Endoscopic Surveillance in Patients With Serrated Polyposis Syndrome and Low-risk of Advanced Neoplasia.
Phase: NA
Conditions: Colonic Polyp, Colonic Neoplasms, Colonic Cancer, Serrated Polyposis, Serrated Polyp of Colon
Sponsor: Hospital Universitario de Móstoles

 
Title: Endoscopic surveillance in patients with serrated polyposis syndrome and low-
risk of advanced neoplasia.  
NCT:  
Principal investigator: Jorge López Vicente.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 15th May 2023.  
 
 
 
 

Title: Endoscopic surveillance in patients with serrated polyposis syndrome and low-
risk of advanced neoplasia.  
STUDY PROTOCOL 
SCIENTIFIC BACKGROUND:  
Colorectal cancer (CRC) is the most frequent neoplasm in developed countries 
considering both sexes and is the second in terms of cancer mortality. The incidence of 
the CRC is increasing in all developed countries.  Detection of precancerous lesions 
(colon polyps) or malignant lesions (adenocarcinoma) in early stages in screening 
programs improves the prognosis and decreases the mortality of these patients. 
Serrated polyposis syndrome (SPS) is the most common colorectal polyposis syndrome 
and is characterized by the combination of large and/or numerous serrated lesions (SL) 
throughout the colorectum. There are three different types of SLs described: 
hyperplastic polyps (HP), sessile serrated lesions (SSL) and traditional serrated 
adenomas (TSA). 
In 2010 the world health organization (WHO) defined the clinical criteria for the 
SPS diagnosis: criteria I, any patient with ≥ 5 serrated lesions proximal to the sigma, 
two of them> 1 cm in size; criteria II, any first degree relative of a SPS patient with at 
least one serrated lesion; criteria II, any patient with ≥20 serrated lesions throughout 
the colon. This criteria were reviewed in 2019 and criteria II was eliminated. The new 
criteria are: criteria 1, any patient with ≥ 5 SL proximal to the rectum, all ≥5 mm in size, 
with at least 2 lesions ≥10 mm in size; criteria 2, any patient with >20 SL of any size 
distributed throughout the colon, with ≥5 lesions proximal to the rectum.  
In recent years, a new pathway in the development of colorectal 
adenocarcinoma have been described, the "serrated pathway". It is associated with 
mutations in BRAF and KRAS genes, the existence of hypermethylation in the promoter 
regions "CpG island" and microsatellite instability phenotype caused by methylation of 
the MLH-1 gene. This new pathway has a faster progression from the serrated polyp to 
the CRC in comparison with the classic "adenoma-carcinoma" pathway, hence the 
importance of detecting and removing these lesions in patients with SPS.  
CRC prevalence in patients diagnosed with SPS is 15-35%, according to different 
studies, and the probability at 5 years of developing a CRC is around 1.3-1.9%. During 
surveillance, the incidence of advanced neoplasia (advanced adenoma or advanced 
serrated lesions) at 3 years is 13% for adenomas and 42 for serrated lesions.  Risk 
factors for developing CRC and advanced neoplasia have been described in several 
studies.  One of these factors is the SPS criteria 2, which has been demonstrated as a 
low risk of CRC and advanced neoplasia during surveillance of SPS patients.  Detecting 
more than two sessile serrated lesions proximal to the spleenic flexure, one sessile 
serrated lesion with high grade of dysplasia and the detection of advanced neoplasia in 

previous colonoscopies, are all risk factors of developing advanced neoplasia during 
surveillance. A recent multicentre prospective study established SPS patient 
surveillance according to lesions detected at last colonoscopy.  Individuals with at least 
one advanced adenoma, an advanced serrated lesion or more than 5 relevant lesions 
(sessile serrated lesions, adenomas of any size or hyperplastic polyps more than 5 mm) 
were followed at one year. Patients with no lesions mentioned before were followed 
at 2 years with colonoscopy. Advanced neoplasia incidence in 2 years recommendation 
surveillance was 15.6% compared with 24.4% in the 1 year recommendation 
surveillance. CRC cumulative 5 years incidence was 1.3%. Regarding SPS type, the 5 
years advanced neoplasia incidence was lower for patients with SPS criteria III of 2010 
(26%) than for patients diagnosed with criteria I (53%) or criteria I and III (59%). In this 
study patients starting their surveillance with clearing phase achieved (clear colon of 
all polyps ≥5mm and all polyps with the optical aspect of adenoma, TSA or SSL) were at 
low risk of advanced neoplasia than patients without this phase achieve prior to study 
inclusion (HR: 0.64; p<0.047). 
 With all the above described, it can be define a SPS patient with low risk of 
advanced neoplasia during surveillance: those patients with clearing phase achieved 
and without any advanced lesion or less than 5 relevant lesions at last colonoscopy.     
The Spanish Society of Gastroenterology (AEG) recommends surveillance with 
colonoscopies in 1-3 years interval for SPS patient, as it does the European Society of 
Digestive Oncology (ESDO). The European Society of Gastrointestinal Endoscopy (ESGE) 
recommends surveillance at 1 o 2 years depending on the last colonoscopy findings, 
annually in case of any advanced adenoma or serrated lesion or ≥5 relevant lesions 
(adenomas, SSL or HP≥5mm) were removed, and two surveillance in all other cases. 
The British Society of Gastroenterology (BSG) recommends annually surveillance for 
SPS patients until all serrated lesions ≥ are removed, and then 2 year-surveillance. All 
these Guidelines mention the limited evidence to support their recommendations and 
the need for prospective studies to evaluate them. As well many authors have 
expressed the possibility of extending the surveillance to 3 or even 5 years in low risk 
patients.    
The aim of the study is to determine if SPS patients with SPS criteria 1 or 2, with 
clearing phase achieved and without any advanced lesion or less than 5 relevant 
lesions at last colonoscopy have the same advanced neoplasia incidence in the 
surveillance colonoscopy at 2 or 3 years.  
 
 
 

OBJECTIVES:  
Principal:  
• Evaluate de incidence of CCR and advanced neoplasia in SPS patients with low 
risk factors of advanced neoplasia during surveillance.  
Secondary:  
• Compare the incidence of advanced neoplasia between patient surveillance 
with colonoscopy at 2 and 3 years. 
• Describe low risk factors of advanced neoplasia in SPS patient in our 
environment. 
• Identify a group of patients with SPS and low risk of advanced neoplasia.  
 
METOHDS 
This is a prospective, randomized (1:1) and multicenter study, in Spanish national 
hospitals, with SPS patients diagnosed according to the reviewed WHO criteria in 2019, 
in a surveillance program and who meet all the inclusion criteria and no exclusion 
criteria.   
Inclusion criteria: 
- 
Patients aged 18 years or older that fulfil WHO criteria 1 or 2 of SPS. 
o Criteria 1: any patient with ≥ 5 SL proximal to the rectum, all ≥5 mm in 
size, with at least 2 ≥10 mm in size. 
o Criteria 2: any patient with >20 SL of any size distributed throughout the 
colon, with ≥5 lesions proximal to the rectum. 
- 
Patients with a previous complete colonoscopy with adequate bowel 
preparation and with all lesions >5mm been resected (“clearance colonoscopy), 
after the diagnostic of SPS.  
- 
Nor advanced adenoma or serrated lesions at prior colonoscopy, and also 
either more than 5 relevant lesion (adenoma, SSL or PH>5mm) at prior 
colonoscopy.  
Exclusion criteria:  
- 
Patients with no inform consent or who do not agree to participate in the 
study. 
- 
Patients with total or partial colectomy.   
- 
Patients with other CCR predisposing syndromes with germinal mutation 
(Familial adenomatous polyposis, Lynch syndrome, Peutz-Jehgers syndrome, 
Cowden syndrome, Juvenile polyposis syndrome…). 

- 
Patients with chronic inflammatory bowel disease. 
- 
Patients with coagulation disorders. 
- 
Fragmented lesion or submucosal invasive lesion at last colonoscopy.  
- 
Inadequate colon preparation: any segment of the colon with <2 points in 
Boston Scale (BBPS).     
 
 
Patients selected for the study will be randomised in two groups for the 
surveillance: group 1, surveillance with colonoscopy in two years; group 2, surveillance 
with colonoscopy in three years.  Randomization will be done at the database program 
(RedCAP).  
 
All colonoscopies will be performed with high definition (HD) system and it will 
be the choice of the endoscopist whether to use chromoendoscopy with indigo 
carmine o virtual chromoendoscopy. Protocol bowel preparation will be recommended 
by each centre. Sedation will be prescribed and decided by the endoscopist during the 
examination.  
 
Data from all the resected and visualized lesions during the colonoscopy will be 
collected on the database. A pathologist familiarized with serrated lesions will be in 
charge of the sample analysis. Serrated lesions will be classified attending de WHO 
criteria for serrated lesions. The investigators define “advanced adenoma” as 
adenomas ≥10 mm with villous histology and/or with high grade of dysplasia (HGD). 
We define “advanced SL” as any SL ≥10mm and any SL with dysplasia.  The 
investigators define “advanced neoplasia” as any CRC, any advanced adenoma or 
advanced SL.   
 
Quality of bowel cleansing will be graded by each endoscopist following the 
Boston Bowel Preparation Scale. This scale evaluates each segment (ascending colon, 
transverse colon and descending colon) of the following form: 0 = segment of colon 
whose mucosa cannot be seen due to the existence of solid stools that cannot be 
eliminated; 1 = mucosa portion of a colonic segment that can be seen, but other areas 
of the colonic segment are not seen, either due to the presence of dirt, feces or 
opaque liquid; 2 = existence of small amount of dirt, small fragments of stool and / or 
opaque liquid, but the mucosa of the colonic segment can be seen well; 3 = all the 
mucosa of the colonic segment can be seen well without residual dirt, small traces of 
stool or opaque liquid. Patients with inadequate preparation (when in any segment the 
score is 0 or 1, or the total score is less than 6) will be excluded from the study. 
 
During colonoscopy all complications as post-polypectomy bleeding, 
perforation or cardio-respiratory events will be registered. Those complications will be 
considered if surgery or hospital admission is required.  

 
SAMPLE SIZE CALCULATION 
 
This is a randomized controlled study for evaluating a non inferiority strategy in 
the surveillance of SPS patients, between colonoscopy in 2 years and colonoscopy in 3 
years, with the incidence of advanced neoplasia as the principal aim of the study. In 
the study from the Netherlands, Bleijenberg and col., the incidence of advanced 
neoplasia in patients at 2 years surveillance was of 15%. The investigators assume an 
acceptable increase of advanced neoplasia at 3 years surveillance of 25%, so the 
margin for no inferiority is 10% between the two groups. Accepting the type I error 
with an unilateral contrast of 0.025, beta risk of 0.2 (power 80%) and considering a 
10% of lost patients, 69 patients in each group (136 in total) are needed to detect 
significance differences between the two groups.  
 
STUDY VARIABLES:      
- 
Demographic variables: Hospital, identification number (number assigned to 
each hospital and consecutive number of each patient), date of birth, sex, SPS 
criteria (according to WHO classification and actualized in2019: 1 or 2), date of 
the last colonoscopy, number and type of lesions resected at the last 
colonoscopy,  number of previous colonoscopies, number of polyps removed so 
far (low risk, high risk and serrated lesions), colon surgery (yes/no) and type of 
surgery (right colectomy, left colectomy, low anterior resection, segmental 
colectomy or others), smoker (yes/no/prev).  
- 
Variables of the procedure: date of the procedure, bowel preparation  
according to BBPS scale 14, study arm (Colonoscopy in2 years/Colonoscopy inn3 
years), number and description of lesions resected during the procedure 
describing its size, shape according to Paris classification15, location of the 
lesions, distance to the anal margin. Inspection time in each exploration (with 
stopwatch and without counting the therapeutic moments). Complications 
during the procedure (bleeding, perforation or cardio-respiratory events).  
 
 
 
STATISTICAL CONSIDERATIONS AND STATISTICAL ANALISIS PLAN 
 
Numeric variables will be collected as integer number; they will be presented as 
mean and standard deviation in case of a normal distribution and compared with a 

Student´s t test. Categorical variables will be collected associated with an integer 
starting from cero; they will be presented as frequencies and compared with the Chi 
Square test. The risk of advanced neoplasia or CRC after 2 year colonoscopy 
surveillance will be compared with the risk of advanced neoplasia and CRC after 3 year 
colonoscopy surveillance using logistical regression analysis and expressed as Odds 
Ratio (OR).  
 
Risk factors identified previously will be assessed in univariate and multivariate 
Cox Regression analysis, adjusted by age, gender and smoking status). They will be 
presented as Hazard Ratio (HR) with 95% of confidence interval. Statistical analysis will 
be performed with SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). 
 
NECESSARY RESOURCES: 
 
Colonoscopies and polypectomies will be done in the usual clinical care 
practice. This protocol does not require additional funding. The explorations will be 
carried out by the researchers who are staff doctors of the Digestive Endoscopy Units. 
The effort, the minimum marginal expenses that may lead to the prolongation of the 
exploration and the collection of data will be assumed by the researchers and the 
Digestive Endoscopy Units. 
ETHICAL CONSIDERATIONS: 
 
This protocol follows the ethical principles of non-malfeasance, beneficence, 
autonomy and justice included in the Declaration of Helsinki (last update, Seoul 2008) 
17, as well as in law 41/2002 on patient autonomy18 and research law 14/2007 
biomedical19. The personal and clinical data of the patients will be anonymized.  
 
 
 
 
 
 
 
INFORMED CONSENT FORM 

Endoscopic surveillance in patients with serrated polyposis syndrome and low-risk of 
advanced neoplasia. 
 
Colon cancer is currently the most common cancer in developed countries taking 
women and men together, and ranks second in cancer mortality. Detection of precancerous 
lesions in the colon (polyps) or malignant lesions (adenocarcinoma) in early stages of the 
disease improves prognosis and decreases patient mortality.*  
 
Serrated polyposis syndrome is defined by multiple serrated or relevantly sized polyps 
throughout the colon. Other polyps may also be found in the colon such as adenomas and also 
have malignancy potential. The histological characteristics and size of these adenomas or 
serrated polyps make some of them considered at increased risk of malignancy (these are 
called advanced serrated adenomas or polyps).  A recent study has shown that patients with 
serrated polyposis syndrome who do not have advanced serrated adenomas or serrated 
polyps in the last colonoscopy, have a low risk of developing advanced lesions within 2 years of 
follow-up (15%) and a very low incidence of colon cancer (less than 1.5%) at 5 years 
surveillance.   
 
The Spanish Association of Gastroenterology (AEG) recommends monitoring patients 
with Serrada Polyposis Syndrome every 1 or 3 years with colonoscopy.  Similarly, the European 
Society of Digestive Oncology (ESDO) also recommends follow-up between 1 and 3 years. 
Moreover, the European Society of Digestive Endoscopy (ESGE) recommends a follow-up of 1 
or 2 years depending on the lesions founded in the last colonoscopy. 
 
From of the mentioned above, we propose to participate in a randomized study in 
patients with serrated polyposis syndrome who are in surveillance program. If no advanced 
adenomas, advanced serrated polyps or less than 5 relevant lesions have been found in the 
last colonoscopy, follow-up randomization will be performed at 2 years or 3 years. You will be 
randomly assigned to perform follow-up colonoscopy at age 2 or 3 years of the last 
colonoscopy, provided you have not had advanced injuries (risky lesions in the last 
colonoscopy).  Data on the lesions removed, as well as the duration of the test and various 
demographic variables in relation to the individual participating in the study, will be recorded 
during colonoscopies. 
 
The aim of the study is to determine the incidence of advanced and non-advanced 
lesions in follow-up, comparing those that are performed colonoscopy at 2 years with those 
performed at age 3.  
We look forward to your selfless collaboration in order to provide you with higher quality 
health care. 
 
(*) -Castells A. Colorectal cancer screening. Gastroenterol Hepatol 2011;34 Suppl 2:60-6. 
- Grau J, et al. Colorectal cancer screening programs in the population at average risk in the European Union and Spain. Gastroenterol Hepatol;33:111-8. 
- Brown SR, Baraza W. Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum. Cochrane Database of Systematic Reviews 2010. 
&Bleijenberg AGC, IJspeertv JE , Van Herwaarden YJ et al. Personalised surveillance for serrated polyposis syndrome: results from a prospective 5-year international cohort 
study. Gut 2020 Jan;69:112-121.   
 

Study title: Endoscopic surveillance in patients with serrated polyposis syndrome and 
low-risk of advanced neoplasia. 
Study Promoter: Digestive Device Section of the University Hospital of Móstoles and 
Digestive Endoscopy Unit. 
Researchers responsible for the study: Dr. López Vicente.  
1. I.................................................. I declare under my responsibility that I have read 
the study information and agree to participate in that study. 
2. A copy of the Patient Information has been given to me. I have been explained the 
characteristics and objective of the study. I've been given time and opportunity to ask 
questions. All questions were answered to my satisfaction 
3. I am free to withdraw from the study at any time for any reason, without having to 
explain and without having to negatively impact my future medical treatment. 
4. I understand that the objective of the study is to assess the population under study 
and that the results of the study shall not be communicated to me except in the event 
that such findings have a significant implication for the health of the participants.  
 
Point 1.- I give  / I do not give  consent to participate voluntarily in the observational 
study of which I have been informed 
 
Date............................. and Signature of the patient....................... 
 
I note that I have explained the characteristics and purpose of the study to the subject 
whose name is written above. The patient consents to participate through his 
signature dated in person. 
 
Date..................... and Signature............................ ( research physician). 
Name of the Investigator or designated person to provide the information.