adenoma. The chemical FOBT test achieved 
a cost-effectiveness ratio of € 3.573/QALY gained, reducing CRC-caused mortality 
by 20%, while for the immunological test the ratio was € 2,224/QALY gained, with a 
reduction in mortality of 52%. These data suggest that the FIT should replace the 
chemical method in future CRC screening campaigns in average-risk population. 
Colonoscopy is the most accurate method that exists for the early detection and 
prevention of CRC. Although studies evaluating the effect of screening with this test 
on CRC-caused mortality in average-risk populations have not yet been published, its 
implementation is recommended based on the following evidence: 1) studies have 
demonstrated that colonoscopy with polypectomy reduces the incidence of CRC by 
40-90% (27,28); 2) At least two case-control studies suggest that screening by flexible 
sigmoidoscopy significantly reduces the risk of death from distal CRC (29,30), an 
effect that lasts for more than 5 years (30) which has enabled extrapolation of its 
effectiveness to colonoscopy; 3) The prevalence of adenomas in cross-sectional 
studies of screening by colonoscopy is twice that observed for sigmoidoscopy 
(18,19,31,32), with colonoscopy also found to be more sensitive than the barium 
enema or virtual colonoscopy for detecting polyps and CRC (26); 4) Approximately 
two out of three patients with advanced cancers of the proximal colon do not show 
neoplasia distal to the splenic flexure, meaning that it would not be detectable in 
screening by sigmoidoscopy (33,34). This is particularly relevant if one considers 
that 40% of CRCs are located proximal to the splenic flexure (35). 
An additional benefit of colonoscopy every 10 years compared to other screening 
strategies in an average-risk population is that it allows a long period of protection, 
which can help improve compliance in the population. It also facilitates diagnosis and 
treatment in one session, which decreases the risk of the loss of patients to follow-up 
that occurs with tests that are purely diagnostic. 
The primary limiting factors for the use of colonoscopy in screening an average-risk 
population are its invasive nature, including a possible risk of potentially serious 
complications 
such 
as 
perforation 
or 
post-polypectomy 
bleeding (1-2 
per 
2,000 examinations), and a higher cost than other screening methods such as the 
FOBT test. 
Despite the proven beneficial effect of secondary prevention on morbidity and 
mortality from CRC, there are significant obstacles that hinder the implementation 
of large-scale CRC screening programmes. First, there is still no agreement as to 
what constitutes an optimal screening strategy. Secondly, there is little compliance 
with them by the target population. This is due mainly to a significant lack of 
information among the target population, and among healthcare managers and staff 
themselves (36-38). Finally, the organisation and resources needed to ensure the 
safety and efficacy of a programme of this nature are not currently available.  
An essential requirement for the implementation of any population screening 
programme for a particular disease is to be cost-effective. Several studies have 
confirmed that CRC screening is cost-effective regardless of the strategy applied (39-
41), with the cost in terms of quality-adjusted life years (QALY) being lower than 
screening for other cancers such as breast or cervical cancer (40). These findings 
were corroborated in a recent analysis by the Evaluation and Planning Unit of the 
Canary Islands Health Service (unpublished data), which found that the costs of CRC 
screening using FIT or colonoscopy every 10 years would be significantly lower 

 
6
(€ 2,500/QALY 
and 
€ 2,300/QALY, 
respectively) 
than 
screening 
for 
breast 
(€ 18,489/QALY), cervical (€ 18,646/QALY) or prostate cancers (€ 12,647/QALY). It is 
worth noting that the National Institute for Health and Clinical Excellence (NICE) has 
recently established that any health intervention that costs less than € 30,000/QALY 
should be considered to be very acceptable from the standpoint of cost-
effectiveness (42) and has, therefore, recommended its implementation. 
Given that CRC is a high-priority health issue, and that sufficient evidence exists to 
show that it is a preventable disease with reasonable economic costs if diagnosed 
early, the Council of the European Union established guidelines in 2003 (43) so that 
population screening for CRC would be included as a priority in the health plans of 
member states. For that reason, the national health plan of the Spanish Ministry of 
Health and Consumer Affairs includes population screening for CRC as a priority as 
part of its comprehensive cancer plan (PICA), which is to be implemented before 
2007 (43). 
The Spanish Association of Gastroenterology (AEG) believes that, in order to reduce 
the mortality and incidence of CRC in Spain, various actions must be taken, among 
which are publicising the CCR prevention strategies, promotion of their 
implementation, establishment of mechanisms for assessment, improvement of the 
efficiency and quality of care levels involved and promotion of comprehensive care 
for patients with this cancer. This Association, therefore, proposes to conduct a 
multicentre, controlled study with a scope that covers several Autonomous Regions 
to establish the efficacy and efficiency of the two principal screening options in the 
average-risk population. 
 

 
7
3. OBJECTIVES 
3.1. Primary objective 
• 
To assess CRC-specific mortality at 10 years after screening using a FIT method 
biennially compared to screening by one-time colonoscopy in an average-risk 
population (asymptomatic individuals aged 50-69 with no personal or family 
history of CRC). 
 
3.2. Secondary objectives 
• 
To compare diagnostic yield and detection rate of CRC and/or advanced 
adenomas in each screening strategy at the completion of the first round.  
• 
To compare the participation rate in each screening strategy at the completion of 
the first round, and identify the factors influencing it (i.e. demographics, 
personal and familial characteristics, socio-economic status, etc.). 
• 
To compare overall diagnostic yield and detection rate of CRC and/or advanced 
adenomas in each screening strategy at 10 years. 
• 
To compare the overall adherence rate in each screening strategy at 10 years, 
and identify the factors influencing it. 
• 
To assess the cost-effectiveness of each screening strategy. 
• 
To assess the rate of serious complications in each screening strategy, both at the 
completion of the first round and overall at 10 years. 
• 
To compare CRC incidence in each screening strategy at 15 years. 
 
3.3. Additional objectives 
Each Autonomous Region, hospital, and/or health centre participating in the study 
can propose additional objectives to be performed in its individual data sets. Any 
proposal should be approved by the Executive Committee of the COLONPREV study. 

 
8
4. STUDY METHODOLOGY 
4.1. Study type 
Pragmatic, non-inferiority, multicentre, randomised and controlled. 
 
4.2. Scope 
The study will be conducted in eight Autonomous Regions: Aragon, Canary Islands, 
Catalonia, Valencia, Galicia, Madrid, Murcia and Basque Country. 
The following centres will participate: Hospital Clínico Lozano Blesa (Zaragoza), 
Hospital Universitario de Canarias (Tenerife),Hospital Clinic de Barcelona, Hospital 
del Mar (Barcelona), Consorcio Hospitalario de Castelló, Hospital la Fe (Valencia),  
Complexo Hospitalario Universitario de Vigo,  Complexo Hospitalario Universitario de 
Ourense, Hospital 12 de Octubre (Madrid), Hospital de la Princesa (Madrid), Hospital 
Puerta de Hierro (Madrid), Hospital Fundación de Alcorcón, Hospital Clínico San 
Carlos (Madrid), Hospital Universitario Virgen de la Arrixaca (Murcia), Hospital Reina 
Sofía (Murcia), Hospital de Donostia (San Sebastian), and Instituto Oncológico, Obra 
Social Kutxa, San Sebastián.  
 
4.3. Target population 
Inclusion criteria: Asymptomatic men and women between 50 and 69 years of age. 
This cutoff of age is the recommended by the Spanish Screening Network for the 
implementation phase of the Spanish CRC screening program. Thereafter, it is 
planned to increase this age cutoff to 74 years when the screening program will be 
extended to the whole country (unfortunately, this stage has not been accomplished 
at the end of COLONPREV study). 
Permanent exclusion criteria: All individuals who meet any of the following 
conditions will be permanently excluded: 
• 
Personal history of inflammatory bowel disease, colorectal polyps, colorectal 
adenoma or CRC. 
• 
Family history of familial adenomatous polyposis syndromes or other hereditary 
polyposis syndromes, hereditary nonpolyposis colorectal cancer (diagnosed by 
the presence of germline mutation in DNA repair genes and/or meeting the 
Amsterdam II criteria), 2 or more first-degree relatives with CRC or 1 first-degree 
relative with CRC diagnosed before the age of 60. 
• 
Severe comorbidity that involves a poor short-term prognosis (disease with a 
mean life expectancy of less than 5 years) or chronic disease that involves major 
limitation of physical activity (performance status  2). 
• 
Individuals who have had a total colectomy. 
Temporary exclusion criteria: All individuals who meet any of the following 
conditions will be temporarily excluded: 
• 
Those who have undergone any of the examinations used in CRC screening, 
regardless of the reason, within the periods specified: history of FOBT screening 
in the past 2 years, or sigmoidoscopy or colonoscopy within the past 5 years (as 
long as its validity is documented) (to avoid this eventuality we will seek to 
conduct the study in a healthcare setting in which the population has not been 
screened previously). Such individuals may enter the study after the time periods 
mentioned have expired.  

 
9
• 
Those showing symptoms suggestive of colorectal disease (rectal bleeding, 
altered frequency of bowel movements, constitutional symptoms, anaemia). 
These individuals may enter the study once their condition has been studied and 
a colorectal cancer or other pathology that would constitute a cause of 
permanent disqualification has been excluded, and if any of the above-
mentioned tests were performed, once the periods mentioned in the previous 
section have expired. 
 
4.4. Study groups, randomisation, and stratification 
Asymptomatic men and women aged 50 to 69 years from each participating 
Autonomous Region will be identified through the corresponding Community Health 
Registry (CHR) for enrolment into this study. Randomisation will be carried out prior 
to invitation, with computer-generated lists in blocks of 4 (block randomisation) from 
the list of health cards, after having previously grouped individuals by household 
(specified by street address, floor, and apartment number) (see Processes of 
selecting and inviting the population to be screened section). 
All eligible patients will be randomised (1:1 ratio) to the two study groups: 
Group 1: Screening by biennial FIT (latex agglutination, OC-Sensor®, cut-off point: 
75 ng Hb/ml, corresponding to 15 g Hb/g of feces), and colonoscopy (after no more 
than 1 month) for patients with a positive result. Determination of FIT will be made 
using a single faecal sample, without dietary restriction or interruption of normal 
treatment of the individual, although the habitual use (>1 month) or recent use (last 
7-15 days) of NSAIDs, aspirin, anti-platelet drugs and anticoagulants will be recorded. 
The above-mentioned cut-off point was used in the baseline round; in subsequent 
rounds, we decided to modify the cut-off to 20 g Hb/g of feces since it is the one 
accepted in the Spanish population-based CRC screening program.  
Group 2: Screening by one-time colonoscopy. The ongoing use (>1 month) or recent 
use (last 7-15 days) of NSAIDs, aspirin, anti-platelet drugs and anticoagulants will also 
be recorded.  
Individuals in Group 1 or Group 2 who do not agree to the type of testing assigned to 
them may require receiving the alternative test and must still be followed up in 
order to carry out efficacy analysis according to the intention to screen analysis. The 
choice of the alternate test will not be actively offered to individuals invited to the study 
and, accordingly, COLONPREV is not considered a study of sequential screening test 
offers. 
Information on the long-term status of individuals in Group 1 or Group 2 who do not 
agree to participate in the study will be obtained through population-based registries 
at the completion of the trial in order to assess efficacy according to the intention to 
screen analysis. 
 
4.5. Sample size calculation 
Considerations for calculation of the sample  
Since there are no study examining the effect of screening with the strategies 
proposed in our trial on CRC-caused mortality, the calculation of the sample in this 
case must be based on hypothetical studies of cost-effectiveness that analyse the 
expected reduction in risk of mortality with biennial FIT or colonoscopy every 
10 years. Furthermore, the calculation should be adjusted, when possible, to the 
local conditions where the strategies are to be implemented. In that sense, it is 
important to note that no study on this subject have yet been published in Spain.  

 
10
Recently, the Evaluation and Planning Unit of the Canary Islands Health Service has 
conducted a study of this type based on real data for sensitivity and specificity of the 
tests in our setting. For a hypothetical population of 100,000 asymptomatic 
individuals aged 50, the estimated mortality reduction brought about by FIT is 51% 
and involves a cost of € 2,101/QALY. For the strategy of colonoscopy, the estimate is 
a reduction in mortality of 75% at a cost of € 2,188/QALY.  
With an alpha risk of 0.025 and a beta risk of 0.10 using one-sided test of 
proportions, 27,749 subjects are required in each arm of the clinical trial 
(total: 55,498) accepting a non-inferiority condition if the absolute difference was 
below 1.6‰ in the CRC-specific mortality rate at 10 years according to the intention 
to screen analysis and with an expected overall compliance of 30%. 
Estimates of recruitment by Autonomous Region 
According to the established sample size, the number of individuals to be recruited in 
each Autonomous Region is 6,937.  
 
4.6. Processes of selecting and inviting the population to be screened 
In each Autonomous Region, randomisation will be done prior to sending the 
invitation letter (Zelen’s design) in order to properly assess the participation in each 
screening group and perform the intention to screen analysis of the results. 
The selection process will be the same as the one used in the Nottingham study (14), 
in which compliance with the programme reached 60%. Briefly, target population will 
be identified from the Community Health Registry (CHR) of each Autonomous Region. 
The CHR is based on the population registry, and includes unique identification for 
each person, such as name, date of birth, social security number, and contact 
address, and it is updated regularly to account for population migration, deaths and 
changes in personal details. This list will be refined using cancer registries or other 
sources of information (primary care medical records, hospital databases, etc.) in 
order to eliminate individuals who meet exclusion criteria (i.e. CRC and colorectal 
adenoma) or who have died. Prior to randomisation, individuals will be clustered by 
household. With such an approach, it is hoped to ensure that all individuals in one 
household will be assigned to the same study group.  
All individuals will receive an initial, pre-invitation letter by mail (which may be 
signed by their primary care doctor or an area specialist, or the person responsible 
for the Autonomous Regions screening programme) with information regarding the 
relevance of CRC as a health problem, the possibility of preventing it by means of 
screening, and the impending start up of a pilot programme (presentation letter), 
along with an informative leaflet which explains existing measures for CRC 
prevention. They will later be sent a second letter (also signed by their primary care 
doctor or area specialist, or the person responsible for the Autonomous Regions 
screening programme) in which they are invited to participate in the study 
(invitation letter) and includes an appointment to the Local Screening Office (LSO) 
and a contact telephone number. In the invitation letter, individuals will also be 
informed of the screening option that applies to them, the characteristics of the test 
and its possible adverse effects. This whole process will be performed by the LSO 
(who may be assisted by staff of the project data manager). 
Individuals who do not respond will receive a reminding letter at 3-4 months after 
sending of the introduction letter. Individuals who do not respond to it will receive a 
second reminding letter 2 months later.  

 
11
The content of the two letters will be identical in all Autonomous Regions. However, 
translation into official languages and the use of logos, institutional images or 
letterheads of each Autonomous Regions is permitted. 
The frequency of sending invitation letters will be adapted to the capacity of each 
LSO to attend individuals wishing to participate in order to diminish the lag time 
between randomisation and participation to less than 3 weeks.  
At the Health Centre, the functions of staff responsible for the study (including 
physicians and nurses of the centre and the data-collector in charge of the study) will 
be: 1) To track selected individuals in the sample who do not respond or who do not 
come to the appointment; 2) For those who come to the appointment, to confirm 
their suitability to participate in the study (compliance with inclusion/exclusion 
criteria); 3) To provide more detailed and exhaustive information about the study 
objective and the strategy they have been assigned in order to facilitate their 
participation; 4) To identify high-risk individuals, and assign them an appointment for 
a high-risk clinic of the reference hospital or the corresponding genetic counselling 
unit (see below); 5) To obtain written informed consent for participation in the 
study; 6) To complete the questionnaire with the data of all individuals contacted 
and include them in the project database; and 7) To provide a FIT kit (Group 1) or 
formalise the appointment at the hospital CRC prevention unit assigned to perform 
the colonoscopy (Group 2). In the event that an attending individual refuses to 
participate in the study, the baseline questionnaire will be completed and the 
reasons for the refusal of the invitation will be recorded. They will also be informed 
that even if they are not examined during screening, they will be contacted 
periodically in order to monitor the state of their health.  
 
4.7. Determination of faecal occult blood 
Reading of the FIT tests will be done in a centralised manner in each Autonomous 
Regions.  
At the baseline round, individuals participating in the FIT arm will be advised of 
returning the completed kit to the LSO within 5 working days and maintaining it in 
their refrigerator until such a moment. From the LSO to the centralized laboratory 
kits will be transported in insulated cooler bags once a day. On subsequent screening 
rounds, logistics for delivering and returning FIT kits will be adapted to the one 
employed in each Autonomous Region (i.e. in person on primary care centres or 
pharmacies without previous appointment, or by mail). 
 
4.8. Technical characteristics of colonoscopies 
All colonoscopies performed in a screening programme must be of the highest quality 
to avoid false negative results and to minimize potential complications. Results of 
colonoscopy will determine the interval until next endoscopic examination, which is 
10 years 
if 
no 
neoplastic 
lesions 
are 
detected, 
according 
to 
current 
recommendations. Colonoscopies will be performed by experienced staff in the 
centres involved in the study, which should be able to make correct diagnoses and 
carry out proper treatment of different types of neoplastic lesions. In addition, these 
examinations will be performed in specific work modules with sufficient resources to 
offer the quality required. In that sense, it is important to keep in mind that more 
than half of the examinations performed to confirm a positive FIT are associated with 
a therapeutic procedure, most often polypectomy.  
The period of time between acceptance to participate and performance of 
colonoscopy in individuals allocated to colonoscopy (Group 2) or between a positive 

 
12
FIT result and performance of colonoscopy in individuals allocated to FIT (Group 1) 
will be established in less than one month.  
Endoscopic procedures will be recorded in the appropriate databases, including high 
quality digital photographs of all lesions detected. The report should contain the 
parameters for quality assessment (caecal intubation, insertion and withdrawal 
times, quality of cleanliness for each colorectal segment, number of polyps 
identified, removed and recovered for histological examination, retroflexion 
manoeuvre in the rectum, immediate complications, etc.).  
Proper cleansing should be another pillar of colonoscopy in the screening programme. 
Whichever method is used, part of the preparation should be administered a few 
hours before the procedure, since in various studies this pattern has resulted in, not 
only better quality cleansing, but also a greater proportion of patients with polyps 
detected. Any of the commercially available methods can be used (polyethylene 
glycol [Bohm® solution] or disodium hydrogen phosphate [Fosfosoda®]), whether 
combined or not with bisacodyl (Dulco Laxo®), taking care to provide the last dose 
for cleansing as close to the time of the colonoscopy as possible.  
All colonoscopies will be performed under sedation.   
In patients treated with anti-platelet agents, both for those in Group 1 with a 
positive FIT test (positive predictive value for colorectal neoplasia greater than 40%) 
and in Group 2 (positive predictive value of 5-7%), withdrawal or changes in 
medication will be assessed 7-10 days before testing. However, it is important to 
note that, according to current scientific recommendations, it is not necessary to 
discontinue anti-platelet agents to perform a polypectomy. Anti-coagulated patients 
(dicoumarol) should be changed, when possible, to subcutaneous administration of 
LMW heparin. Finally, the usefulness of metal clips has been described for the 
prophylaxis and treatment of post-polypectomy bleeding in at-risk groups, including 
in anti-coagulated patients. 
The American Heart Association does not recommend the use of antibiotics prior to 
completion of endoscopic procedures (including colonoscopy and polypectomy) for 
prophylaxis of infectious endocarditis (http://circ.ahajournals.org/cgi/reprint/ 
CIRCULATIONAHA.106.183095). 
Biopsy of the polyp will be sought before polypectomy, especially for patients in 
whom it is anticipated that it will be difficult to obtain after the procedure. This 
measure aims to reduce the number of polyps not histologically studied. 
In cases where colon cleansing is not adequate, the colonoscopy will be repeated. 
In cases of failure to achieve complete colonoscopy, the procedure will be repeated 
or a CT-colonography will be offered. 
Quality standards will be established for all the above requirements according to the 
recommendations made by the Quality Assurance Task Group of the National 
Colorectal Cancer Roundtable (44), which shall be subject to internal auditing during 
the course of the study. This will be the responsibility of the Quality Committee 
created specifically for this purpose (see below).  
 
4.9. Quality assurance programme 
A specific program will be designed to assure the quality of the whole process. It will 
include the following measures: 

 
13
• 
A communication plan based in a comprehensive informative campaign designed 
and launched by the Spanish Alliance for CRC Prevention involving national and 
local media. 
• 
Data will be registered in a centralized, safe database accessible online 
(www.coloncrib.org). 
• 
Quality of FIT measurements will be assured by daily calibration at each 
reference laboratory, and external validation with samples provided by the 
manufacturer every 6 months.  
• 
Colonoscopy quality will be ensured following the guidelines of the Spanish 
Gastroenterological Association and the Spanish Society for Digestive Endoscopy. 
A specific Quality Committee will be created to oversee the quality assurance 
programme all over the study. This committee will meet in a periodical basis and will 
monitor by means of periodic audits the three main phases of the study (recruitment 
process, FIT determinations and colonoscopy). 

 
14
5. DEVELOPMENT OF THE STUDY 
This research project is included within the population-based screening programme 
of each Autonomous Region. This screening programme will ensure the recall of 
individuals for appointments in successive rounds of screening, while also continuing 
the strategy assigned to them during the randomisation of the study. The 
investigators will also be responsible to electronically or manually transfer to the LSO 
the information derived from the study that is of interest to the population screening 
programme. 
Each Autonomous Region is committed with recruiting the same number of 
individuals regardless of the number of participating health centres or hospitals in 
each region.  
The dynamics of the study are summarised as follow: 
 
• 
Participants in Group 1 with a negative FIT will remain in their assigned group 
and will be offered the next round of screening at 2-year intervals until the age 
of 69. All of them will be sent a letter informing them of the test result and the 
date of the next round of screening. Individuals who enter the study at the age 
of 68 or 69 will undergo a single round of screening. 
• 
Participants in Group 1 with a positive FIT will be contacted by phone and sent a 
letter informing them of the test result and the date of their appointment with 
the primary care physician (or specialist) or the person responsible for the 
screening programme, depending on the Autonomous Region They may be 
assisted in this task by the project staff. During the visit they will be informed 
about the colonoscopy procedure and will be scheduled for this procedure. 
• 
Participants in Group 1 with a positive FIT but who have normal colonoscopies or 
in whom only non-neoplastic disease is detected will remain in the FIT arm and 
will be offered the next round of screening using the biennial FOBT test at 
10 years after performance of the colonoscopy. 
• 
Participants in Group 2 who are found to be negative in colonoscopy or in whom 
only non-neoplastic disease is detected, will remain in the colonoscopy arm and 
will be offered a new colonoscopy at 10 years after performance of the baseline 
colonoscopy.  
Surveillance colonoscopy for patients with adenomas will be carried out according to 
the Joint Guideline from the US Multi-Society Task Force (USMTF) (45). 
• 
Participants in either Group 1 or Group 2 in whom only 1 or 2 non-advanced 
adenomas (low-risk adenomas) are detected, will be included in a surveillance 
programme and offered a new colonoscopy at 5 years.  
• 
Participants in either Group 1 or Group 2 in whom 3 or more non-advanced 
adenomas or 1 or more advanced adenomas (high-risk adenomas) are detected 
will be included in a surveillance programme and offered a new colonoscopy after 
3 years.  
• 
Participants in either Group 1 or Group 2 in whom >10 adenomas are detected in 
a single examination will be scheduled for surveillance colonoscopy in less than 3 
years. 
• 
Participants in either Group 1 or Group 2 in whom a large sessile adenoma is 
detected and removed by piecemeal resection will undergo a colonoscopy in 2-6 
months to verify complete removal.  

 
15
• 
The interval between subsequent surveillance colonoscopies will depend on the 
findings of the earlier examinations. In general, if a neoplastic lesion is detected, 
the above-mentioned criteria will be applied. On the other hand, if the 
examination is normal or if only non-neoplastic disease is detected, the next 
colonoscopy will be performed 5 years later. 
• 
For participants in either Group 1 or Group 2 in whom a malignant polyp is 
detected (pT1N0M0) and for whom endoscopic polypectomy is deemed sufficient 
(see criteria below), a new colonoscopy will be performed with biopsy of the 
resected area within a period of no more than 2-3 months to confirm that 
complete resection of the lesion was achieved. Subsequently, new colonoscopies 
will be performed after 1 and 3 years. 
• 
Participants in either Group 1 or Group 2 in whom an invasive CRC is detected 
will be treated and followed up according to the specific protocol of each centre, 
but always including a colonoscopy 1 year after the resection, and every 3 years 
thereafter.  
Any individual may refuse the screening examination assigned and request an 
alternative method. Any such individual will be assessed according to the group to 
which he/she was randomised for the “intention to screen” analysis, and according 
to the procedure actually performed in the “as-screened” analysis. These same 
criteria will be applied when any screening examination is performed (FOBT, 
colonoscopy, CT-colonography, or colonic capsule) and that is not foreseen in the 
study, regardless of the reason. 
All randomised subjects, whether the appropriate screening strategies have been 
performed or not, will be followed up for the purpose of tracking changes in the 
state of their health.  
Individuals who are not contacted will be registered for calculation of the invited 
population. 
For subsequent screening rounds, the same system of invitation will be used and 
according to each Autonomous Region policy.  
The CRC prevention units will ensure the performance of colonoscopies no more than 
4 weeks after the procedure is indicated. Patients in whom any neoplastic colorectal 
lesion is detected will be treated and followed up properly. 
The treatment of lesions detected in any screening examination will be conducted 
according to the specific protocol of each centre. 
 
5.1. Screening phases 
Phase 1: 
• 
It begins when the presentation letter, containing information on the CRC 
screening programme and the rationale of the study, is sent. 
• 
Four weeks later, the invitation letter indicating in which screening strategy the 
individual has been allocated, is sent. 
• 
It ends with receipt of the FIT test results (and performance of colonoscopy in 
those individuals with a positive result) (Group 1), or after completion of 
colonoscopy (Group 2). 

 
16
Phase 2 (individuals who require retesting):  
• 
In Group 1, it begins with repetition of the FIT test in patients for whom the 
previous test was invalid and ends when it is delivered and properly read. 
• 
In Group 2, it begins with repetition of colonoscopy in cases in which the bowel 
preparation was inadequate, or repetition of colonoscopy or performance of CT-
colonography when the colonoscopy was incomplete. 
Phase 3: includes all Group 1 respondents for phases I and II who are included in the 
subsequent biennial rounds until completion of the 10 years. In Group 2, phase III will 
be completed 10 years after completion of the first examination. 
 
5.2. Organisation and management of the project 
To ensure the viability and effectiveness of this project the following is necessary: 1) 
Ensuring specific CRC prevention units (CRCPU) in the gastroenterology departments 
of each participating hospitals; 2) Effective coordination between hospital CRCPU, 
LSO and primary care physicians; 3) Implementation of an educational programme for 
the general population and primary care physicians; 4) Assurance of the development 
of the above-mentioned field work and an effective system for recording the results 
of the programme in order to determine its true impact and to correct potential 
malfunctions; and 5) The provision of the financial resources required for ensuring 
the viability of the project. 
CRC prevention units (CRCPU) 
These units will be located in the Gastroenterology Departments of each participant 
hospitals. They will have a coordinator and will work with a separate agenda in order 
not to interfere with the regular activity of the endoscopy units. People with a 
positive FIT as well as all participants in the Group 2 that accepted colonoscopy will 
be received in these CRCPU. These units should warrant a correct diagnosis, 
treatment and surveillance of participants. Finally, CRCPU will give assistance to 
individuals identified as having a high risk for developing CRC. 
Coordination between Local Screening Offices and primary care physicians 
The LSO will have a person responsible for the study. There will be also a study 
coordinator in each Health Care Centre participating in the study, who will be 
responsible for its development. Moreover, it will be a data collector in charge of the 
information task and recruitment; this data collector could be located at the LSO, 
Health Centre or CRCPU. 
Educational programme and measures for improving study participation 
The educational programme is aimed to improve the knowledge of the target 
population and primary care physicians on natural history of CRC, symptoms, 
treatment, prognosis, and diagnostic tests in order to improve participation in the 
study. This aspect is critical to achieve a high adherence with screening. 
Possible actions include informative leaflets about CRC screening, campaign in the 
media (TV, radio and press), programme web page, organization of a "CRC prevention 
awareness day", among others (see Quality assurance programme). 
Data recording 
Demographic data, results of diagnostic tests, treatments and pathological data will 
be recovered in an online, centralized and protected database (www.coloncrib.org).  
 

 
17
6. DEFINITIONS 
• 
Pragmatic study: study designed to clarify whether an intervention works under 
real-life conditions and whether it works in terms that matter to the patient. It 
is simply concerned with whether the intervention works, not how or why.  
• 
Target population: 50-69 year-old individuals with verified address in sanitary 
card. 
• 
Invited population: target population excluding non-contacted individuals.  
• 
Eligible population: target population excluding non-contacted and excluded 
individuals. 
• 
Participant population: individuals who returned the FIT test (Group 1) or who 
completed colonoscopy (Group 2). 
• 
Screening inclusion data: data of sending the invitation letter. 
• 
Incomplete colonoscopy: colonoscopy in which caecal intubation is not possible. 
When an incomplete colonoscopy occurs, this examination must be repeated or 
completed with a CT-colonography.  
• 
Inadequate colon cleansing: when less than 90% of colorectal mucosa can be 
properly evaluated due to the presence of faeces, this examination must be 
repeated.  
• 
Non-neoplastic polyp: hyperplastic, hamartomatous or inflammatory polyps. 
• 
Non-advanced adenoma: any tubular adenoma <1 cm and with low-grade 
dysplasia. 
• 
Advanced adenoma: adenoma >1 cm in size, or with high-grade dysplasia, or with 
villous component (>25%). 
• 
High-risk adenoma: 3 or more non-advanced adenomas, or any advanced 
adenoma. 
• 
Low-risk adenoma: 1 or 2 non-advanced adenomas. 
• 
Non-invasive colorectal cancer: colorectal carcinoma without submucose 
invasion (pTis). It includes intramucous carcinoma and intraepithelial carcinoma. 
• 
Invasive colorectal cancer: colorectal carcinoma beyond the muscularis mucosa 
(pTNM stages I, II, III and IV). 
• 
Advanced neoplasia: colorectal advanced adenoma or cancer. 
• 
Malignant polyp: adenoma that harbours an area of carcinoma invading 
submucose (pT1). 
• 
Polyposis: existence of >10 polyps. Depending on the histology, it could be 
adenomatous, hamartomatous or hyperplastic. 
• 
Non-neoplastic colorectal diseases: any non-neoplastic disease detected in the 
colonoscopy (i.e. haemorrhoids, diverticulosis, angiodysplasia, etc.).  
 
6.1. Classification of colorectal polyps 
Colorectal polyps will be classified following the Paris classification (protruded, flat-
elevated and flat-depressed). The size of the polyps will be established ex vivo after 
resection and before formaldehyde fixation. 

 
18
When pathological study is not available because the polyp could not be recovered 
and pre-resection biopsy was not taken, it will be conservatively considered as 
adenoma. 
 
6.2. Treatment of malignant polyps 
Endoscopic polypectomy will be considered definitive treatment of a malignant polyp 
(pT1) if it fulfils all the following characteristics:  
• 
Well or moderate differentiation degree, 
• 
No vascular or lymphatic invasion, and 
• 
Free resection margin >1 mm 
In these patients, a new colonoscopy will be performed within 2-3 months with 
biopsies of the resection area (see Development of the study section). 
 
6.3. Classification of colorectal cancer 
CRC patients detected in the study will be classified as: 1) Screening CRC: CRC 
detected in the screening Groups 1 and 2; 2) Interval CRC: CRC diagnosed after a 
negative FIT (Group 1) or after a negative colonoscopy (Group 2), or detected after a 
positive FIT with a negative colonoscopy or if colonoscopy was not accepted by the 
patient (Group 1); 3) Sporadic CRC: CRC diagnosed in patients that did not accept 
screening in the study.  
CRC stage will be established using TNM classification (American Joint Committee on 
Cancer, 6th edition):  
Primary tumour (pT) 
• 
Tx: It is not possible to evaluate primary tumour 
• 
T0: There is not evidence of primary tumour  
• 
Tis (in situ carcinoma): intraepithelial o intramucous tumour 
• 
T1: Tumour invades submucose  
• 
T2: Tumour invades muscularis propria  
• 
T3: Tumour invades subserose or pericolic/perirectal tissues through muscularis 
propria 
• 
T4: Tumour invades other organs or perforates the peritoneum 
Regional lymph nodes (pN)  
• 
Nx: It is not possible to evaluate regional lymph nodes  
• 
N0: No metastasis in any regional lymph nodes  
• 
N1: Metastasis in 1-3 regional lymph nodes  
• 
N2: Metastasis in 4 or more regional lymph nodes 
Distant metastasis (pM) 
• 
Mx: It is not possible to evaluate distant metastasis  
• 
M0: No distant metastasis  
• 
M1: Distant metastasis  

 
19
Tumour TNM stages 
 
Stage   0 
Tis 
 
N0 
 
M0 
 
Stage  I 
T1-2 
 
N0 
 
M0 
 
Stage  IIA 
T3 
 
N0 
 
M0 
 
Stage  IIB 
T4 
 
N0 
 
M0 
 
Stage  IIIA 
T1-2 
 
N1 
 
M0 
 
Stage  IIIB 
T3-4 
 
N1 
 
M0 
 
Stage  IIIC 
T1-4 
 
N2 
 
M0 
 
Stage  IV 
T1-4 
 
N0-2 
 
M1 
 

 
20
7. STATISTICAL ANALYSIS PLAN (SAP) 
Because of the study design, which allows for cross-over between both strategies, 
the main outcomes of the study will be analysed by intention-to-screen, as-screened 
and per-protocol.  
Intention-to-treat 
Cumulative incidence curves for the invitation arms will be estimated with the 
Kaplan-Meier estimator, considering the period from the day of randomization to the 
end of follow-up. The Kaplan-Meier estimator with daily outcome events will be used 
to compute the probability (risk) of the outcome during the period. For CRC 
incidence and mortality, non-CRC events will be considered as censoring events. We 
will calculate the 10-year risk differences and risk ratios between the trial arms, 
whereas 95% confidence intervals (95% CI) will be computed using the normal 
approximation. 
As-screened 
Cumulative incidence curves for the screening procedure actually performed will be 
estimated with the Kaplan-Meier estimator, considering the period from the day of 
randomization to the end of follow-up. The Kaplan-Meier estimator with daily 
outcome events will be used to compute the probability (risk) of the outcome during 
the period. For CRC incidence and mortality, non-CRC events will be considered as 
censoring events. We will calculate the 10-year risk differences and risk ratios 
between the trial arms, and 95% CI will be computed using the normal 
approximation. To provide adjusted estimates, the Kaplan-Meier estimator will be 
weighted with inverse probability of weighting (IPW). In this causal contrast, 
propensity scores for colonoscopy, FIT and no screening will be estimated with a 
multinomial logistic regression. The included covariates will be age, sex and centre 
of participants with a 3-degree of freedom natural spline. 
Per-protocol 
Cumulative incidence curves for the compliers (i.e. those individuals who completed 
the treatment originally allocated) will be estimated with the Kaplan-Meier 
estimator, considering the period from the day of randomization to the end of 
follow-up. The Kaplan-Meier estimator with daily outcome events will be used to 
compute the probability (risk) of the outcome during the period. For CRC incidence 
and mortality, non-CRC events will be considered as censoring events. We will 
calculate the 10-year risk differences and risk ratios between the trial arms, and 95% 
CI will be computed using the normal approximation. To provide adjusted estimates, 
the Kaplan-Meier estimator will be weighted with IPW. In this causal contrast, 
propensity scores for colonoscopy, FIT and no screening will be estimated with a 
multinomial logistic regression. The included covariates will be age, sex and centre 
of participants with a 3-degree of freedom natural spline. 
 
End points of the study 
Primary end point:  
CRC-specific mortality at 10 years 
Secondary end points:  
1. Participation, detection rate, diagnostic yield and complication rate at the 
completion of the first round and at the end of study (10 years) 
Definitions of these four key outcomes are as follows: 

 
21
• 
Participation: number of participating individuals (i.e. individuals who completed 
colonoscopy in the colonoscopy group and individuals who returned the test in 
the FIT arm) relative to the number of eligible individuals. 
• 
Detection rate: number of true positives relative to the number of participating 
individuals. 
• 
Diagnostic yield: number of true positives relative to the number of eligible 
individuals. 
• 
Complication 
rate: 
number 
of 
major 
complications 
(i.e. 
perforation, 
postpolypectomy 
bleeding 
requiring 
hospitalization, 
and 
cardiovascular/ 
pulmonary complications requiring medical management) relative to the number 
of participating individuals. 
Differences in these four key outcomes between both strategies will be established 
by logistic regression analysis, adjusted by age, gender and participating centre, and 
reported as odds ratios (OR) with 95% CI.  
2. Overall survival at the end of study (10 years) 
3. CRC incidence at the end of study (10 years and 15 years) 
4. Cost-effectiveness analysis 
Cost-effectiveness will be studied with a Markov’s model at the completion of study. 
Results will be reported in terms of quality-adjusted life years (QALY). 
5. Analysis of factors influencing participation in the study 
Factors associated with participation at the completion of first round and at the end 
of study (10 years) in each screening strategies will be analysed by logistic regression 
analysis and results reported as OR with 95% CI. Parameters analysed will include 
demographics, personal and familial characteristics, socio-economic status, etc.  
6. Number needed to screen to detect a colorectal cancer 
The number needed to screen to detect a CRC will be calculated using the inverse of 
risk (i.e. the number of participants receiving a given screening modality divided by 
the number of positive cases in that given modality), with 95% CI computed using the 
inverse of the binomial standard approximation. 

 
22
8. CHRONOGRAM 
The study will be developed according to the following chronogram: 
• 
Initial meeting: October 28th, 2008  
• 
Formative meeting for data-collectors and other auxiliary staff: December 12th, 
2008 
• 
Informative campaign launched by the Spanish Alliance for CRC Prevention and 
involving national and local media: from November 2008 to March 2009 
• 
Recruitment period will be initiated in June 2009 
• 
Quality Committee meetings will be held during the first round according to the 
following calendar:  
• June 12th, 2009  
• December 11th, 2009 
• June 11th, 2010 
• December 10th, 2010 
• 
First round of screening will be finished in June 2011 
• 
First follow-up meeting (first-round interim analysis): July 2011 
• 
Other follow-up meetings will be held regularly during the study period, in a 
biennial basis (date will be announced properly) 
• 
Other Quality Committee meetings will be held regularly during the study period, 
in a annual basis (date will be announced properly) 
• 
Completion of the study: December 2021 
• 
Analyses of main end point results (i.e. CRC mortality and incidence and any-
cause mortality at 10 years): June 2024 
• 
Follow-up conference calls among members of the Executive Committee will be 
held periodically, every four months, during the study period. 

 
23
9. ETHICAL QUESTIONS 
The study will respect the Helsinki declaration, the European Council Human Rights 
and Biomedicine, and the UNESCO Universal Declaration about human genome and 
human rights. Moreover, the study will fulfil established requisites about biomedical 
investigation, data protection and bioethics of the Spanish law.  
People included in this study will receive appropriate information about objective, 
methodology and study procedures. Thereafter, they will provide written informed 
consent for participating in the study.  
This study receives the approval of the Ethics Committee of Clinical Investigation and 
the Research Committee of every of the participant hospitals.  
  

 
24
10. RESEARCH PROJECT TEAM 
All the investigators will be grouped together under the name of “Grupo Cooperativo 
para el Cribado del Cáncer Colorrectal en España“ or “COLONPREV study”. 
Every LSO, hospital and Heath Centre will designate a responsible. Among them, a 
Local Coordination Committee will be chosen and a Coordinator will be named. 
Local Coordinators of all Autonomous Regions will constitute the Executive 
Committee. This committee will name the National Coordinators and will establish 
publication criteria for the study. 
In the heading of the publications related to the main and secondary objectives of 
the study will appear, at least, the National Coordinators, members of the Executive 
Committee, responsible of every participant hospital, LSO and Health Centre, and 
the methodological assessors, followed by “on behalf of the Grupo Cooperativo para 
el Cribado del Cáncer Colorrectal en España” or “on behalf of COLONPREV study 
investigators”. All other investigators will appear in a supplementary note at the end 
of the publication. 

 
25
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