Detection of Progressive Disease in Metastatic Colorectal Cancer Patients by NPY Methylation in Liquid Biopsies
Phase: NA
Conditions: Metastatic Colorectal Cancer
Sponsor: University Hospital, Antwerp

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
 
 
 
 
1 
 
Title: 
 
Detection of Progressive Disease in Metastatic Colorectal 
Cancer Patients by NPY Methylation in Liquid Biopsies 
 
 
LEAD-IN 
FOLICOLOR TRIAL 
 
 
 
 
Clinical Study Sponsor: 
Antwerp University Hospital 
 
Drie Eikenstraat 655 
 
B-2650 EDEGEM 
 
 
 
 
 
 
Confidentiality Notice 
This document contains confidential information. 
This document must not be disclosed to anyone other than the study staff and members of 
the independent ethics committee/institutional review board. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Antwerp University Hospital. 
If you have questions regarding how this document may be used or shared, please 
send a mail to folicolor@uza.be 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
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PROTOCOL SIGNATURE SHEET  
 
Detection of Progressive Disease in Metastatic Colorectal Cancer Patients 
by NPY Methylation in Liquid Biopsies  
 
LEAD-IN  
FOLICOLOR Trial 
 
Version: v.3.0 – Belgium (11 August 2020) 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Principal Investigator agrees to conduct the trial in compliance with the approved protocol and will 
adhere to the principles outlined in the requirements for the conduct of clinical trials in the EU as 
provided for in "Directive 2001/20/EC”, and any subsequent amendments, GCP guidelines, the Belgian 
law of May 7th 2004 regarding experiments on the human person, the Sponsor’s SOPs, and other 
regulatory requirements as amended. I agree to ensure that the confidential information contained in 
this document will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
Name + function 
Site 
Signature 
Date 
(DD/MM/YYYY) 
 
 
 
 
 
 
Principal Investigator 
Belgium 
 
 
 
 
       
 
 

Protocol Number: v.3.0 
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PROTOCOL SYNOPSIS 
Study title 
LEAD-IN FOLICOLOR TRIAL: 
DETECTION OF PROGRESSIVE DISEASE 
IN METASTATIC COLORECTAL CANCER 
PATIENTS BY NPY METHYLATION IN 
LIQUID BIOPSIES 
Type of study 
Prospective, multicentric interventional study 
Sponsor 
Antwerp University Hospital (UZA) 
Funding 
Amgen 
Indication 
RAS and BRAF wild-type, unresectable, 
metastatic 
colorectal 
cancer, 
first-line 
treatment 
FOLFOX/FOLFIRI 
and 
panitumumab. 
Study design 
Prospective, multicentric interventional study 
to optimize the cutoff value of NPY methylation 
in liquid biopsies in metastatic colorectal 
cancer 
patients 
treated 
with 
first-line 
FOLFOX/FOLFIRI and panitumumab. 
Inclusion is possible after histologically or 
cytologically 
proven 
colorectal 
adenocarcinoma 
with 
metastatic 
lesions 
according to RECIST 1.1 at the start of first-
line treatment using FOLFOX/FOLFIRI and 
panitumumab. Patient must have a proven 
RAS and BRAF wild-type tumor. 
 
Patients will be followed by study protocol up 
to and including the first CT scan following the 
last liquid biopsies taken, or when a follow-up 
period of 11 months is reached, until death, 
until metastasectomy, until lost to follow-up or 
until (consent) withdrawal.
Study objectives 
The primary objective of this study is to 
optimize the cutoff value of NPY methylation in 
liquid biopsies (ctDNA) in metastatic colorectal 
cancer patients receiving first-line FOLFOX/ 
FOLFIRI and panitumumab.   
 
The secondary objective is to determine the 
progression free and 9-month survival of 
metastatic colorectal cancer patients. 
 
Exploratory objectives will include, but will 
not be limited to the following:  
 
To explore and compare the use of ctDNA 
and CEA to predict progression; 
 
Further exploration of ctDNA in liquid 

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biopsies 
and 
searching 
for 
novel 
biomarkers; 
 
To assess the quality of life and the patient 
experience of metastatic colorectal cancer 
patients with regard to the use of liquid 
biopsies for follow-up.  
Included treatment 
First-line 
FOLFOX/FOLFIRI 
and 
panitumumab. 
 
 
Included dosing regimen and route 
Chemotherapeutic agents will be given as an 
intravenous infusion at a dose and interval 
consistent with standard institutional practice. 
 
Study population 
Metastatic colorectal cancer patients starting 
first-line FOLFOX/FOLFIRI and panitumumab. 
 
 
 
Main inclusion criteria 
Key Inclusion Criteria (see 5.1 for complete list 
of inclusion criteria): 
 
Man or woman ≥ 18 years of age at the 
time the informed consent is obtained
 
ECOG performance status of 0 or 1
 
Histologically or cytologically confirmed 
adenocarcinoma of the colon or rectum in 
subjects with unresectable metastatic 
(M1) disease
 
At least 1 uni-dimensionally measurable 
lesion of at least 10 mm per RECIST 1.1 
guidelines using conventional techniques 
(CT scan). Lesion must not be chosen 
from a previously irradiated field, unless 
there has been documented disease 
progression in that field after irradiation 
and prior to inclusion. All sites of disease 
must be evaluated  28 days prior to the 
start of first-line therapy
 
Wild-type RAS tumor status (of tumor 
tissue)
 
Wild-type BRAF tumor status (of tumor 
tissue)
 
Adequate hematologic, renal, hepatic and 
coagulation function
 
Starting a first-line treatment with a 
combination of FOLFOX/FOLFIRI and 
panitumumab 
 
Main exclusion criteria 
Key Exclusion Criteria (see 5.2 for complete 
list of exclusion criteria): 
 
History of prior or concurrent central 
nervous system metastases
 
History of other malignancy, except:
o 
Malignancy treated with curative 
intent and with no known active 
disease present for ≥ 3 years prior 
to start therapy and felt to be at 
low risk for recurrence by the 
treating physician 
o 
Adequately 
treated 
non-

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melanomatous skin cancer or 
lentigo maligna without evidence 
of disease 
o 
Adequately 
treated 
cervical 
carcinoma in situ without evidence 
of disease 
o 
Prostatic intraepithelial neoplasia 
without 
evidence 
of 
prostate 
cancer 
 
Prior chemotherapy or other systemic 
anticancer therapy for the treatment of 
metastatic colorectal carcinoma including 
but not limited to bevacizumab and anti-
EGFR 
therapy 
(e.g. 
cetuximab, 
panitumumab, erlotinib, gefitinib, lapatinib)
 
Prior adjuvant chemotherapy (including 
oxaliplatin therapy) or other adjuvant 
systemic anticancer therapy including but 
not limited to bevacizumab and anti-EGFR 
therapy (e.g. cetuximab, panitumumab, 
erlotinib, 
gefitinib, 
lapatinib) 
for 
the 
treatment of colorectal cancer ≤ 6 months 
prior to start therapy with the following 
exceptions:
o 
Subjects may have received prior 
fluoropyrimidine 
therapy 
if 
administered 
solely 
for 
the 
purpose of radiosensitization for 
the 
adjuvant 
or 
neoadjuvant 
treatment of rectal cancer 
 Radiotherapy ≤ 14 days prior to start 
therapy. Subjects must have recovered 
from all radiotherapy-related toxicities.
 Significant cardiovascular risk 
 History of interstitial lung disease (e.g., 
pneumonitis or pulmonary fibrosis) or 
evidence of interstitial lung disease on 
diagnostic CT scan
 Active inflammatory bowel disease or 
other bowel disease causing chronic 
diarrhea (defined as ≥ CTC grade 2, 
[CTCAE version 5.0])
 Peripheral sensory neuropathy (≥ CTC 
grade 2 [CTCAE version 5.0] 
Total sample size 
The calculated sample size is 60 subjects  
 
 
 

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Planned study visits 
Screening period/eligibility check (Mb): 
 
Additional visit for CT scan if diagnostic 
CT scan is > 28 days before start of first-
line therapy 
 
1 EDTA tube to check hematologic, 
renal, 
hepatic, 
metabolic, 
and 
coagulation function < 14 days before 
start of first-line therapy 
 
Inclusion 
 
Questionnaire 
o 
Quality of Life (EORTC QLQ-
C30 & EORTC QLQ-CR29) 
 
Start first-line therapy (M0): 
 
Start cycle 1 of first-line therapy 
(FOLFOX/FOLFIRI and panitumumab) 
 
Liquid biopsy sampling: 
o 
LB0 to measure the ctDNA level  
o 
LBa and LBb for further research 
 
Follow-up: 
 
Biweekly liquid biopsy sampling up to 
and including 9 months after start first-
line therapy  
 
Every 8 weeks: CT scan combined with 
CEA up to and including the first CT scan 
following the last liquid biopsies taken  
 
M9: Quality of Life (EORTC QLQ-C30 & 
EORTC 
QLQ-CR29) 
+ 
patient 
experience 
 
End of Study (EOS): 
 
Day on which the first CT scan is 
performed following the last liquid 
biopsies taken, or when 11 months of 
follow-up is reached.  
Safety parameters 
Clinical and laboratory events will be reported 
according to the National Cancer Institute – 
Common Terminology Criteria for Adverse 
Events (NCI-CTCAE v.5.0). 
Efficacy parameters 
Progression will be assessed using standard 
imaging (CT scan) based on RECIST criteria 
1.1. The level of ctDNA will be assessed 
through NPY methylation. 
Laboratory parameters and biomarkers 
ctDNA 
levels 
and 
standard 
laboratory 
parameters (hematology, biochemistry, liver 
function tests, TSH, urinalysis). Additional 
laboratory assessments as deemed necessary 
by the treating physician. CEA every 8 weeks 
(combined with CT scan and LB) 
Imaging parameters 
Computed tomography (CT) 

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Statistics 
 
To determine the optimal cut-off value of the 
NPY methylation to discriminate between 
progressive and non-progressive disease (as 
determined by CT), we will develop a Receiver 
Operating Characteristic (ROC) curve with 
data of this lead-in study. ROC curves show 
the trade-off between sensitivity and specificity 
and the Area Under the Curve (AUC) is 
considered as an index of accuracy.  In order 
to construct a 95% confidence interval for the 
AUC of width 0.2 and assuming an AUC of 0.9 
we need a least a group of 27 patients with 
progressive disease and a group of 27 patients 
without progressive disease. Assuming a 
median PFS of 9 months, we would need to 
include 54 patients and follow them up for 9 
months. However, it is expected that about 10-
15% of the study population may become 
resectable by conversion therapy. Taking this 
into account, the total number of patients to be 
included is 60. 
 
 
 
 

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ABBREVIATION LIST 
 
Abbreviation  
Definition/Explanation 
UZA 
Antwerp University Hospital 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count  
aPTT 
Activated partial thromboplastin time 
AST 
Aspartaat-aminotransferase 
cfDNA 
Cell free DNA 
CEA 
Carcinoembryonic antigen  
CMG 
Centre of Medical Genetics 
CNS 
Central nervous system 
CNS 
CR 
Central nervous system 
Complete response 
CRC 
Colorectal cancer 
CSR 
Clinical study report 
CTC 
Common terminology criteria 
CTCAE 
Common terminology criteria for adverse events 
ctDNA 
Circulating tumor DNA 
ddPCR 
Digital droplet PCR  
DICOM 
Digital Imaging and Communications in Medicine 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of Study 
GDP 
Guanosine 5’-diphosphate 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GOT 
Glutamic-oxaloacetic transaminase 
GPT 
Glutamic-pyruvic transaminase 
GTP 
Guanosine-5’-triphosphate  
HCG 
Human chorionic gonadotropin 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 

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ICH 
International conference on harmonization 
ID 
Identification number 
INR 
International normalized ratio 
LB 
Liquid biopsy 
LDH 
Lactate dehydrogenase 
MAP 
Mitogen-activated protein kinase  
mCRC 
Metastatic colorectal cancer 
MSI 
Microsatellite instability 
NCI-CTCAE 
National cancer institute – common terminology criteria for adverse 
events 
PACS 
PD 
Picture Archiving and Communication System  
Progressive disease 
PFS 
PR 
Progression-free survival 
Partial response 
PTT 
Partial thromboplastin time  
PTT 
Partial thromboplastin time 
QoL 
Quality of life 
RAF 
Rapidly accelerated fibrosarcoma 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
SD 
Serious adverse event 
Stable disease 
TGF-α 
Transforming growth factor alpha 
TMG 
Trial management group 
TSH 
Thyroid stimulating hormone 
UPC 
Urine protein creatinine 
USA 
United States of America 
VPN 
Virtual private network 
 
 
 
 

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TABLE OF CONTENTS 
 
Protocol Synopsis .................................................................................................................... 3 
Abbreviation list ........................................................................................................................ 8 
Table of Contents ................................................................................................................... 10 
1 
Background and rationale ............................................................................................. 13 
 
Disease and treatment...................................................................................... 13 
 
Circulating Tumor DNA ..................................................................................... 13 
 
Exploration of epigenetic methylation alterations in ctDNA ............................. 14 
 
Rationale ........................................................................................................... 14 
2 
Objectives ..................................................................................................................... 16 
 
Primary objective .............................................................................................. 16 
 
Secondary objectives ........................................................................................ 16 
 
Exploratory objectives....................................................................................... 16 
3 
Study endpoints ............................................................................................................ 17 
 
Primary endpoint ............................................................................................... 17 
 
Secondary endpoints ........................................................................................ 17 
 
Exploratory endpoints ....................................................................................... 17 
4 
Study population ........................................................................................................... 17 
 
Number of centers ............................................................................................ 17 
5 
Subject eligibility ........................................................................................................... 18 
 
Inclusion Criteria ............................................................................................... 18 
 
Disease related ................................................................................. 18 
 
Demographic .................................................................................... 18 
 
Laboratory ......................................................................................... 18 
 
Exclusion Criteria .............................................................................................. 20 
 
Disease Related ............................................................................... 20 
 
Other Medications ............................................................................ 20 
 
General ............................................................................................. 20 
6 
Study schedule and procedures ................................................................................... 22 
 
Screening period/ eligibility check .................................................................... 22 
 
Pre-screening ................................................................................... 22 
 
Signing of Informed Consent ............................................................ 22 
 
Post-screening .................................................................................. 22 
 
Inclusion ............................................................................................................ 23 
 
Start first-line therapy ........................................................................................ 23 
 
Follow-up........................................................................................................... 23 
 
Sample collection .............................................................................................. 25 

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RAS and BRAF wild-type tumor status ............................................ 25 
 
CEA level .......................................................................................... 25 
 
Liquid biopsies .................................................................................. 25 
 
Questionnaire .................................................................................................... 26 
 
Protocol compliance ......................................................................................... 26 
 
End of study ...................................................................................................... 26 
 
Study completion .............................................................................. 26 
 
Changes in a patient’s condition ...................................................... 27 
 
Metastasectomy ............................................................................... 27 
 
Death ................................................................................................ 28 
 
Withdrawal of consent ...................................................................... 28 
 
Withdrawn consent with data withdrawal ......................................... 28 
 
Lost to follow-up ............................................................................... 28 
 
Duration of the study ......................................................................................... 29 
 
Early study termination ..................................................................... 29 
7 
Methodology ................................................................................................................. 30 
 
Study schedule ................................................................................................. 30 
 
Assessments and study visits .......................................................................... 31 
 
Screening period (Mb) ...................................................................... 31 
 
Start first-line therapy (M0) ............................................................... 32 
 
M0 + every 2 weeks (up to and including M9) ................................. 32 
 
M0 + every 8 weeks ......................................................................... 33 
 
End of study [EOS] in case of study completion .............................. 33 
 
End of study in case of metastasectomy ......................................... 34 
 
End of study in case of changes in a patient’s condition ................. 34 
 
End of study in case of withdrawal ................................................... 34 
 
End of study in case of lost to follow-up .......................................... 34 
 
End of study in case of death ........................................................... 34 
 
Summary of study procedures ......................................................................... 35 
 
Summary of study specific procedures ............................................ 35 
 
Summary of standard of care study procedures .............................. 35 
 
Data collection and data storage encoding ...................................................... 36 
 
Evaluation of data ............................................................................................. 36 
 
Tumor response evaluation .............................................................. 36 
 
ctDNA analysis ................................................................................. 36 
8 
Statistical considerations .............................................................................................. 36 
 
Sample size calculation .................................................................................... 36 
 
Primary analysis................................................................................................ 37 
 
Secondary analysis ........................................................................................... 37 
 
Exploratory analysis .......................................................................................... 37 
9 
Safety reporting............................................................................................................. 39 
 
Ethical Committee ............................................................................................. 39 

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Adverse events ................................................................................................. 39 
 
Definition Adverse Event (AE) .......................................................... 39 
 
Definition Unexpected Adverse Event (UAE) .................................. 39 
 
Recording of AEs .............................................................................. 39 
 
Follow-up of adverse events ............................................................ 40 
 
Serious Adverse Events ................................................................................... 40 
 
Definition Serious Adverse Event .................................................... 40 
 
Recording of SAEs ........................................................................... 40 
 
(Suspected) Unexpected (Serious) Adverse Reactions .................................. 41 
 
Annual report .................................................................................................... 41 
10 
Administration procedures and publication .................................................................. 42 
 
Regulatory Approval ......................................................................................... 42 
 
Publication Policy .............................................................................................. 42 
 
Contractual and Financial Details ..................................................................... 42 
 
Insurance, Indemnity and Compensation ......................................................... 42 
11 
Monitoring ..................................................................................................................... 43 
 
Overview of data collection ............................................................................... 43 
 
Mandatory data ................................................................................................. 44 
 
Data entry & monitoring guidelines .................................................................. 44 
12 
Study administration ..................................................................................................... 45 
 
Coordinating Study Team ................................................................................. 45 
13 
Conflict of Interest Policy .............................................................................................. 45 
14 
References .................................................................................................................... 46 
15 
Appendix ....................................................................................................................... 49 
 
Follow-Up Scheme ........................................................................................... 49 
 
Questionnaire 1 (Dutch version) ....................................................................... 50 
 
Questionnaire 1 (French version) ..................................................................... 55 
 
Questionnaire 2 (Dutch version) ....................................................................... 60 
 
Questionnaire 2 (French version) ..................................................................... 69 
 
RECIST guideline (version 1.1) ........................................................................ 78 
 
 

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1 BACKGROUND AND RATIONALE 
 Disease and treatment 
Colorectal cancer (CRC) is the third most common cancer in both men and women and a major 
cause of cancer related death. In 2018, there were approximately 1.8 million new cases of CRC 
worldwide and an estimated number of 881.000 deaths, accounting for 10% of all cancer related 
deaths. The incidence and mortality of CRC is still rising (1). Of newly diagnosed patients, 15% to 
25% have metastatic disease at diagnosis and up to 50% of all patients eventually develop 
metastatic disease (2, 3).  
As of 2009, three monoclonal antibodies have regulatory approval in multiple countries for the 
treatment of colorectal cancer (CRC): cetuximab (Erbitux®) and panitumumab (Vectibix®), both of 
which are directed against the epidermal growth factor receptor (EGFR), and bevacizumab 
(Avastin®), which is directed against vascular endothelial growth factor. The development of these 
three agents has provided additional therapeutic options for patients. However, metastatic 
colorectal cancer (mCRC) cannot be cured with the currently available chemotherapy regimens, 
and there is a continued need to improve the current treatment. The EGFR pathway has been 
shown to play an important role in carcinogenesis, and inhibiting this pathway with anti-EGFR 
antibodies has been shown to have clinical efficacy in the treatment of metastatic colorectal cancer 
in subjects whose tumors express wild-type RAS (4-6). Approximately 60% of subjects presenting 
with mCRC have tumors without activating RAS mutations (6). RAS mutation status may have 
prognostic significance and is predictive of response to cetuximab and panitumumab therapy in 
CRC (5-8). The addition of EGFR-targeted therapies to chemotherapy for the first-line treatment of 
wild-type (WT) RAS metastatic colorectal cancer has improved patient’s objective response rate 
(ORR), progression-free survival (PFS) and overall survival (OS) (9-12). For this reason, current 
guidelines recommend their use in combination with the most common backbone 
chemotherapeutic regimens such as FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or 
FOLFIRI [folinic acid, 5- fluorouracil, and irinotecan] (13). 
 Circulating Tumor DNA 
In the past five years, liquid biopsies have been intensively studied as a new promising technique 
for the diagnosis and follow-up of CRC. Liquid biopsy is a technique in which non-solid biological 
tissues such as urine, stool or peripheral blood are sampled and analyzed (14). They are, for 
example, used for the detection of abnormally expressed biological markers manifested during 
carcinogenesis.  
Circulating tumor DNA (ctDNA) originates from tumors as a result of cancer cells undergoing 

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apoptosis and necrosis, thereby releasing their DNA into the bloodstream. CtDNA liquid biopsies 
are very suitable for diagnosis as ctDNA can be detected in the plasma of even early-stage cancer 
patients. Moreover, ctDNA reflects the cumulative tumor burden as it is released in all regions of 
the tumor. This offers an advantage over traditional tissue biopsies, which contain only a minor part 
of the tumor and are not representative for tumor heterogeneity (15). 
The use of liquid biopsies and the analysis of ctDNA in CRC patients is not new and has been 
performed in the past (16)(17-20). However, until now, a strong focus existed on the detection of 
tumor specific mutations, which has several limitations. First, tumor specific alterations need to be 
identified a priori by DNA sequencing of tumor biopsies, making it a costly and time-consuming 
practice. Second, since these somatic mutations can vary from case to case, a personal assay 
might have to be developed. Third, the amount of mutations that are found in a given primary tumor 
are highly variable. For some tumors, few mutations are present in the primary tumor, hence 
severely limiting sensitivity for plasma-based mutation detection markers. Several liquid biopsy 
tests have been proposed in the past (21), but all lack the sensitivity to have strong clinical utility.  
In contRASt to genetic mutations, also epigenetic changes such as DNA hypermethylation of 
neuropeptide Y protein (NPY) have been described in CRC (16, 22, 23). Digital droplet PCR 
(ddPCR) allows to measure NPY methylation in a highly sensitive manner to determine the amount 
of ctDNA in plasma samples. In fact, NPY methylation is a surrogate marker for tumor burden in 
CRC patients. The main advantage of methylation assays is the applicability in almost every 
patient, while the use of mutation assays requires prior knowledge of mutations present in the 
tumor. 
 Exploration of epigenetic methylation alterations in ctDNA 
Epigenetic changes in cancer have attracted great attention in the last years. It is widely accepted 
that the initiation and progression of cancer involve epigenetic abnormalities, such as DNA 
methylation. Changes in DNA methylation are considered an early event in carcinogenesis (24-26) 
and have already been proposed for early diagnosis of cancer. In CRC in particular, aberrant 
methylation has been observed, allowing non-invasive population screening using blood samples 
(23, 27-30) and follow-up during therapy (31-33).  
Methylated ctDNA in liquid biopsies is valuable in cancer prognosis and tumor response. Therefore, 
it is of interest to further explore the use of DNA methylation in liquid biopsies in clinical practice. 
 Rationale 
Many advances in systemic therapies have significantly improved the survival of patients with CRC 
(34). However, there is a high variability of therapeutic responses among patients and determining 
the optimal personalized treatment plan is challenging. Conventional monitoring of the therapy 

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response is based on imaging as suggested in RECIST 1.1 (35) and measurements of CEA and 
CA19.9 derived from plasma. However, radiological assessments are usually limited in frequency 
(radiation exposure, costs, logistics,…), have a detection limit, are not suited for small metastases 
and cannot describe intrinsic characteristics of each tumor. Therefore, other predictive biomarkers 
of treatment outcomes and disease progression are of great value to enable early therapy response 
evaluation and early change of therapy avoiding unnecessary side effects, enhancing efficacy and 
minimizing costs.  
Quantification of ctDNA in real-time renders information on tumor characteristics and has been 
shown to be associated with treatment responses in mCRC (16, 36). Recently, our research group 
has shown that quantifying ctDNA through the methylation analysis of NPY in circulating DNA is a 
good marker for total tumor burden and can therefore be used for the follow-up of mCRC patients 
(22).  
It could be demonstrated that the amount of ctDNA in plasma, measured using NPY ddPCR 
methylation assays, decreased immediately (14 days) after treatment start. The amount of ctDNA 
remained low or undetectable in patients undergoing curative metastasectomy, while the amount 
of ctDNA increased in patients showing progressive disease (22). As progressive disease might be 
detected earlier using liquid biopsies as compared to observations by radiographic evaluation, the 
use of liquid biopsies might be a promising tool to guide treatment options. 
The aim of this study is to determine the optimal cutoff value of the liquid biopsy test (using a ROC 
curve based on the data of this study). This cutoff value will be used in a follow-up study to detect 
progressive disease in patients with metastatic colorectal cancer treated with first-line 
FOLFOX/FOLFIRI and panitumumab. Additionally, the follow-up trial will determine if ctDNA 
detects progression earlier than conventional used imaging techniques and will estimate the effect 
on progression-free survival in case therapy is guided by NPY methylation levels in liquid biopsy. 
Furthermore, in the LEAD-IN FOLICOLOR Trial we will exploratively compare liquid biopsies to 
tumor markers (CEA and/or CA19.9) in their ability to predict progressive disease. This innovative 
study will add evidence to the clinical relevance of ctDNA during treatment.  
 
 

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2 OBJECTIVES 
This is a prospective, multicenter interventional study designed to optimize the cutoff value of NPY 
methylation in liquid biopsies (ctDNA) in patients with metastatic colorectal cancer receiving first-
line FOLFOX/FOLFIRI and panitumumab. 
 Primary objective 
The primary objective of the LEAD-IN FOLICOLOR Trial is to optimize the cutoff value of NPY 
methylation in liquid biopsies (ctDNA) of patients with metastatic colorectal cancer receiving first-
line FOLFOX/FOLFIRI and panitumumab.  
 Secondary objectives 
The secondary objective is to determine the progression free and 9-month survival of RAS and 
BRAF wild-type metastatic colorectal cancer patients. 
 Exploratory objectives 
The exploratory objectives will include, but will not be limited to the following: 
 
To compare the use of ctDNA and CEA to predict progression. 
 
Further exploration of ctDNA in liquid biopsies and searching for novel biomarkers.  
 
To explore the quality of life and the patient experience in this patient population with regard 
to the use of liquid biopsies for follow-up through questionnaires. 
This will include, but will not be limited to the following: 
o Burden of extra blood samples (extra blood samples during routine blood test) 
o Burden of CT scan with intravenous contrast 
o Confidence in liquid biopsy guided therapy (ctDNA analysis) compared to CT scan 
guided therapy 
o Preference between extra blood sample and CT scan (taking into account: burden, 
pain, time in the hospital, extra travel time to the hospital, confidence in technique…) 
 
 

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3 STUDY ENDPOINTS 
 Primary endpoint 
Using the data of this LEAD-IN study, a Receiver Operating Characteristic (ROC) curve will be 
developed in order to determine the optimal cutoff value for NPY methylation in liquid biopsies to 
predict progression on CT scan. 
 Secondary endpoints 
• 
To determine the progression free survival in patients with metastatic colorectal cancer defined 
as time from inclusion to the date of first disease progression among subjects with metastatic 
colorectal cancer per RECIST 1.1 criteria, or death. 
• 
The 9-month survival will be determined as percentage surviving at 9 months after the start of 
first-line therapy. 
 Exploratory endpoints 
• 
Explore and compare the use of NPY methylated ctDNA and CEA to predict progression 
• 
Further exploration of ctDNA in liquid biopsies and searching for novel biomarkers.  
• 
To assess the (health-related) quality of life in patients with colorectal cancer by the use of the 
following validated questionnaires: EORTC QLQ-C30 and EORTC QLQ-CR29 (cfr. Appendix 
15.2 & 15.3). 
• 
To assess the patient experience through a questionnaire (cfr. Appendix 15.4 & 15.5). 
 
4 STUDY POPULATION 
 Number of centers 
This study is a multicenter trial of which all mCRC patients will be recruited at approximately 10 
hospitals in Belgium, including the Antwerp University Hospital. 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
18 
 
5 SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate (date of birth), date of screening, and 
outcome of the screening process (e.g., enrolled into study, or reason for refusal to participate). 
 Inclusion Criteria 
 
Disease related 
 Histologically or cytologically confirmed adenocarcinoma of the colon or rectum in 
subjects with unresectable metastatic (M1) disease 
 
 Starting first-line FOLFOX/FOLFIRI and panitumumab for metastatic colorectal 
cancer 
 
 At least 1 uni-dimensionally measurable lesion of at least 10 mm per RECIST 1.1 
guidelines (see Appendix 15.6) using conventional techniques (CT scan). Lesion 
must not be chosen from a previously irradiated field, unless there has been 
documented disease progression in that field after irradiation and prior to 
inclusion. All sites of disease must be evaluated  28 days prior to the start of first-
line therapy. 
 
 Wild-type RAS tumor status of the tumor tissue tested by the local hospital. This 
test must be performed during screening phase.  
 
 Wild-type BRAF tumor status of the tumor tissue tested by the local hospital. This 
test must be performed during screening phase.  
 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 
 
Demographic 
 Man or woman 18 years of age or older at the time the informed consent is 
obtained. 
 
 
Laboratory 
To be performed ≤ 14 days prior to the start of first-line therapy, unless otherwise specified: 
 
5.1.3.1 Hematologic function within the following limits: 
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
o Platelet count ≥ 100 x 109/L (without platelet transfusion  14 days prior to 
start therapy)
o Hemoglobin (Hgb) ≥ 9.0 g/dL
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
19 
 
5.1.3.2 Renal function within the following limits: 
o Creatinine clearance (GFR)  50 mL/min calculated by the Cockcroft-Gault 
method as follows:
 
Male creatinine clearance = (140 – age in years) x (weight in kg) / 
(serum creatinine in mg/dL x 72) 
 
Female creatinine clearance = (140 – age in years) x (weight in kg) x 
0.85 / (serum creatinine in mg/dL x 72) 
o Urinary protein ≤ 30 mg by urinalysis or ≤ 1+ by dipstick or urine protein 
creatinine (UPC) ratio ≤ 0.5 by urinalysis (unless excretion of < 1000 mg of 
protein per day as determined by 24-hour urine collection).
 
Note: UPC ratio of spot urine is an estimation of the 24 urine protein 
excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine 
protein of 1 gm. UPC ratio is calculated using one of the following 
formula: 
[urine protein]/[urine creatinine] - if both urine protein and creatinine 
are reported in mg/dL. 
[(urine protein) x0.088]/[urine creatinine] - if urine creatinine is 
reported in mmol/L. 
 
5.1.3.3 Hepatic function within the following limits: 
o Total bilirubin ≤ 1.5 x ULN
o Alkaline phosphatase ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN)
o Aspartate aminotransferase (AST) ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN)
o Alanine aminotransferase (ALT) ≤ 2.5 x ULN (if liver metastases, ≤ 5 x ULN)
 
5.1.3.4 Metabolic function within the following limits: 
o Magnesium ≥ lower limit of normal

5.1.3.5 Coagulation function within the following limits: 
o Partial thromboplastin time (PTT)/activated partial thromboplastin time 
(aPTT) ≤ 1.0 x ULN and international normalized ratio (INR) < 1.5, unless the 
subject is on therapeutic anticoagulation therapy. Patients on therapeutic 
anticoagulation are eligible if the following criteria are met:
 
The subject has an in-range INR (usually between 2 and 3) on a stable 
dose of oral anticoagulant or is on a stable dose of low molecular weight 
heparin. 
 
The subject has no active bleeding or pathological condition that carries 
high risk of bleeding (e.g., tumor involving major vessels or known 
varices) 
5.1.3.6 Negative pregnancy test  
o Serum pregnancy test ≤ 14 days prior to start therapy (for women of 
childbearing potential only) 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
20 
 
 Exclusion Criteria 
 
Disease Related 
 
History of prior or concurrent central nervous system (CNS) metastases 
 
 
History of other malignancy, except: 
 
o Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years prior to the start of first-line therapy and felt to be at 
low risk for recurrence by the treating physician 
o Adequately treated non-melanomatous skin cancer or lentigo maligna 
without evidence of disease 
o Adequately treated cervical carcinoma in situ without evidence of disease 
o Prostatic intraepithelial neoplasia without evidence of prostate cancer 
 
 
Cancer Therapy 
o Prior chemotherapy or other systemic anticancer therapy for the treatment 
of metastatic colorectal carcinoma including but not limited to bevacizumab 
and anti-EGFR therapy (e.g. cetuximab, panitumumab, erlotinib, gefitinib, 
lapatinib) 
 
 
Prior adjuvant chemotherapy (including oxaliplatin therapy) or other adjuvant 
systemic anticancer therapy including but not limited to bevacizumab and anti-
EGFR therapy (e.g. cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) for the 
treatment of colorectal cancer ≤ 6 months prior to the start of first-line therapy with 
the following exceptions: 
o Subjects may have received prior fluoropyrimidine therapy if 
administered solely for the purpose of radiosensitization for the adjuvant 
or neoadjuvant treatment of rectal cancer 
 
 
Radiotherapy ≤ 14 days prior to start therapy. Subjects must have recovered from 
all radiotherapy-related toxicities. 
 
 
Unresolved toxicities from prior anti-cancer therapy that, in the opinion of the 
investigator, excludes subject from participation 
 
 
Other Medications 
 Infection requiring a course of systemic anti-infectives that was completed ≤ 14 
days before start therapy (exception can be made at the judgment of the 
investigator for oral treatment of an uncomplicated urinary tract infection (11)) 
 
 
General 
 Significant cardiovascular risk: 
o Myocardial infarction, grade 2 or greater peripheral vascular disease, 
arterial thrombotic event, visceral arterial ischemia, cerebrovascular 
ischemia, transient ischemic attack, percutaneous transluminal 
coronary angioplasty/stent or unstable angina ≤ 24 weeks prior to start 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
21 
 
therapy 
o Symptomatic and/or serious uncontrolled cardiac arrhythmia 
o Symptomatic congestive heart failure (New York Heart Association 
Class III or IV) 
o Uncontrolled blood pressure defined as > 150 mmHg systole or > 90 
mmHg diastole. Anti-hypertensive medications are allowed if 
hypertension is stably controlled at the time of start therapy. 
o Pulmonary embolism, deep vein thrombosis, or other significant venous 
event ≤ 8 weeks before start therapy 
 
 History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or 
evidence of interstitial lung disease on baseline CT scan 
 
 Active inflammatory bowel disease or other bowel disease causing chronic 
diarrhea (defined as ≥ CTC grade 2, [CTCAE version 5.0]) 
 
 Peripheral sensory neuropathy (≥ CTC grade 2 [CTCAE version 5.0] 
 
 Any co-morbid disease or condition that could increase the risk of toxicity (such as 
clinically significant ascites) 
 Subjects known to be human immunodeficiency virus (HIV) positive or known to 
have chronic or active hepatitis B or C infection 
 
 Subject is currently enrolled in, or ≤ 30 days has passed since subject completed 
another investigational device or drug study(s), or subject is receiving other 
investigational agent(s) 
 
 Women of child-bearing potential is evidently pregnant (e.g., positive HCG test) or 
is breast feeding 
 
 Men and women of childbearing potential who do not consent to use adequate 
contraception during the course of the study. Adequate contraceptive precautions 
includes double barrier contraceptive methods (e.g., diaphragm and condom) or 
abstinence 
 
 History of any medical or psychiatric condition or addictive disorder, or laboratory 
abnormality that, in the opinion of the investigator, may increase the risks 
associated with study participation or study drug administration or may interfere 
with 
the 
conduct 
of 
the 
study 
or 
interpretation 
of 
study 
results 
 
 Subject has previously been included into this study 
 
 Subject unwilling or unable to comply with study requirements (e.g., will not be 
available for follow-up assessment) 
 
 Subject has any kind of disorder that compromises the ability of the subject to give 
written informed consent and/or to comply with study procedures (except for 
subjects with a legally acceptable representative) 
 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
22 
 
6 STUDY SCHEDULE AND PROCEDURES 
 Screening period/ eligibility check 
The screening period is also referred to as ‘Mb’ (cfr. Appendix 15.1). 
 
 
Pre-screening 
The indications of eligibility (cfr. 5.1.1 & 5.1.2): 
 
Wild-type RAS tumor status (of tumor tissue) 
 
Wild-type BRAF tumor status (of tumor tissue)  
 
Unresectable mCRC 
 
First-line treatment: FOLFOX/FOLFIRI + panitumumab 
 
ECOG performance status of 0 or 1 
 
Man or woman 18 years of age or older at the time the informed consent is obtained 
 
Not meeting the exclusion criteria (cfr. 5.2) 
 
Note1: Subjects that are determined not eligible after pre-screening must be listed as screen failure 
together with the reason for screen failure. Complete the eCRF ‘End of Study Form’. 
 
 
Signing of Informed Consent 
Potentially eligible subjects (cfr. 6.1.1) are asked to sign the informed consent form (ICF). Only 
subjects who have signed the ICF will enter into the post-screening phase.  
 
Note1: Subjects that are determined eligible after pre-screening, but who do not wish to participate 
should be listed as screen failure together with the reason for screen failure. Complete the eCRF 
‘End of Study Form’. 
 
Note2: The ICF must be signed < 28 days before the start of the first-line therapy. 
 
 
Post-screening 
To check the hematologic, renal, hepatic, metabolic, and coagulation function of the patient (cfr. 
5.1.3 Laboratory), 1 EDTA tube must be sampled within 14 days before the start of the first-line 
therapy. The EDTA tube will be analyzed in the local hospital, i.e. the hospital where the patient 
will be treated. If the laboratory criteria (as described in 5.1.3 Laboratory) are also met, the subject 
is eligible to include.  
 
Note1: If the CT scan at diagnosis (CT0) has been performed more than 28 days before the start of 
the first-line therapy, an additional CT scan needs to be performed < 28 days before the start of 
the first-line therapy.  
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
23 
 
Note2: Subjects that are determined not eligible after post-screening must be listed as screen failure 
together with the reason for screen failure. Complete the eCRF ‘End of Study Form’. 
 
 Inclusion 
Subjects who meet all inclusion criteria during the pre- and post-screening phase are included in 
the trial. From now on, the patient’s study identification number (ID) must be used to identify the 
subject throughout the entire clinical study. This unique study ID is automatically assigned by the 
Electronic Data Capture System “Castor EDC” (cfr. 7.4). The study ID consists of three parts: the 
trial ID (abbreviation of the trial ‘LIFT’), followed by the center ID (abbreviation of the participating 
center) and the patient ID (three-digit number). The sponsor assigns the abbreviation of the 
participating center.  
 
Note1: For example, an eligible patient in the Antwerp University Hospital could be assigned the 
study ID ‘LIFT_UZA_001’. 
 
As soon as the patient is officially included, the patient is asked to complete the Quality of Life 
questionnaire, including the EORTC QLQ-C30 and QLQ-CR29 (cfr. Appendix 15.2 & 15.3). This 
questionnaire must be completed by the day on which first-line therapy starts (M0) at the latest.  
 
 Start first-line therapy 
Patients will receive FOLFOX/FOLFIRI and panitumumab with therapy guidance according to CT 
scans. The day on which the first-line therapy starts is named as ‘M0’. First-line therapy 
(FOLFOX/FOLFIRI and panitumumab) is planned to be administered every 2 weeks (± 3 days) (not 
including the time to recover from toxicities). On the same day of, but before the administration of 
the first chemotherapy cycle, 3 liquid biopsies (LB0, LBa en LBb) must be sampled. LB0 will be used 
to measure the ctDNA level at baseline, and LBa and LBb will be used for further research. The 3 
LB’s must be transported to CMG Antwerp (cfr. 6.5.3).  
 Follow-up 
LB sampling will occur biweekly (not taking into account the time to recover from toxicities, therapy 
pause or delay) up to and including 9 months after the start of first-line therapy. The collection 
of the liquid biopsy samples will move along with the first day of administration of a new 
chemotherapy cycle. Each time a next therapy cycle starts, three liquid biopsies should be collected 
before the therapy is administered. These three liquid biopsies include one Streck tube to measure 
the ctDNA level, and two Streck tubes that will be used for further research or, if necessary, as a 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
24 
 
reserve sample. The LBs should be named after the applicable chemotherapy cycle; LB2 for the 
2nd chemotherapy cycle, LB3 for the 3th chemotherapy cycle…). It is advised to combine the LB 
sampling with a routine blood test (standard of care).  
When the last liquid biopsies have been collected (i.e. on the day of, but before the administration 
of the last therapy cycle that takes place in the 9 months after starting first-line therapy), the LB 
sampling stops. The patient has to complete the EORTC QLQ-C30, QLQ-CR29, and the patient 
experience questionnaire (cfr. Appendix 15.4 & 15.5). A time window of 7 days after M9 is allowed 
to complete the questionnaire. 
After this, the treating physician will continue the patients’ treatment conform the standard clinical 
practice.  
 
Tumor response assessment will be performed by the local investigator per modification of 
RECIST 1.1 guidelines on bimonthly CT scans (not taking into account the time to recover from 
toxicities, therapy pause or delay) together with a CEA test, up to and including the next imaging 
(CT scan) that is performed after the collection of LBs has stopped. Thus, the CT scans will also 
move along with the administered chemotherapy cycles. In case of biweekly administration of 
therapy without delay or therapy pause, the bimonthly CT scans and CEA test correspond to the 
moments of evaluation of chemotherapy cycle 4, 8, 12, 16 and 20. Treatment is changed upon CT 
scan results (conform standard clinical practice).  
 
With the exception of what is described in chapter 6.8, the subjects will be followed (and thus 
the collection of follow-up data continues) until the next imaging (CT scan) that is performed 
after the collection of LBs has stopped, provided that this imaging is performed within 11 
months of follow-up (cfr. Appendix 15.1). The imaging refers to the CT scan that aims to evaluate 
the last administered chemotherapy cycle that was given within 9 months after the start of first-line 
therapy. If, for any reason, this CT scan will be performed > 11 months after the start of first-line 
therapy, or no CT scan will be performed after the last collection of LBs, the study ends when the 
subject has reached 11 months of follow-up. 
 
Notes: 
 
In the event that chemotherapy is delayed due to poor blood results, and 3 liquid biopsies 
were already collected together with the routine blood test, 3 new liquid biopsies must be 
collected on the same day of, but before the administration of the newly scheduled 
chemotherapy cycle. 
 
No limitation is imposed on the duration of therapy pause. As soon as the therapy is 
restarted, the LB sampling continues as described in the protocol. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
25 
 
 
If the therapy changes (i.e. stop FOLFOX/FOLFIRI and panitumumab) throughout the 
follow-up period, the follow-up procedure continues according to the protocol (i.e. LB-
sampling on the first day of administration of the new therapy cycle up to and including 9 
months after the start of the first-line therapy). 
 
If a metastasectomy is planned, 1 liquid biopsy must be taken on the day of, but before 
surgery. A second liquid biopsy must be collected within the next 2 days, excluding the day 
of surgery. After this, no more liquid biopsy samples need to be collected.  
 
After progression on CT scan, the patient will continue with standard of care as decided 
by the treating physician. The follow-up schedule is maintained. The LB sampling still 
continues up to and including 9 months after the start of first-line therapy but will then be 
linked/combined with the new therapy.  
 
If it is appropriate to perform a MRI scan during follow-up, this should be reported in the 
eCRF. 
  Sample collection 
 
RAS and BRAF wild-type tumor status 
The local hospital is responsible for analyzing the wild-type RAS and BRAF tumor status of the 
tumor tissue. 
 
CEA level 
The local hospital is responsible for analyzing the bimonthly CEA level, which has to be reported 
in the appropriate eCRF. 
 
Liquid biopsies 
The sponsor provides pre-prepared kits, each consisting of three Streck tubes for liquid biopsy 
sampling. The pre-prepared kit must be used when collecting the biweekly liquid biopsies. All 
samples will be transported to the Center for Medical Genetics (CMG) in Antwerp for NPY 
methylation analyses.  
 
The local investigator (team) is responsible for registering the samples in a specific Excel-file, also 
provided by the sponsor, which has to be sent by e-mail to the CMG Antwerp. The samples are 
preferably sent on the day of collection (if not possible; no later than the following day) with a 
transport company to the CMG. Delivery is only possible on workdays (Monday to Friday) between 
8:00 am and 4:30 pm. Samples that are collected on Friday and that cannot be sent the same day 
due to circumstances must be transported to the CMG next Monday. Until then, the liquid biopsy 
samples must be stored between 6°C and 37°C. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
26 
 
 
Note1: In the case of metastasectomy, 1 liquid biopsy must be taken on the day of, but before 
surgery. A second liquid biopsy must be collected within the next 2 days, excluding the day of 
surgery. However, both LB samples must be transported together to the CMG. Both samples are 
preferably sent on the day of collection of the second LB sample (if not possible; not later than the 
following day). If the second sample is collected on Friday and it is not possible to send both LBs 
the same day, the samples must be transported to the CMG next Monday. 
 
Note2: In the event that chemotherapy is delayed due to poor blood results, and 3 liquid biopsies 
were already collected  together with the routine blood test, 3 new liquid biopsies must be collected 
on the same day of, but before the administration of the newly scheduled chemotherapy cycle. All 
LB samples (a total of 6 Streck tubes) must be transported together to the CMG.  
 
Note3:The Sponsor decides which transport company to work with. 
 Questionnaire 
The questionnaire is available both on paper and digitally. The patient is free to choose which option 
he/she prefers. Paper questionnaires must be entered into the database Castor EDC by the local or 
central study team, and must be saved on site. Digital questionnaires are available via a web link, 
which Castor EDC automatically sends to the patient via email. Completed digital questionnaires 
are automatically imported into the patient record in Castor EDC. Completing the digital 
questionnaire is only possible if the patient explicitly indicates in the Informed Consent whether 
he/she agrees to share his/her email address with the Sponsor.  
 Protocol compliance 
Protocol compliance will be checked after inclusion of the first 20 patients. This approach will 
guarantee that no important aspects are overlooked in order to follow the protocol faultless. The 
flow of collecting and transport of blood samples, communication of both blood results and CT 
evaluation, and completion of the eCRFs will be checked for unexpected barriers. 
 End of study 
 
Study completion 
The study is completed after performing the first imaging (CT scan) following the last collection of 
liquid biopsies according to the study protocol, provided that this imaging is performed within 11 
months of follow-up. However, a maximum follow-up period of 11 months applies to all study 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
27 
 
patients, regardless of whether or not the first imaging following the last collection of liquid biopsies 
has been performed. When study completion is reached, the collection of follow-up data stops. 
(S)AE reporting continues until 14 days after study completion. 
 
Note1: In case of biweekly administration of therapy without delay or therapy pause, the moment of 
study completion corresponds to the 10th month of follow-up.  
 
Changes in a patient’s condition  
This section refers to (1) changes in a patient’s condition that renders the patient not suitable for 
further treatment/participation in the judgment of the investigator, or (2) major protocol violation or 
discovery of information that, if previously known, would have rendered the patient ineligible for 
study.  
6.8.2.1 Before 9 months of follow-up 
The collection of liquid biopsies stops. 
The patient has to complete the 2nd questionnaire including the EORTC QLQ-C30, QLQ-CR29, and 
the patient experience questionnaire (cfr. Appendix 15.4 & 15.5). A time window of 7 days after end 
of study is allowed to complete the questionnaire. 
The collection of follow-up data (i.e. (serious) adverse event reporting, chemotherapy information, 
response imaging and CEA level) continues until 11 months of follow-up (i.e. 11 months after M0) 
is reached. 
 
6.8.2.2 After 9 months of follow-up 
The collection of liquid biopsies has already stopped after M9.  
The collection of follow-up data (i.e. (serious) adverse event reporting, chemotherapy information, 
response imaging and CEA level) continues until the next imaging (CT scan) that is performed after 
the collection of LBs has stopped (at M9). If, for any reason, this CT scan will not be performed, the 
collection of follow-up data continues until 11 months of follow-up is reached.  
 
Metastasectomy 
In the case that the patient will undergo metastasectomy, one liquid biopsy must be taken on the 
day of, but before surgery. A second liquid biopsy must be collected within the next 2 days, 
excluding the day of surgery. 
6.8.3.1 Before 9 months of follow-up 
The further collection of liquid biopsies stops.  
The patient has to complete the 2nd questionnaire including the EORTC QLQ-C30, QLQ-CR29, 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
28 
 
and the patient experience questionnaire (cfr. Appendix 15.4 & 15.5). A time window of 7 days 
after end of study is allowed to complete the questionnaire. 
The collection of follow-up data (i.e. (serious) adverse event reporting, chemotherapy information, 
response imaging and CEA level) continues until 11 months of follow-up is reached. 
6.8.3.2 After 9 months of follow-up 
The further collection of liquid biopsies stops.  
The collection of follow-up data (i.e. (serious) adverse event reporting, chemotherapy information, 
response imaging and CEA level) continues until the next imaging (CT scan) that is performed 
after the collection of LBs has stopped at 9 months of follow-up. If, for any reason, this CT scan 
will not be performed, the collection of follow-up data continues until 11 months of follow-up is 
reached. 
 
Death 
When a patient dies, all efforts should be made to complete and report the observations as 
thoroughly as possible.  
 
Withdrawal of consent 
Patients can leave the study at any time for any reason if they wish to do so without any 
consequences. Should a patient decide this by withdrawal of consent, all efforts will be made to 
complete and report the observations as thoroughly as possible. No further data (including the 
questionnaire) and liquid biopsies will be collected after the date of withdrawal from study. Data 
that was already collected will be stored and used for analysis. The Investigator should contact the 
patient or a responsible relative by telephone or through a personal visit to establish as completely 
as possible the reason for the withdrawal. A complete final evaluation at the time of the patient’s 
withdrawal should be made with an explanation of why the patient is withdrawing from the study. 
 
Withdrawn consent with data withdrawal 
Patient withdraws informed consent and requests to delete all of his/her previously collected data 
from the study. No further data (including the questionnaire) and liquid biopsies will be collected 
after the date of withdrawal from study.  
 
Lost to follow-up 
In the case of patients who miss scheduled visits, several attempts should be made by the site to 
contact these patients for follow-up information. The collection of follow-up data is extremely 
important regarding the reliable estimation of study endpoints, therefore at least 3 attempts within 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
29 
 
a reasonable extent of time should be made to try to contact the patients if they do not attend clinic 
visits. If any of the trial patients are lost to follow-up, contact will initially be attempted through the 
trial research nurse or the lead investigator at each center. Where this attempt is unsuccessful, the 
patient’s general practitioner will be contacted and asked to contact the patient or her/his family 
and provide follow-up information to the recruiting center. It is only after sufficient attempts at 
contacting the patient have been unsuccessful, that a patient may be declared “Lost to follow-up”. 
The collection of follow-up data (i.e. (serious) adverse event reporting, chemotherapy information, 
response imaging and CEA level) stops as soon as the patient has been declared ‘lost to follow-
up’. 
 Duration of the study 
Inclusion of patients in this trial starts when all necessary ethical approvals have been obtained, 
and the Clinical Trial Agreement has been signed. The subject accrual period runs until the 
predetermined number of study patients is reached (i.e. 60 subjects).  
First-line therapy is administered at the start of the study (i.e. M0 or chemotherapy cycle n°1). The 
study ends for the patient when the first imaging (CT scan) is performed following the last collection 
of LBs according to the study protocol, when a follow-up period of 11 months is reached, after 
surgery (metastasectomy), after withdrawal of the written consent or when the patient dies (cfr. 
6.8). 
 
Early study termination 
The Sponsor may terminate this study at any time. Reasons for termination may include, but are 
not limited to the following: 
 
Insufficient subject enrolment. 
 
Any information becoming available during the study that substantially changes the 
expected benefit of the study. 
 
The subject accrual period stops immediately. However, the follow-up of previously enrolled subjects  
continues according to the protocol.  
The collection of LBs stops as soon as 9 months of follow-up is reached (except for metastasectomy 
cfr. 6.8.3, and death). At M9, the patient has to complete the EORTC QLQ-C30, QLQ-CR29 and the 
patient experience questionnaire (cfr. Appendix 15.4 & 15.5). A time window of 7 days after M9 is 
allowed to complete the questionnaire. The collection of follow-up data (i.e. adverse event reporting, 
chemotherapy information, response imaging and CEA level) continues until the next imaging (CT 
scan) that is performed after the collection of LBs has stopped, or when 11 months of follow-up is 
reached.  
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
30 
 
7 METHODOLOGY 
 Study schedule 
The complete schedule of assessments is outlined in Table 1. 
Additional assessments, such as urinalysis or other laboratory assessments, can always be 
performed by the treating physician if deemed necessary. Additional CT scans can also be made, 
for example when the treating physician has clinical indications for progression. Results from 
additional tests or data from additional visits (for example if requested by the patient) will be collected 
for the study. Study visits in the hospital will take place in the treating hospital of the patient.  
 
Table 1. Schedule of assessments 
 
Pre-screening 
Post-screening 
Start first-line therapy - M0 
M0 + every 2 weeks▲ 
(up to and including M9) 
 M0 + every 8 weeks 
EOS: study completion (i.e. 
first CT scan after last LB 
collection∆) 
EOS:  
metastasectomy, changes in 
patient’s condition 
EOS :  
withdrawal, death, lost to 
follow-up 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Informed consent  
 
X 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
X 
X 
X¤ 
Medical history 
X 
 
 
 
 
 
 
 
Pregnancy test■ 
 
X 
 
 
 
 
 
 
Laboratory 
assessments 
 
X 
 
Xπ 
Xπ 
 
 
 
CT scan 
 
X* 
 
 
X 
X∆ 
 
 
Blood sample for 
LBa and LBb 
 
 
X2 
 
 
 
 
 
Blood sample for 
LBx 
 
 
X1 
X3 
X3 
 
X2** 
 
CEA level 
 
X 
 
 
X 
X∆ 
 
 
Therapy information  
X 
 
X 
X 
X 
X 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
31 
 
Quality 
of 
Life 
Questionnaire 
(EORTC QLQ-C30 
+ QLQ-CR29  
 
 
X∞ 
X♦ 
 
 
X¥ 
 
Patient Experience 
Questionnaire 
 
 
 
X♦ 
 
 
X¥ 
 
(S)AE’s 
 
Continuously 
Documentation 
+ 
reason end of study 
 
 
 
 
 
X 
X 
X 
 
∞ To be completed as soon as the patient is included, and by the day on which first-line therapy starts (M0) 
at the latest  
¥ To be completed only if < 9 months follow-up 
▲ At the start of, but before the administration of each chemotherapy cycle (cfr. 6.4. Follow-up, Notes) 
■ Serum pregnancy test; to be performed ≤ 14 days prior to start therapy (for women of childbearing potential 
only) 
♦ To be completed only after reaching 9 months of follow-up (i.e. last collection of LBs) 
∆  If, for any reason, no CT scan will be performed after the collection of LBs have stopped, study completion 
is reached after 11 months of follow-up 
π It is advised to combine the LB sampling with a routine blood test (standard of care) 
¤ ECOG should not be determined in case of death  
* Only if diagnostic CT scan is performed > 28 days before the start of the first-line therapy 
** Only in the case of metastasectomy: collection of one LB sample on the day of surgery but before the 
operation, and a second LB sample within the next 2 days, excluding the day of surgery 
1 Only one blood sample (Streck tube) is needed 
2 Two blood samples (Streck tubes) are needed  
3 Three blood samples (Streck tubes) are needed 
 
 Assessments and study visits 
 
Screening period (Mb) 
Pre-screening 
 
Eligibility check (inclusion/exclusion criteria) including BRAF and RAS WT 
 
Demographics (age) 
 
ECOG 
 
Medical history 
 
Therapy information 
 
Written informed consent should be obtained prior to enrolment in the post-screening phase: 
 
Demographics (age, sex, ethnic origin) 
 
Therapy information 
 
Serum pregnancy test ≤ 14 days prior to start therapy (for women of childbearing potential 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
32 
 
only) 
 
Laboratory assessments:  
hematology (erythrocytes/haematocrit, hemoglobin, neutrophils, thrombocytes, leukocytes, 
leukocyte formula), biochemistry (creatinine, creatinine clearance, ureum, sodium, 
potassium, chloride, bicarbonate, calcium, phosphor, magnesium, uric acid, CRP, total 
protein, albumin, glucose (serum), LDH, AST(GOT), ALT(GPT), alkaline phosphatase, GGT, 
amylase, bilirubin + fractions, cholesterol, triglycerides), liver function tests (PTT, aPTT, 
INR), TSH, urinalysis (urinary protein or UPC) 
 
CT scan  only if diagnostic CT scan is performed > 28 days before the start of first-line 
therapy  
 
CEA level at baseline 
 
 
Start first-line therapy (M0) 
 
Streck tubes for LB0, LBa and LBb   
 
Questionnaire (EORTC QLQ-C30 + QLQ-CR29): to be completed as soon as the patient is 
included, and by the day on which first-line therapy starts (M0) at the latest 
 
Therapy information 
 
If applicable: (S)AE reporting  
 
 
M0 + every 2 weeks (up to and including M9) 
Note: Biweekly LB sampling is only applicable if there is no therapy pause or delay; LB sampling will 
move along with the start of a new chemotherapy cycle. 
 
 
Chemotherapy cycle 2, 3, 4, ..., 19 
 
Laboratory assessments: routine blood test  
 
The routine blood test should include, but will not be limited to the following: 
o Hematology 
o Erythrocytes/hematocrit 
o Hemoglobin 
o Neutrophils 
o Thrombocytes 
o Leukocytes 
o Leukocyte formula 
 
Collection of liquid biopsies 
o Streck tube for LBx 

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o Extra Streck tubes for further research 
 
Therapy information 
 
Questionnaire: Quality of Life (QLQ-C30 + QLQ-CR29) & Patient Experience: to be 
completed when reaching 9 months of follow-up (i.e. last collection of LBs) 
 
If applicable: (S)AE reporting 
 
 
M0 + every 8 weeks 
Note: Bimonthly CT scan is only applicable if there is no therapy pause or delay; CT scans will 
move along with the administered chemotherapy cycles. 
 
 
Laboratory assessments: routine blood test (cfr. 7.2.3) 
 
CT scan (last imaging to be performed is the next CT scan following the last LBs that have 
been collected at M9) 
 
CEA level (up to and including the next CT scan following the last LBs that have been 
collected at M9) 
 
Collection of liquid biopsies 
o Streck tube for LBx (up to and including M9) 
o Extra Streck tubes for further research (up to and including M9) 
 
Therapy information 
 
If applicable: (S)AE reporting  
 
 
End of study [EOS] in case of study completion  
 
EOS is reached after performing the next imaging (CT scan) following the last liquid 
biopsies that have been collected at M9 
o CT scan 
o CEA level 
 
ECOG 
 
Therapy information 
 
If applicable: (S)AE reporting until 14 days after EOS 
 
Confirmation and documentation reason for end of study  
 
Note: If, for any reason, no CT scan will be performed after the collection of LBs have stopped, 
study completion is reached after 11 months of follow-up. 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
34 
 
 
End of study in case of metastasectomy 
 
Collection of liquid biopsies 
o One Streck tube on the day of surgery but before the operation 
o Second Streck tube within the next 2 days, excluding the day of surgery 
 
ECOG 
 
Therapy information 
 
Questionnaire: Quality of Life (QLQ-C30 + QLQ-CR29) & Patient Experience: to be 
completed if metastasectomy takes place before 9 months of follow-up 
 
If applicable: (S)AE reporting until 14 days after EOS 
 
Confirmation and documentation reason for end of study  
 
 
End of study in case of changes in a patient’s condition 
 
ECOG 
 
Therapy information 
 
Questionnaire: Quality of Life (QLQ-C30 + QLQ-CR29) & Patient Experience: to be 
completed if metastasectomy takes place before 9 months of follow-up 
 
If applicable: (S)AE reporting until 14 days after EOS 
 
Confirmation and documentation reason for end of study  
 
 
End of study in case of withdrawal 
 
ECOG 
 
Confirmation end of study + documentation reason of withdrawal 
 
 
End of study in case of lost to follow-up 
 
ECOG 
 
Confirmation end of study + documentation of lost to follow-up 
 
 
End of study in case of death 
 
Confirmation end of study + documentation reason of death 
 
 
 

Protocol Number: v.3.0 
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35 
 
 Summary of study procedures 
 
Summary of study specific procedures 
The procedures listed and described in this section are specific to the study and are not part of 
standard clinical care. 
• 
Screening period 
o Informed Consent Form 
o eCRF completion 
o Specific laboratory assessments (cfr. 5.1.3) < 14 days before start therapy  
o Serum pregnancy test (if applicable) 
o Additional CT scan if the CT scan at diagnosis (CT0) is performed > 28 days before 
start therapy 
o Quality of Life questionnaire 
 
• 
Start first-line therapy 
o Collection of liquid biopsies (LB) 
o Transportation of LBs to CMG Antwerp 
o eCRF completion 
 
• 
Follow-up 
o Biweekly collection of liquid biopsies(3 samples) up to and including M9 
 
Exceptions: delay of therapy (cfr. 6.4. Notes) and metastasectomy (cfr. 6.8.3)  
o Transportation of LBs to CMG Antwerp 
o Bimonthly CEA test up to and including the next imaging (CT scan) following the last 
LBs that have been collected at M9 
o eCRF completion 
o M9: Quality of Life and Patient Experience questionnaire 
 
 
 
Summary of standard of care study procedures 
• 
Screening period 
o CEA level at baseline 
 
• 
Start first-line therapy 
o First-line therapy FOLFOX/FOLFIRI and panitumumab planned to be administered 
every 2 weeks (± 3 days) 
o Bimonthly CT scan 
 
• 
Follow-up 
o Routine blood test before the start of new chemotherapy cycle 
o Tumor response assessment per modification of RECIST 1.1 guidelines on bimonthly 
CT scan 
o Decision of the treating physician to change therapy according to the outcome of the 
bimonthly CT scan 
o Decision of the treating physician to delay chemotherapy  
o Decision of the treating physician to perform a metastasectomy 

Protocol Number: v.3.0 
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36 
 
 Data collection and data storage encoding 
Clinical information about the patients, collected at the study visits in the hospital or by the external 
partner will be encoded and put in an eCRF of the Electronic Data Capture System “Castor EDC”. 
The management of this central database is performed by the Multidisciplinary Oncology Centre 
Antwerp (MOCA) of the Antwerp University Hospital in Edegem, Belgium. UZA is owner of the 
database and the information will be kept for at least 30 years after study termination. 
Patient reported outcomes are collected through questionnaires on a web-based customized 
survey (created in Castor EDC) meeting the requirements of the privacy commission. The results 
from the analysis of liquid biopsies will be collected in the eCRFs in Castor EDC, as well as in an 
encrypted Excel-file on a shared IT-platform of UZA. Only investigators of CMG Antwerp and 
MOCA will have access to this encrypted document. All individual patient documentation is stored 
encoded and the same code is used in both the central database with CRFs and the web-based 
survey. All liquid biopsies will be stored at the biobank of UZA. Biobank specimens and the patient’s 
associated clinical data will be stored for 30 years. The management of intellectual property rights 
and the ownership of the data is discussed in detail in the contract documents. 
 Evaluation of data 
 
Tumor response evaluation 
CT scan: Image analysis will be performed locally and also the decision about progression will be 
made in the treating center. 
 
ctDNA analysis 
As described, liquid biopsies contain, except for ctDNA, circulating DNA originating from non-
malignant cells. One can differentiate ctDNA from non-malignant DNA by selecting on a base of 
NPY methylation (22). The blood samples will be centrifuged according to protocol (two-step high 
speed). Hereafter, the plasma fraction and cell pellet will be stored and analyzed separately. To 
enable an objective analysis, the CMG Antwerp is blinded and will therefore not be aware of the 
disease status of the study patients during the course of the study. The results of the NPY 
methylation analyses will be reported to the central study coordinator of the Antwerp University 
Hospital. 
 
8 STATISTICAL CONSIDERATIONS 
 Sample size calculation 
The primary endpoint is the optimal cutoff value of NPY methylation to discriminate between 

Protocol Number: v.3.0 
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37 
 
progressive and non-progressive disease (as determined by CT). For the sample size calculation, 
we have based ourselves on the Area Under the Curve (AUC) of the Receiver Operating 
Characteristic (ROC) curve using NPY methylation. In order to construct a 95% confidence interval 
for the AUC of width 0.2 and assuming an AUC of 0.9 we need at least a group of 27 patients with 
progressive disease and a group of 27 patients without progressive disease. Assuming a median 
PFS of 9 months, we will need to include 54 patients and follow them up for 9 months. However, it 
is expected that about 10-15% of the study population (RAS and BRAF WT unresectable mCRC) 
may become resectable by conversion therapy (FOLFOX/FOLFIRI and panitumumab) (37-39). 
Taking this into account, the total number of patients to be included is 60. 
 Primary analysis 
To determine the optimal cutoff value of the NPY methylation to discriminate between progressive 
and non-progressive disease (as determined by CT), we will develop a Receiver Operating 
Characteristic (ROC) curve with data of this lead-in study. ROC curves show the trade-off between 
sensitivity and specificity and the Area Under the Curve (AUC) is considered as an index of 
accuracy.  The AUC will be calculated, and the optimal cutoff will be determined. 
 Secondary analysis 
 
In the primary analysis we compare NPY methylation values and progression status (as 
determined by CT) taken at the same time point. As a secondary analysis we will study if NPY 
methylation values at earlier time points can predict progression status later on. For this also 
ROC-curves will be used. 
 
A logistic regression model predicting progressive disease using NPY methylation values as a 
predictor will be considered. This model will allow correction for other variables (e.g. age). 
 
To determine the progression free survival in patients with metastatic colorectal cancer defined 
as time from inclusion to the date of first disease progression among subjects with metastatic 
colorectal cancer per RECIST 1.1 criteria, or death. Progression free survival will be presented 
with a Kaplan-Meier curve and median progression free survival with corresponding 95% 
confidence interval will be reported.  
 
For the 9-month survival the percentage alive at 9 months after start of first-line therapy will be 
reported with corresponding 95% confidence interval. 
 Exploratory analysis 
 
In this study, we will exploratively compare the use of ctDNA and CEA to predict progression, 
through logistic regression models. To compare these two methods, we will take sensitivity, 

Protocol Number: v.3.0 
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38 
 
specificity, negative predictive value and positive predictive value into account. This study will 
result in useful preliminary data that can be further studied in future projects. Moreover, this data 
might lead to more correct determination of effect sizes, which can be used for power 
calculations for future studies. 
 
The further exploration of ctDNA in liquid biopsies and search for novel biomarkers can result in 
important leads that can be systematically studied in deeper extent in further projects. 
 
We will exploratively study patient experience through short questionnaires. The results of these 
questionnaires can lead to interesting qualitative information which can be used to optimize 
patient care and/or the protocol of the next (randomized) phase of the FOLICOLOR trial.  
 
The quality of life and the patient experience measured by the questionnaires will be reported 
with descriptive statistics. 
 
 

Protocol Number: v.3.0 
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39 
 
9 SAFETY REPORTING 
 Ethical Committee 
The investigator will inform the subjects and the reviewing accredited Ethical Committee if anything 
occurs, on the basis of which it appears that the disadvantages of participation may be significantly 
greater than was foreseen in the research proposal. The study will be suspended pending further 
review by the accredited Ethical Committee, except insofar as suspension would jeopardize the 
subjects’ health. The investigator will take care that all subjects are kept informed.  
 
 Adverse events 
 
Definition Adverse Event (AE) 
Adverse events are defined as any undesirable experience occurring to a subject during the study 
that need not be related to treatment. An adverse event is any unfavorable, unintended diagnosis, 
symptom, sign (including abnormal laboratory finding), syndrome, or disease that occurs during the 
study, having been absent at baseline, or –if present at baseline- appears to worsen. All adverse 
events, including chemotherapy toxicities of all grades, reported spontaneously by the subject or 
observed by the investigator or his staff will be recorded. 
 
 
Definition Unexpected Adverse Event (UAE) 
An unexpected adverse event is defined as an adverse event that is not mentioned in the protocol 
or consent documents, or an AE that has not been seen before. Additionally, unexpected AEs in this 
study can be considered as unanticipated problems involving risks to study participants and others 
as an event that meets all of the following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the informed consent 
document; and (b) the characteristics of the subject population being studied; 
2. related or possibly related to participation in the research (i.e. the incident, experience, or 
outcome may have been caused by the procedures involved in the research). 
 
 
Recording of AEs 
All AEs, reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded on the AE form of the CRF with the following information: 
1. The severity grade according to the NCI-CTCAE version 5.0, published November 27, 2017 
(The complete document can be reviewed and downloaded from the following internet site: 

Protocol Number: v.3.0 
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40 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_5x7.pdf (1=mild, 2=moderate, 3=severe, 4=life threatening) 
2. Whether it constitutes an UAE or SAE  
 
All AEs should be treated appropriately. Treatment may include one or more of the following: no 
action taken (i.e. further observation only); chemotherapy temporarily interrupted; chemotherapy 
permanently discontinued due to this AE; concomitant medication given; non-drug therapy given; 
patient hospitalized/patient’s hospitalization prolonged. The action taken to treat the AE should be 
recorded on the AE CRF.  
Once an AE is detected, it should be followed until its resolution or until it is judged to be permanent, 
and assessment should be made at each visit (or more frequently, if necessary) of any changed in 
severity, the interventions required to treat it, and the outcome.  
 
 
Follow-up of adverse events 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
 
 Serious Adverse Events  
 
Definition Serious Adverse Event 
A serious adverse event is any untoward medical occurrence or effect that at any dose:  
• results in death  
• is life threatening (at the time of the event)  
• requires hospitalization or prolongation of existing patients’ hospitalization  
• results in persistent or significant disability or incapacity   
 
Note: In this study, admission for diagnosis or treatment of recurrences are not considered a SAE  
 
 
Recording of SAEs 
All SAEs must be reported initially in Castor EDC. The PI must sign the completed SAE report 
electronically in Castor EDC as soon as possible but no later than one working day from the time 
the local investigator has first knowledge of the SAE. Castor EDC will automatically send a 
notification to the central study coordinator when the SAE report has been created. The central 
Ethics Committee of UZA will inform the Medical Ethics Committee(s) of the participating centers. 

Protocol Number: v.3.0 
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41 
 
The (S)AE report must be updated after initial submission in Castor EDC as soon as final data 
related to the (S)AE is available. 
 
 (Suspected) Unexpected (Serious) Adverse Reactions 
Since the LEAD-IN FOLICOLOR Trial is a prospective interventional study in which there is no 
investigational product, (S)U(S)AR reporting does not apply.  
 
 Annual report  
The sponsor will submit once a year throughout the clinical trial an annual report to the central ethical 
committee of the UZA for distribution to all ethical advisory boards of participating hospitals.  
 
This annual report consists of: 
• 
A status update of the trial, including but not limited to the following: date of EC approval, 
date of inclusion of first study patient, total number of patients included, total number of 
patients who discontinued their participation (end of study); 
• 
An aggregated summary table of all serious adverse events, ordered by organ system. 
 
 

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10 ADMINISTRATION PROCEDURES AND PUBLICATION 
 
Regulatory Approval 
As required by local regulations, the sponsor will ensure all legal regulatory aspects are covered, 
and obtain approval of the appropriate regulatory bodies, prior to study initiation in regions where 
an approval is required. 
 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organizations involved in the funding 
or conduct of the study, including medical writers or statisticians subject to the consent of each 
individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study.  
 
 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the sponsor 
will sign a clinical study agreement prior to the start of the study, outlining overall sponsor and 
investigator responsibilities in relation to the study. 
 
Insurance, Indemnity and Compensation 
The sponsor has a liability insurance which will be annually renewed. 
 
 
 

Protocol Number: v.3.0 
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43 
 
11 MONITORING 
Monitoring in Belgium will be done according to ICH-GCP E6 Guideline and by medically qualified 
personnel. The LEAD-IN FOLICOLOR Trial is classified as a low-risk trial and therefore minimal 
monitoring is required. The purposes of trial monitoring are to verify that: 
 
The rights and well-being of human subjects are protected. 
 
The reported trial data are accurate, complete, and verifiable from source documents. 
 
The conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with GCP, and with the applicable regulatory requirement(s). 
 
Objective of on-site monitoring: 
 
To identify procedural errors in the execution of the research 
Central monitoring: 
 
Detection of missing, late and inaccurate research 
Source Data Verification:  
 
Monitoring will be performed according to the Data Monitoring Plan, which can be consulted 
in the Trial Master File that is saved in the Antwerp University Hospital.  
 
 
Overview of data collection 
 
Demographics 
- 
Sex 
- 
Age 
- 
Language 
- 
Race 
- 
Date of birth 
- 
Weight  
Inclusion criteria 
- 
Cfr. 5.1 
Exclusion criteria 
- 
Cfr. 5.2 
Baseline 
- 
Location of tumor 
- 
Relevant medical history 
- 
Recent blood transfusion 
Follow-up 
- 
Chemotherapy information: name, dose, (date of) 
administration 
- 
Imaging: imaging technique, date of imaging 
- 
Report of target lesions: sum of diameters, general evolution 
- 
Report of non-target lesions: sum of diameters, general 
evolution 
- 
Assessment of new lesions: type, location 
- 
CEA: level, date 
Adverse Events 
- 
According to the NCI-CTCAE version 5.0, published November 
27, 2017 
- 
System organ code 
- 
AE term 

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44 
 
- 
Start date 
- 
Outcome 
- 
End date 
- 
Severity 
- 
Relation to therapy 
- 
Relation to liquid biopsy sampling 
- 
Action with (chemo)therapy 
- 
Treatment of AE (incl. medications) 
- 
Unexpected AE 
Serious Adverse 
Events 
- 
Patient initials 
- 
System organ code 
- 
SAE term 
- 
Description of the SAE incident 
- 
Onset period & date 
- 
Severity 
- 
Category 
- 
Outcome 
- 
Date of recovery 
- 
Relation to therapy 
- 
Relation to liquid biopsy sampling 
- 
Action with (chemo)therapy 
- 
Treatment of SAE (incl. surgery, medications) 
- 
Relevant medical history 
- 
Contact person (name, e-mail address, telephone number) 
Death  
- 
Date of death 
- 
Autopsy (report) 
- 
Cause of death 
End of Study  
- 
Last date in study 
- 
ECOG 
- 
Reason for end of study 
- 
Date of metastasectomy 
Questionnaire 
- 
Dutch: cfr. Appendix 15.2 & 15.3 
- 
French: cfr. Appendix 15.4 & 15.5 
Liquid Biopsy Sampling 
- 
Confirmation LB collection 
- 
Date of collection 
- 
Reason for missing LBs 
- 
Confirmation shipment of LBs 
 
 
Mandatory data 
Castor EDC visualizes which data is mandatory, and which data can be entered without obligation. 
 
 
Data entry & monitoring guidelines 
The guidelines for data entry and monitoring in Castor EDC can be consulted in the Data Entry 
Manual. 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
45 
 
12 STUDY ADMINISTRATION 
 
Coordinating Study Team 
The Coordinating Study Team will govern the conduct of the study. The Coordinating Study Team 
will be composed of the Chief Investigator, the central study coordinator of UZA, representatives of 
CMG Antwerp, representatives of the UZA Biobank, and representatives of Amgen.  
13 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the trial. 

Protocol Number: v.3.0 
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46 
 
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Cohen JD, Javed AA, Thoburn C, Wong F, Tie J, Gibbs P, et al. Combined 
circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection 
of pancreatic cancers. Proc Natl Acad Sci U S A. 2017;114(38):10202-7. 
22. 
Boeckx N, Op de Beeck K, Beyens M, Deschoolmeester V, Hermans C, De 
Clercq P, et al. Mutation and Methylation Analysis of Circulating Tumor DNA Can Be Used 
for Follow-up of Metastatic Colorectal Cancer Patients. Clin Colorectal Cancer. 
2018;17(2):e369-e79. 
23. 
Roperch JP, Incitti R, Forbin S, Bard F, Mansour H, Mesli F, et al. Aberrant 
methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of 
colorectal cancer. BMC cancer. 2013;13:566. 
24. 
Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological 
and translational implications. Nat Rev Cancer. 2011;11(10):726-34. 
25. 
Garrigou S, Perkins G, Garlan F, Normand C, Didelot A, Le Corre D, et al. A 
Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer 
Biomarker. Clin Chem. 2016;62(8):1129-39. 
26. 
Danese E, Minicozzi AM, Benati M, Montagnana M, Paviati E, Salvagno GL, et al. 
Comparison of genetic and epigenetic alterations of primary tumors and matched plasma 
samples in patients with colorectal cancer. PloS one. 2015;10(5):e0126417. 
27. 
Warren JD, Xiong W, Bunker AM, Vaughn CP, Furtado LV, Roberts WL, et al. 
Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC 
Med. 2011;9:133. 
28. 
Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al. 
Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic 
colorectal cancer. Gut. 2014;63(2):317-25. 
29. 
Lange CP, Campan M, Hinoue T, Schmitz RF, van der Meulen-de Jong AE, 
Slingerland H, et al. Genome-scale discovery of DNA-methylation biomarkers for blood-
based detection of colorectal cancer. PloS one. 2012;7(11):e50266. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
48 
 
30. 
Young GP, Pedersen SK, Mansfield S, Murray DH, Baker RT, Rabbitt P, et al. A 
cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-
derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Med. 
2016;5(10):2763-72. 
31. 
Barault L, Amatu A, Siravegna G, Ponzetti A, Moran S, Cassingena A, et al. 
Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive 
monitoring of treatment response in metastatic colorectal cancer. Gut. 2018;67(11):1995-
2005. 
32. 
Dong Y, Zhao H, Li H, Li X, Yang S. DNA methylation as an early diagnostic 
marker of cancer (Review). Biomed Rep. 2014;2(3):326-30. 
33. 
Lam K, Pan K, Linnekamp JF, Medema JP, Kandimalla R. DNA methylation 
based biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta. 
2016;1866(1):106-20. 
34. 
McQuade RM, Stojanovska V, Bornstein JC, Nurgali K. Colorectal Cancer 
Chemotherapy: The Evolution of Treatment and New Approaches. Current medicinal 
chemistry. 2017;24(15):1537-57. 
35. 
Eisenhauer EA, TheRASse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
European journal of cancer (Oxford, England : 1990). 2009;45(2):228-47. 
36. 
Thomsen CB, Hansen TF, Andersen RF, Lindebjerg J, Jensen LH, Jakobsen A. 
Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal 
cancer by serial analysis of tumor specific DNA in plasma. Journal of experimental & 
clinical cancer research : CR. 2018;37(1):55. 
37. 
Hofheinz R, Mineur L, Greil R, Kohne C, Letocha H, Thaler J, et al. Panitumumab 
(pmab) with FOLFIRI as first-line treatment of patients (pts) with metastatic colorectal 
cancer (mCRC): Resections and curative surgery in a phase II single arm, multicenter 
study (20060314). Journal of Clinical Oncology. 2010;28(15_suppl):3545-. 
38. 
Symonds LK, Cohen SA. Use of perioperative chemotherapy in colorectal cancer 
metastatic to the liver. Gastroenterology Report. 2019;7(5):301-11. 
39. 
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final 
results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-
line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25(7):1346-55. 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
49 
 
15 APPENDIX 
 
Follow-Up Scheme 
 
  

Protocol Number: v.3.0 
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50 
 
 
Questionnaire 1 (Dutch version) 
Meetmoment vragenlijst: start eerstelijnstherapie    
Mijn geboortedatum (ter controle):  __ __ / __ __ / __ __ __ __   (Dag/Maand/ Jaar) 
Datum van vandaag:  __ __ / __ __ / __ __ __ __   (Dag/Maand/ Jaar) 
Mijn geslacht:    Man    Vrouw    
Volgende pagina, a.u.b. 
EORTC QLQ-C30 – Kwaliteit van leven 
Wilt u alle vragen zelf beantwoorden door het getal te omcirkelen dat het meest op u van toepassing is? 
Er zijn geen “juiste” of “onjuiste” antwoorden. De informatie die u geeft zal strikt vertrouwelijk worden 
behandeld. 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
1. Heeft u moeite met het doen van inspannende 
activiteiten zoals het dragen van een zware 
boodschappentas of een koffer? 
 
 
1 
2 
3 
4 
2. Heeft u moeite met het maken van een lange 
wandeling? 
 
 
1 
2 
3 
4 
3. Heeft u moeite met het maken van een korte 
wandeling buitenshuis? 
 
 
1 
2 
3 
4 
4. Moet u overdag in bed of in een stoel blijven? 
 
 
1 
2 
3 
4 
5. Heeft u hulp nodig met eten, aankleden, u zelf 
wassen of naar het toilet gaan? 
 
 
1 
2 
3 
4 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
6. Was u beperkt bij het doen van uw werk of andere 
dagelijkse bezigheden? 
 
 
1 
2 
3 
4 
7. Was u beperkt in het uitoefenen van uw hobby’s of 
bij andere bezigheden die u in uw vrije tijd doet? 
 
 
1 
2 
3 
4 
8. Was u kortademig? 
 
 
1 
2 
3 
4 
9. Heeft u pijn gehad? 
 
 
1 
2 
3 
4 
10.  Had u behoefte om te rusten? 
 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
51 
 
Volgende pagina, a.u.b. 
11. Heeft u moeite met slapen gehad? 
 
 
1 
2 
3 
4 
12. Heeft u zich slap gevoeld? 
 
 
1 
2 
3 
4 
13. Heeft u gebrek aan eetlust gehad? 
 
 
1 
2 
3 
4 
14. Heeft u zich misselijk gevoeld? 
 
 
 
1 
2 
3 
4 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
15. Heeft u overgegeven? 
 
 
1 
2 
3 
4 
16. Had u last van obstipatie? (Was u verstopt?) 
 
 
1 
2 
3 
4 
17. Had u diarree? 
 
 
1 
2 
3 
4 
18. Was u moe? 
 
 
1 
2 
3 
4 
19. Heeft 
pijn 
u 
gehinderd 
in 
uw dagelijkse 
bezigheden? 
 
1 
2 
3 
4 
20. Heeft u moeite gehad met het concentreren op 
dingen, zoals een krant lezen of televisie kijken? 
 
1 
2 
3 
4 
21. Voelde u zich gespannen? 
 
 
1 
2 
3 
4 
22. Maakte u zich zorgen? 
 
 
1 
2 
3 
4 
23. Voelde u zich prikkelbaar? 
 
 
1 
2 
3 
4 
24. Voelde u zich neerslachtig? 
 
 
1 
2 
3 
4 
25. Heeft u moeite gehad met het herinneren van 
dingen? 
 
1 
2 
3 
4 
26. Heeft uw lichamelijke toestand of medische 
behandeling uw familieleven in de weg gestaan? 
 
1 
2 
3 
4 
27. Heeft uw lichamelijke toestand of medische 
behandeling 
u 
belemmerd 
in 
uw 
sociale 
bezigheden? 
 
1 
2 
3 
4 
28. Heeft uw lichamelijke toestand of medische 
behandeling financiële moeilijkheden met zich 
meegebracht? 
 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
52 
 
 
 
 
Volgende pagina, a.u.b. 
Wilt u voor de volgende vragen het getal tussen 1 en 7 omcirkelen dat het meest op u van 
toepassing is: 
 
29. Hoe zou u uw algehele gezondheid gedurende de afgelopen week beoordelen? 
 
1                   2                   3                   4                   5                   6                   7 
       Erg slecht 
 
 
Uitstekend 
 
 
 
 
30. Hoe zou u uw algehele “kwaliteit van het leven” gedurende de afgelopen week 
beoordelen? 
 
1                   2                   3                   4                   5                   6                   7 
       Erg slecht 
 
 
Uitstekend 
 
 
 
 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
EORTC QLQ-CR29 – Ziekte-specifieke levenskwaliteit 
Soms zeggen patiënten dat ze de volgende klachten of problemen hebben. Wilt u aangeven in 
welke mate u deze klachten of problemen gedurende de afgelopen week heeft ervaren? Wilt u 
de vragen beantwoorden door het vakje aan te kruisen dat het meest op u van toepassing is? 
 
 
Gedurende de afgelopen week: 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
31. Heeft u overdag meer dan gewoonlijk geplast? 
 
1 
2 
3 
4 
 
32. Heeft u ’s nachts meer dan gewoonlijk geplast? 
 
1 
2 
3 
4 
 
33. Heeft u ongewild urine verloren? 
 
1 
2 
3 
4 
 
34. Heeft u pijn gehad bij het plassen? 
 
1 
2 
3 
4 
 
35. Heeft u buikpijn gehad? 
 
1 
2 
3 
4 
 
36. Heeft u pijn gehad in uw zitvlak of bij uw anus? 
 
1 
2 
3 
4 
 
37. Heeft u een opgeblazen gevoel gehad in uw buik? 
 
 
1 
2 
3 
4 
38. Heeft u bloed in uw ontlasting gehad? 
 
1 
2 
3 
4 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
53 
 
 
Volgende pagina, a.u.b. 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
39. Heeft u slijm in uw ontlasting gehad? 
 
1 
2 
3 
4 
 
40. Heeft u een droge mond gehad? 
 
1 
2 
3 
4 
 
41. Heeft u haaruitval gehad ten gevolge van uw 
behandeling? 
 
1 
2 
3 
4 
 
42. Heeft u problemen met uw smaak gehad? 
 
1 
2 
3 
4 
 
43. Heeft u zich zorgen gemaakt over uw gezondheid 
in de toekomst? 
 
1 
2 
3 
4 
44. Heeft 
u 
zich 
zorgen 
gemaakt 
over 
uw 
gewicht(sverlies)? 
 
1 
2 
3 
4 
45. Voelde u zich lichamelijk minder aantrekkelijk ten 
gevolge van uw ziekte of behandeling? 
 
1 
2 
3 
4 
46. Voelde u zich minder vrouwelijk/mannelijk ten 
gevolge van uw ziekte of behandeling? 
 
1 
2 
3 
4 
47. Was u ontevreden met uw lichaam? 
 
1 
2 
3 
4 
 
48. Heeft u een stoma? (dunnedarm-stoma of dikkedarm-stoma) 
 Ja 
 Nee 
 
Beantwoord deze vragen (vraag 49 tot en met 55) ALLEEN ALS U EEN STOMA HEEFT, zo niet, 
ga dan naar vraag 56. 
 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
49. Heeft u last gehad van het ongewild vrijkomen van 
gas (winderigheid) uit uw stoma? 
 
1 
2 
3 
4 
50. Was er lekkage van ontlasting uit uw stomazakje? 
 
 
1 
2 
3 
4 
51. Heeft u een pijnlijke huid gehad rond uw stoma? 
 
 
1 
2 
3 
4 
52. Heeft u overdag vaak het stomazakje moeten 
vervangen? 
 
1 
2 
3 
4 
53. Heeft u ’s nachts vaak het stomazakje moeten 
vervangen? 
 
1 
2 
3 
4 
54. Voelde u zich ongemakkelijk/opgelaten door uw 
stoma? 
 
1 
2 
3 
4 
55. Heeft u problemen gehad met de verzorging van 
uw stoma? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
54 
 
 
Gedurende de afgelopen 4 weken: (alleen voor MANNEN) 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
62. In hoeverre had u zin in seks? 
 
1 
2 
3 
4 
 
63. Indien u seksueel actief was (met of zonder 
geslachtsgemeenschap): had u moeite met het 
stijf worden of blijven van uw penis? 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
Gedurende de afgelopen 4 weken: (alleen voor VROUWEN) 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
64. In hoeverre had u zin in seks? 
 
1 
2 
3 
4 
 
65. Indien u geslachtsgemeenschap heeft gehad: 
had 
u 
pijn 
of 
ongemak 
tijdens 
de 
gemeenschap? 
 
1 
2 
3 
4 
 
 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
 
Bedankt voor het invullen van deze vragenlijst! 
Het FOLICOLOR Lead-In onderzoeksteam 
 
Beantwoord deze vragen (vraag 56 tot en met 61) ALLEEN ALS U GEEN STOMA HEEFT. 
 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
56. Heeft u last gehad van het ongewild vrijkomen van 
gas (winderigheid)? 
 
1 
2 
3 
4 
57. Heeft u ongewild ontlasting verloren? 
 
1 
2 
3 
4 
 
58. Heeft u een pijnlijke huid gehad rondom uw anus? 
 
1 
2 
3 
4 
59. Heeft u overdag vaak ontlasting gehad? 
 
1 
2 
3 
4 
 
60. Heeft u ’s nachts vaak ontlasting gehad? 
 
1 
2 
3 
4 
 
61. Voelde u zich ongemakkelijk/opgelaten door uw 
ontlastingspatroon? 
 
1 
2 
3 
4 
 
 
 
 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
55 
 
 
Questionnaire 1 (French version) 
 Questionnaire à remplir après 9 mois de suivi ou fin d’étude prématuré    
Ma date de naissance (pour vérification):  __ __ / __ __ / __ __ __ __   (Jour/Mois/ Année) 
Date d’aujourd’hui: __ __ / __ __ / __ __ __ __   (Jour/Mois/ Année) 
Sexe:    Masculin    Féminin   (marquer d’une croix la bonne case) 
 
EORTC QLQ-C30 – Qualité de vie 
Répondez vous-même à toutes les questions en entourant le chiffre qui correspond le mieux à votre 
situation. Il n’y a pas de “bonne” ou de “mauvaise” réponse.  Ces informations sont strictement 
confidentielles. 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
66. Avez-vous des difficultés à faire certains efforts 
physiques pénibles comme porter un sac à 
provisions chargé ou une valise? 
 
 
1 
2 
3 
4 
67. Avez-vous des difficultés à faire une longue 
promenade ?  
 
 
1 
2 
3 
4 
68. Avez-vous des difficultés à faire un petit tour 
dehors? 
 
 
1 
2 
3 
4 
69. Etes-vous obligée de rester au lit ou dans un 
fauteuil pendant la journée? 
 
 
1 
2 
3 
4 
70. Avez-vous besoin d’aide pour manger, vous 
habiller, faire votre toilette ou aller aux 
toilettes? 
 
 
1 
2 
3 
4 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
71. Avez- vous été gênée pour faire votre travail ou 
vos activités de tous les jours? 
 
 
1 
2 
3 
4 
72. Avez-vous été gênée dans vos activités de 
loisirs? 
 
 
1 
2 
3 
4 
73. Avez-vous eu le souffle court? 
 
 
1 
2 
3 
4 
74. Avez-vous ressenti de la douleur? 
 
 
1 
2 
3 
4 
75.  Avez-vous eu besoin de repos? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
56 
 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
 
Assez Beaucoup 
76. Avez-vous eu des difficultés pour dormir? 
 
 
1 
2 
3 
4 
77. Vous êtes-vous sentie faible? 
 
 
1 
2 
3 
4 
78. Avez-vous manqué d’appétit? 
 
 
1 
2 
3 
4 
79. Avez-vous eu des nausées (mal au coeur)? 
 
 
1 
2 
3 
4 
80. Avez-vous vomi? 
 
 
1 
2 
3 
4 
81. Avez-vous été constipée? 
 
 
1 
2 
3 
4 
82. Avez-vous eu de la diarrhée? 
 
 
1 
2 
3 
4 
83. Etiez-vous fatiguée? 
 
 
1 
2 
3 
4 
84. Des douleurs ont-elles perturbé vos activités 
quotidiennes? 
 
1 
2 
3 
4 
85. Avez-vous eu des difficultés à vous concentrer 
sur certaines choses par exemple pour lire le 
journal ou regarder la télévision? 
 
1 
2 
3 
4 
86. Vous êtes-vous sentie tendue? 
 
 
1 
2 
3 
4 
87. Vous êtes-vous fait du souci? 
 
 
1 
2 
3 
4 
88. Vous êtes-vous sentie irritable? 
 
 
1 
2 
3 
4 
89. Vous êtes-vous sentie déprimée? 
 
 
1 
2 
3 
4 
90. Avez-vous eu des difficultés pour vous souvenir 
de certaines choses? 
 
1 
2 
3 
4 
91. Votre état physique ou votre traitement médical 
vous ont-ils gênée dans votre vie familiale? 
 
1 
2 
3 
4 
92. Votre état physique ou votre traitement médical 
vous ont-ils gênée dans vos activités sociales 
(par exemple, sortir avec des amis, aller au 
cinéma…)? 
 
1 
2 
3 
4 
93. Votre état physique ou votre traitement médical 
vous ont-ils causé des problèmes financiers? 
 
 
 
1 
2 
3 
4 
Voir page suivante S.V.P. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
57 
 
Veuillez répondre en entourant le chiffre entre 1 et 7 qui s’applique le mieux à votre situation: 
 
94. Comment évalueriez-vous votre état de santé au cours de la semaine passée? 
 
1                   2                   3                   4                   5                   6                   7 
Très mauvais 
 
 
Excellent 
 
 
 
 
95. Comment évalueriez-vous l’ensemble de votre qualité de vie au cours de la semaine 
passée? 
 
1                   2                   3                   4                   5                   6                   7 
Très mauvaise 
 
 
Excellente 
 
 
 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
EORTC QLQ-CR29 – Qualité de vie spécifique à la maladie 
Les patients rapportent parfois les symptômes ou problèmes suivants. Pourriez-vous indiquer, 
s’il vous plaît, si, durant la semaine passée, vous avez été affecté(e) par l’un de ces symptômes 
ou problèmes. Entourez, s’il vous plaît, le chiffre qui correspond le mieux à votre situation. 
 
 
Au cours de la semaine passée: 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
96. Avez-vous fréquemment uriné dans la journée? 
 
1 
2 
3 
4 
 
97. Avez-vous fréquemment uriné pendant la nuit? 
 
1 
2 
3 
4 
 
98. Avez-vous eu des fuites urinaires? 
 
1 
2 
3 
4 
 
99. Avez-vous eu des douleurs en urinant? 
 
1 
2 
3 
4 
 
100. 
Avez-vous eu mal au ventre? 
 
1 
2 
3 
4 
 
101. 
Avez-vous ressenti des douleurs au niveau 
de la région anale? 
 
1 
2 
3 
4 
 
102. 
Vous êtes-vous senti(e) ballonné(e)? 
 
 
1 
2 
3 
4 
103. 
Avez-vous vu du sang dans vos selles? 
 
1 
2 
3 
4 
 
 
 
 
 
 
Voir page suivante S.V.P. 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
58 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
104. 
Avez-vous constaté des glaires dans vos 
selles? 
 
1 
2 
3 
4 
 
105. 
Avez-vous eu la bouche sèche? 
 
1 
2 
3 
4 
 
106. 
Avez-vous perdu des cheveux du fait de 
votre traitement? 
 
1 
2 
3 
4 
 
107. 
Les 
aliments 
avaient-ils 
un 
goût 
inhabituel ? 
 
1 
2 
3 
4 
 
108. 
Vous êtes-vous inquiété(e) de votre santé 
pour l’avenir? 
 
1 
2 
3 
4 
109. 
Vous êtes-vous inquiété(e) de votre poids? 
 
 
1 
2 
3 
4 
110. 
Vous êtes-vous senti(e) moins attirant(e) 
du fait de votre maladie ou de votre 
traitement ? 
 
1 
2 
3 
4 
111. 
Vous 
êtes-vous 
senti(e) 
moins 
femme/homme du fait de votre maladie ou de 
votre traitement ? 
 
1 
2 
3 
4 
112. 
Votre corps vous a-t-il déplu? 
 
1 
2 
3 
4 
 
113. 
Avez-vous un anus artificiel (stomie)?  
 Oui 
 Non 
 
Ne répondez aux questions 49 – 55 que SI VOUS AVEZ UN ANUS ARTIFICIEL. Dans le cas 
contraire, passez directement à la série de questions 58 - 63. 
 
 
 
 
 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
114. 
Avez-vous eu des fuites de gaz par votre 
anus artificiel (stomie)? 
 
1 
2 
3 
4 
115. 
Avez-vous eu des fuites de matières fécales 
en dehors de votre poche de stomie? 
 
1 
2 
3 
4 
116. 
La peau entourant votre anus artificiel 
(stomie) vous a-t-elle fait souffrir? 
 
1 
2 
3 
4 
117. 
Avez-vous dû souvent changer votre poche 
de stomie au cours de la journée? 
 
1 
2 
3 
4 
118. 
Avez-vous dû souvent changer votre poche 
de stomie au cours de la nuit? 
 
1 
2 
3 
4 
119. 
Vous êtes-vous senti(e) gêné(e) à cause de 
votre poche? 
 
1 
2 
3 
4 
120. 
Les soins de votre poche de stomie vous 
ont-ils posé des problèmes? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
59 
 
 
Ne répondez aux questions 56 – 61 que SI VOUS N’AVEZ PAS D’ANUS ARTIFICIEL. 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
121. 
Avez-vous 
eu 
des 
fuites 
de 
gaz 
involontaires par l’anus? 
 
1 
2 
3 
4 
122. 
Avez-vous eu des fuites de matières fécales 
par l’anus? 
 
1 
2 
3 
4 
 
123. 
La peau entourant votre anus vous a-t-elle 
fait souffrir? 
 
1 
2 
3 
4 
124. 
Avez-vous dû fréquemment aller à la selle 
au cours de la journée? 
 
1 
2 
3 
4 
 
125. 
Avez-vous dû fréquemment aller à la selle 
au cours de la nuit? 
 
1 
2 
3 
4 
 
126. 
Vous êtes-vous senti(e) gêné(e) lorsque 
vous alliez à la selle? 
 
1 
2 
3 
4 
 
 
 
 
 
 
Au cours des 4 dernières semaines: 
 
Pour les HOMMES uniquement: 
 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
127. 
Dans quelle mesure vous êtes-vous 
intéressé à la sexualité? 
 
1 
2 
3 
4 
 
128. 
Avez-vous eu des difficultés à avoir 
une érection ou à rester en érection? 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
Au cours des 4 dernières semaines: 
 
Pour les FEMMES uniquement: 
 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
129. 
Dans quelle mesure vous êtes-vous 
intéressée à la sexualité? 
 
1 
2 
3 
4 
 
130. 
Avez-vous ressenti des douleurs ou 
une gêne lors des rapports sexuels? 
 
1 
2 
3 
4 
 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
 
Merci d’avoir rempli ce questionnaire ! 
L’équipe de recherche de LEAD-IN FOLICOLOR Trial  
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
60 
 
 
Questionnaire 2 (Dutch version) 
In te vullen na 9 maanden follow-up of bij vroegtijdig beëindigen van de studie 
Mijn geboortedatum (ter controle):  __ __ / __ __ / __ __ __ __   (Dag/Maand/ Jaar) 
Dag van vandaag: __ __ / __ __ / __ __ __ __   (Dag/Maand/ Jaar) 
Mijn geslacht:    Man    Vrouw    
EORTC QLQ-C30 – Kwaliteit van leven 
Wilt u alle vragen zelf beantwoorden door het getal te omcirkelen dat het meest op u van toepassing is? 
Er zijn geen “juiste” of “onjuiste” antwoorden. De informatie die u geeft zal strikt vertrouwelijk worden 
behandeld. 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
131. 
Heeft u moeite met het doen van inspannende 
activiteiten zoals het dragen van een zware 
boodschappentas of een koffer? 
 
 
1 
2 
3 
4 
132. 
Heeft u moeite met het maken van een lange 
wandeling? 
 
 
1 
2 
3 
4 
133. 
Heeft u moeite met het maken van een korte 
wandeling buitenshuis? 
 
 
1 
2 
3 
4 
134. 
Moet u overdag in bed of in een stoel blijven? 
 
 
1 
2 
3 
4 
135. 
Heeft u hulp nodig met eten, aankleden, u zelf 
wassen of naar het toilet gaan? 
 
 
1 
2 
3 
4 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
136. 
Was u beperkt bij het doen van uw werk of 
andere dagelijkse bezigheden? 
 
 
1 
2 
3 
4 
137. 
Was u beperkt in het uitoefenen van uw 
hobbies of bij andere bezigheden die u in uw vrije tijd 
doet? 
 
 
1 
2 
3 
4 
138. 
Was u kortademig? 
 
 
1 
2 
3 
4 
139. 
Heeft u pijn gehad? 
 
 
1 
2 
3 
4 
140. 
 Had u behoefte om te rusten? 
 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
61 
 
141. 
Heeft u moeite met slapen gehad? 
 
 
1 
2 
3 
4 
142. 
Heeft u zich slap gevoeld? 
 
 
1 
2 
3 
4 
143. 
Heeft u gebrek aan eetlust gehad? 
 
 
1 
2 
3 
4 
144. 
Heeft u zich misselijk gevoeld? 
 
 
 
1 
2 
3 
4 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
145. 
Heeft u overgegeven? 
 
 
1 
2 
3 
4 
146. 
Had u last van obstipatie? (Was u verstopt?) 
 
 
1 
2 
3 
4 
147. 
Had u diarree? 
 
 
1 
2 
3 
4 
148. 
Was u moe? 
 
 
1 
2 
3 
4 
149. 
Heeft pijn u gehinderd in uw dagelijkse 
bezigheden? 
 
 
1 
2 
3 
4 
150. 
Heeft u moeite gehad met het concentreren op 
dingen, zoals een krant lezen of televisie kijken? 
 
1 
2 
3 
4 
151. 
Voelde u zich gespannen? 
 
 
1 
2 
3 
4 
152. 
Maakte u zich zorgen? 
 
 
1 
2 
3 
4 
153. 
Voelde u zich prikkelbaar? 
 
 
1 
2 
3 
4 
154. 
Voelde u zich neerslachtig? 
 
 
1 
2 
3 
4 
155. 
Heeft u moeite gehad met het herinneren van 
dingen? 
 
1 
2 
3 
4 
156. 
Heeft uw lichamelijke toestand of medische 
behandeling uw familieleven in de weg gestaan? 
 
1 
2 
3 
4 
157. 
Heeft uw lichamelijke toestand of medische 
behandeling u belemmerd in uw sociale bezigheden? 
 
1 
2 
3 
4 
158. 
Heeft uw lichamelijke toestand of medische 
behandeling financiële moeilijkheden met zich 
meegebracht? 
 
 
1 
2 
3 
4 
 
 
Volgende pagina, a.u.b. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
62 
 
Wilt u voor de volgende vragen het getal tussen 1 en 7 omcirkelen dat het meest op u van 
toepassing is: 
 
159. 
Hoe zou u uw algehele gezondheid gedurende de afgelopen week beoordelen? 
 
1                   2                   3                   4                   5                   6                   7 
       Erg slecht 
 
 
Uitstekend 
 
 
 
 
160. 
Hoe zou u uw algehele “kwaliteit van het leven” gedurende de afgelopen week 
beoordelen? 
 
1                   2                   3                   4                   5                   6                   7 
       Erg slecht 
 
 
Uitstekend 
 
 
 
 
 
 
 
EORTC QLQ-CR29 – Ziekte-specifieke levenskwaliteit 
Soms zeggen patiënten dat ze de volgende klachten of problemen hebben. Wilt u aangeven in 
welke mate u deze klachten of problemen gedurende de afgelopen week heeft ervaren? Wilt u 
de vragen beantwoorden door het vakje aan te kruisen dat het meest op u van toepassing is? 
 
 
Gedurende de afgelopen week: 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
161. 
Heeft u overdag meer dan gewoonlijk geplast? 
 
1 
2 
3 
4 
 
162. 
Heeft u ’s nachts meer dan gewoonlijk geplast?  
1 
2 
3 
4 
 
163. 
Heeft u ongewild urine verloren? 
 
1 
2 
3 
4 
 
164. 
Heeft u pijn gehad bij het plassen? 
 
1 
2 
3 
4 
 
165. 
Heeft u buikpijn gehad? 
 
1 
2 
3 
4 
 
166. 
Heeft u pijn gehad in uw zitvlak of bij uw anus?  
1 
2 
3 
4 
 
167. 
Heeft u een opgeblazen gevoel gehad in uw 
buik? 
 
 
1 
2 
3 
4 
168. 
Heeft u bloed in uw ontlasting gehad? 
 
1 
2 
3 
4 
 
 
 
 
Volgende pagina, a.u.b. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
63 
 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
169. 
Heeft u slijm in uw ontlasting gehad? 
 
1 
2 
3 
4 
 
170. 
Heeft u een droge mond gehad? 
 
1 
2 
3 
4 
 
171. 
Heeft u haaruitval gehad ten gevolge van uw 
behandeling? 
 
1 
2 
3 
4 
 
172. 
Heeft u problemen met uw smaak gehad? 
 
1 
2 
3 
4 
 
173. 
Heeft u zich zorgen gemaakt over uw 
gezondheid in de toekomst? 
 
1 
2 
3 
4 
174. 
Heeft u zich zorgen gemaakt over uw 
gewicht(sverlies)? 
 
1 
2 
3 
4 
175. 
Voelde u zich lichamelijk minder aantrekkelijk 
ten gevolge van uw ziekte of behandeling? 
 
1 
2 
3 
4 
176. 
Voelde u zich minder vrouwelijk/mannelijk ten 
gevolge van uw ziekte of behandeling? 
 
1 
2 
3 
4 
177. 
Was u ontevreden met uw lichaam? 
 
1 
2 
3 
4 
 
178. 
Heeft u een stoma? (dunnedarm-stoma of dikkedarm-stoma) 
 Ja 
 Nee 
 
Beantwoord deze vragen (vraag 49 tot en met 55) ALLEEN ALS U EEN STOMA HEEFT, zo niet, 
ga dan naar vraag 58. 
 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
179. 
Heeft u last gehad van het ongewild vrijkomen 
van gas (winderigheid) uit uw stoma? 
 
1 
2 
3 
4 
180. 
Was er lekkage van ontlasting uit uw 
stomazakje? 
 
 
1 
2 
3 
4 
181. 
Heeft u een pijnlijke huid gehad rond uw 
stoma? 
 
 
1 
2 
3 
4 
182. 
Heeft u overdag vaak het stomazakje moeten 
vervangen? 
 
1 
2 
3 
4 
183. 
Heeft u ’s nachts vaak het stomazakje moeten 
vervangen? 
 
1 
2 
3 
4 
184. 
Voelde u zich ongemakkelijk/opgelaten door 
uw stoma? 
 
1 
2 
3 
4 
185. 
Heeft u problemen gehad met de verzorging 
van uw stoma? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
64 
 
 
Beantwoord deze vragen (vraag 56 tot en met 61) ALLEEN ALS U GEEN STOMA HEEFT. 
 
Gedurende de afgelopen week: 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
186. 
Heeft u last gehad van het ongewild vrijkomen 
van gas (winderigheid)? 
 
1 
2 
3 
4 
187. 
Heeft u ongewild ontlasting verloren? 
 
1 
2 
3 
4 
 
188. 
Heeft u een pijnlijke huid gehad rondom uw 
anus? 
 
 
1 
2 
3 
4 
189. 
Heeft u overdag vaak ontlasting gehad? 
 
1 
2 
3 
4 
 
190. 
Heeft u ’s nachts vaak ontlasting gehad? 
 
1 
2 
3 
4 
 
191. 
Voelde u zich ongemakkelijk/opgelaten door 
uw ontlastingspatroon? 
 
1 
2 
3 
4 
 
 
 
 
 
 
Gedurende de afgelopen 4 weken: 
 
Alleen voor MANNEN: 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
192. 
In hoeverre had u zin in seks? 
 
1 
2 
3 
4 
 
193. 
Indien u seksueel actief was (met of 
zonder geslachtsgemeenschap): had u moeite 
met het stijf worden of blijven van uw penis? 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
Gedurende de afgelopen 4 weken: 
 
Alleen voor VROUWEN: 
 
 
Helemaal 
niet 
Een 
beetje 
Nogal Heel 
erg 
 
194. 
In hoeverre had u zin in seks? 
 
1 
2 
3 
4 
 
195. 
Indien u geslachtsgemeenschap heeft 
gehad: had u pijn of ongemak tijdens de 
gemeenschap? 
 
1 
2 
3 
4 
Volgende pagina, a.u.b. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
65 
 
Vragenlijst m.b.t. ervaring van patiënten  
 
Beste patiënt, 
Uw mening telt. 
Om de zorg voor patiënten met darmkanker te verbeteren, doen we onderzoek naar 
opvolgingsmethodes voor darmkanker. In deze korte vragenlijst willen we peilen naar uw ervaring 
met de verschillende opvolgingsmethodes. Deze vragenlijst wordt anoniem verwerkt. 
Alvast bedankt voor uw deelname. 
 
Het FOLICOLOR LEAD-IN onderzoeksteam 
 
Vraag 1 
Wanneer u terugdenkt aan uw ervaring tijdens de CT-scan met toediening van contrastvloeistof (via 
een infuus), kunt u aangeven in hoeverre u de volgende ongemakken ervaarde: 
Omcirkel het getal dat het meest op u van toepassing is (maximaal één antwoord mogelijk)  
 
 
Helemaal 
niet 
Nauwelijks 
In redelijke 
mate 
In hoge 
mate 
In zeer 
hoge mate 
 
1. Pijn bij plaatsen van het 
infuus  
1 
2 
3 
4 
5 
2. Warm gevoel, gevoel dat je 
moet plassen na toediening 
van contrast 
1 
2 
3 
4 
 
5 
3. Onwel gevoel na toediening 
van contrast 
1 
2 
3 
4 
5 
4. Onaangename 
smaak 
na 
toediening van contrast 
1 
2 
3 
4 
5 
5. Angst in de scan 
1 
2 
3 
4 
 
5 
6. Claustrofobisch gevoel in de 
CT-scan 
1 
2 
3 
4 
 
5 
 
 
Volgende pagina, a.u.b. 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
66 
 
 
 
Helemaal 
niet 
Nauwelijks 
In redelijke 
mate 
In hoge 
mate 
In zeer 
hoge mate 
 
7. Gevoel van isolatie, alleen te 
zijn tijdens de scan 
1 
2 
3 
4 
5 
8. Oncomfortabele positie in de 
CT-scan 
1 
2 
3 
4 
5 
9. Ongemak ten gevolge van te 
lange duurtijd van de scan 
1 
2 
3 
4 
5 
10. Andere, namelijk: 
1 
2 
3 
4 
5 
……………………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………………………………………… 
 
 
 
 
Vraag 2 
Wanneer u terugdenkt aan uw ervaring tijdens de afname van de twee extra bloedtubes voor 
deze studie bovenop uw standaard bloedafname, kunt u aangeven in hoeverre u de volgende 
ongemakken ervaarde: 
Omcirkel het getal dat het meest op u van toepassing is (maximaal één antwoord mogelijk):   
 
 
Helemaal 
niet 
Nauwelijks 
In redelijke 
mate 
In hoge 
mate 
In zeer 
hoge mate 
 
1. Angst tijdens bloedafname 
1 
2 
3 
4 
5 
2. Pijn tijdens bloedafname 
1 
2 
3 
4 
5 
3. Andere, namelijk: 
1 
2 
3 
4 
5 
……………………………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………………………………………… 
 
 
 
 
 
Volgende pagina, a.u.b. 
 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
67 
 
Vraag 3 
Stel dat zowel de opvolging op basis van een CT-scan als de opvolging op basis van een bloedafname 
allebei bewezen evenwaardige en even doeltreffende opvolgingsmethoden voor patiënten met 
darmkanker zijn, welke van deze methoden zou dan uw voorkeur genieten? Kruis het hokje aan van 
uw keuze (maximaal één antwoord mogelijk). 
 Opvolging van uw ziekte op basis van een CT-scan met toediening van contrastvloeistof via 
een infuus en dit om de 8 weken (dit is de huidige standaardzorg),  
 Opvolging van uw ziekte op basis van een bloedafname en dit om de 2 weken.  
 
Vraag 4 
Stel dat zowel de opvolging op basis van een CT-scan als de opvolging op basis van een bloedafname 
allebei bewezen evenwaardige en even doeltreffende opvolgingsmethoden voor patiënten met 
darmkanker zijn, welke van deze methoden zou dan uw voorkeur genieten? Kruis het hokje aan van 
uw keuze (maximaal één antwoord mogelijk). 
 Opvolging van uw ziekte op basis van een CT-scan met toediening van contrastvloeistof via 
een infuus en dit om de 8 weken (dit is de huidige standaardzorg),  
 Opvolging van uw ziekte op basis van een bloedafname en dit om de 4 weken.  
 
Vraag 5 
Stel dat zowel de opvolging op basis van een CT-scan als de opvolging op basis van een bloedafname 
allebei bewezen evenwaardige en even doeltreffende opvolgingsmethoden voor patiënten met 
darmkanker zijn, welke van deze methoden zou dan uw voorkeur genieten? Kruis het hokje aan van 
uw keuze (maximaal één antwoord mogelijk). 
 Opvolging van uw ziekte op basis van een CT-scan met toediening van contrastvloeistof via 
een infuus en dit om de 8 weken (dit is de huidige standaardzorg),  
 Opvolging van uw ziekte op basis van een bloedafname en dit om de 8 weken.  
 
Vraag 6 
Stel dat zowel de opvolging op basis van een CT-scan als de opvolging op basis van een bloedafname 
allebei bewezen evenwaardige en even doeltreffende opvolgingsmethoden voor patiënten met 
darmkanker zijn, welke van deze methoden zou dan uw voorkeur genieten? (maximaal één 
antwoord mogelijk) 
 Opvolging van uw ziekte op basis van een CT-scan met toediening van contrastvloeistof via 
een infuus, ongeacht de frequentie  ga naar vraag 7 
 Opvolging van uw ziekte op basis van een bloedafname, ongeacht de frequentie  ga naar 
vraag 8 
Volgende pagina, a.u.b. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
68 
 
Vraag 7  
Waarom kiest u ervoor om zich in dat geval toch te laten opvolgen aan de hand van een CT-scan 
met contrasttoediening? (meerdere antwoorden zijn mogelijk) 
 Ik ervaar minder angst voor dit onderzoek 
 Ik vind dat dit onderzoek minder pijnlijk is 
 Ik vind dit een meer aangename, meer comfortabele methode 
 Ik heb meer vertrouwen in deze methode 
 Ik vind dat ik mij dan minder moet verplaatsen naar het ziekenhuis 
 Ik vind dat ik dan minder tijd moet doorbrengen in het ziekenhuis 
 Andere: 
……………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………… 
Vraag 8  
Waarom kiest u ervoor om zich in dat geval toch te laten opvolgen aan de hand van regelmatige 
bloedafnames? (meerdere antwoorden zijn mogelijk) 
 Ik ervaar minder angst voor dit onderzoek 
 Ik vind dat dit onderzoek minder pijnlijk is 
 Ik vind dit een meer aangename, meer comfortabele methode 
 Ik heb meer vertrouwen in deze methode 
 Ik vind dat ik mij dan minder moet verplaatsen naar het ziekenhuis 
 Ik vind dat ik dan minder tijd moet doorbrengen in het ziekenhuis 
 Andere: 
……………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………… 
 
Heeft u nog opmerkingen? Noteer deze hier:  
……………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………
………………………………………………………………………………………………………… 
 
Bedankt voor het invullen van deze vragenlijst! 
Het FOLICOLOR Lead-In onderzoeksteam 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
69 
 
 
Questionnaire 2 (French version) 
Questionnaire à remplir après 9 mois de suivi ou fin d’étude prématuré    
Ma date de naissance (pour vérification):  __ __ / __ __ / __ __ __ __   (Jour/Mois/ Année) 
Date d’aujourd’hui: __ __ / __ __ / __ __ __ __   (Jour/Mois/ Année) 
Sexe:    Masculin    Féminin   (marquer d’une croix la bonne case) 
 
EORTC QLQ-C30 – Qualité de vie 
Répondez vous-même à toutes les questions en entourant le chiffre qui correspond le mieux à votre 
situation. Il n’y a pas de “bonne” ou de “mauvaise” réponse.  Ces informations sont strictement 
confidentielles. 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
196. 
Avez-vous des difficultés à faire certains 
efforts physiques pénibles comme porter un sac 
à provisions chargé ou une valise? 
 
 
1 
2 
3 
4 
197. 
Avez-vous des difficultés à faire une longue 
promenade ?  
 
 
1 
2 
3 
4 
198. 
Avez-vous des difficultés à faire un petit 
tour dehors? 
 
 
1 
2 
3 
4 
199. 
Etes-vous obligée de rester au lit ou dans 
un fauteuil pendant la journée? 
 
 
1 
2 
3 
4 
200. 
Avez-vous besoin d’aide pour manger, vous 
habiller, faire votre toilette ou aller aux 
toilettes? 
 
 
1 
2 
3 
4 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
201. 
Avez- vous été gênée pour faire votre 
travail ou vos activités de tous les jours? 
 
 
1 
2 
3 
4 
202. 
Avez-vous été gênée dans vos activités de 
loisirs? 
 
 
1 
2 
3 
4 
203. 
Avez-vous eu le souffle court? 
 
 
1 
2 
3 
4 
204. 
Avez-vous ressenti de la douleur? 
 
 
1 
2 
3 
4 
205. 
 Avez-vous eu besoin de repos? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
70 
 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
 
Assez Beaucoup 
206. 
Avez-vous eu des difficultés pour dormir? 
 
 
1 
2 
3 
4 
207. 
Vous êtes-vous sentie faible? 
 
 
1 
2 
3 
4 
208. 
Avez-vous manqué d’appétit? 
 
 
1 
2 
3 
4 
209. 
Avez-vous eu des nausées (mal au coeur)? 
 
 
1 
2 
3 
4 
210. 
Avez-vous vomi? 
 
 
1 
2 
3 
4 
211. 
Avez-vous été constipée? 
 
 
1 
2 
3 
4 
212. 
Avez-vous eu de la diarrhée? 
 
 
1 
2 
3 
4 
213. 
Etiez-vous fatiguée? 
 
 
1 
2 
3 
4 
214. 
Des douleurs ont-elles perturbé vos 
activités quotidiennes? 
 
1 
2 
3 
4 
215. 
Avez-vous eu des difficultés à vous 
concentrer sur certaines choses par exemple 
pour lire le journal ou regarder la télévision? 
 
1 
2 
3 
4 
216. 
Vous êtes-vous sentie tendue? 
 
 
1 
2 
3 
4 
217. 
Vous êtes-vous fait du souci? 
 
 
1 
2 
3 
4 
218. 
Vous êtes-vous sentie irritable? 
 
 
1 
2 
3 
4 
219. 
Vous êtes-vous sentie déprimée? 
 
 
1 
2 
3 
4 
220. 
Avez-vous eu des difficultés pour vous 
souvenir de certaines choses? 
 
1 
2 
3 
4 
221. 
Votre état physique ou votre traitement 
médical vous ont-ils gênée dans votre vie 
familiale? 
 
1 
2 
3 
4 
222. 
Votre état physique ou votre traitement 
médical vous ont-ils gênée dans vos activités 
sociales (par exemple, sortir avec des amis, aller 
au cinéma…)? 
 
1 
2 
3 
4 
223. 
Votre état physique ou votre traitement 
médical vous ont-ils causé des problèmes 
financiers? 
 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
71 
 
 
Veuillez répondre en entourant le chiffre entre 1 et 7 qui s’applique le mieux à votre situation: 
 
224. 
Comment évalueriez-vous votre état de santé au cours de la semaine passée? 
 
1                   2                   3                   4                   5                   6                   7 
Très mauvais 
 
 
Excellent 
 
 
 
 
225. 
Comment évalueriez-vous l’ensemble de votre qualité de vie au cours de la semaine 
passée? 
 
1                   2                   3                   4                   5                   6                   7 
Très mauvaise 
 
 
Excellente 
 
 
 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
EORTC QLQ-CR29 – Qualité de vie spécifique à la maladie 
Les patients rapportent parfois les symptômes ou problèmes suivants. Pourriez-vous indiquer, 
s’il vous plaît, si, durant la semaine passée, vous avez été affecté(e) par l’un de ces symptômes 
ou problèmes. Entourez, s’il vous plaît, le chiffre qui correspond le mieux à votre situation. 
 
 
Au cours de la semaine passée: 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
226. 
Avez-vous fréquemment uriné dans la 
journée? 
 
1 
2 
3 
4 
 
227. 
Avez-vous fréquemment uriné pendant la 
nuit? 
 
1 
2 
3 
4 
 
228. 
Avez-vous eu des fuites urinaires? 
 
1 
2 
3 
4 
 
229. 
Avez-vous eu des douleurs en urinant? 
 
1 
2 
3 
4 
 
230. 
Avez-vous eu mal au ventre? 
 
1 
2 
3 
4 
 
231. 
Avez-vous ressenti des douleurs au niveau 
de la région anale? 
 
1 
2 
3 
4 
 
232. 
Vous êtes-vous senti(e) ballonné(e)? 
 
 
1 
2 
3 
4 
233. 
Avez-vous vu du sang dans vos selles? 
 
1 
2 
3 
4 
 
 
 
 
 
 
Voir page suivante S.V.P. 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
72 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
234. 
Avez-vous constaté des glaires dans vos 
selles? 
 
1 
2 
3 
4 
 
235. 
Avez-vous eu la bouche sèche? 
 
1 
2 
3 
4 
 
236. 
Avez-vous perdu des cheveux du fait de 
votre traitement? 
 
1 
2 
3 
4 
 
237. 
Les 
aliments 
avaient-ils 
un 
goût 
inhabituel ? 
 
1 
2 
3 
4 
 
238. 
Vous êtes-vous inquiété(e) de votre santé 
pour l’avenir? 
 
1 
2 
3 
4 
239. 
Vous êtes-vous inquiété(e) de votre poids? 
 
 
1 
2 
3 
4 
240. 
Vous êtes-vous senti(e) moins attirant(e) 
du fait de votre maladie ou de votre 
traitement ? 
 
1 
2 
3 
4 
241. 
Vous 
êtes-vous 
senti(e) 
moins 
femme/homme du fait de votre maladie ou de 
votre traitement ? 
 
1 
2 
3 
4 
242. 
Votre corps vous a-t-il déplu? 
 
1 
2 
3 
4 
 
243. 
Avez-vous un anus artificiel (stomie)?  
 Oui 
 Non 
 
Ne répondez aux questions 49 – 55 que SI VOUS AVEZ UN ANUS ARTIFICIEL. Dans le cas 
contraire, passez directement à la série de questions 58 - 63. 
 
 
 
 
 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
244. 
Avez-vous eu des fuites de gaz par votre 
anus artificiel (stomie)? 
 
1 
2 
3 
4 
245. 
Avez-vous eu des fuites de matières fécales 
en dehors de votre poche de stomie? 
 
1 
2 
3 
4 
246. 
La peau entourant votre anus artificiel 
(stomie) vous a-t-elle fait souffrir? 
 
1 
2 
3 
4 
247. 
Avez-vous dû souvent changer votre poche 
de stomie au cours de la journée? 
 
1 
2 
3 
4 
248. 
Avez-vous dû souvent changer votre poche 
de stomie au cours de la nuit? 
 
1 
2 
3 
4 
249. 
Vous êtes-vous senti(e) gêné(e) à cause de 
votre poche? 
 
1 
2 
3 
4 
250. 
Les soins de votre poche de stomie vous 
ont-ils posé des problèmes? 
 
1 
2 
3 
4 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
73 
 
 
Ne répondez aux questions 56 – 61 que SI VOUS N’AVEZ PAS D’ANUS ARTIFICIEL. 
 
Au cours de la semaine passée: 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
251. 
Avez-vous 
eu 
des 
fuites 
de 
gaz 
involontaires par l’anus? 
 
1 
2 
3 
4 
252. 
Avez-vous eu des fuites de matières fécales 
par l’anus? 
 
1 
2 
3 
4 
 
253. 
La peau entourant votre anus vous a-t-elle 
fait souffrir? 
 
1 
2 
3 
4 
254. 
Avez-vous dû fréquemment aller à la selle 
au cours de la journée? 
 
1 
2 
3 
4 
 
255. 
Avez-vous dû fréquemment aller à la selle 
au cours de la nuit? 
 
1 
2 
3 
4 
 
256. 
Vous êtes-vous senti(e) gêné(e) lorsque 
vous alliez à la selle? 
 
1 
2 
3 
4 
 
 
 
 
 
 
Au cours des 4 dernières semaines: 
 
Pour les HOMMES uniquement: 
 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
257. 
Dans quelle mesure vous êtes-vous 
intéressé à la sexualité? 
 
1 
2 
3 
4 
 
258. 
Avez-vous eu des difficultés à avoir 
une érection ou à rester en érection? 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
Au cours des 4 dernières semaines: 
 
Pour les FEMMES uniquement: 
 
 
 
Pas du 
tout 
Un 
peu 
Assez Beaucoup 
259. 
Dans quelle mesure vous êtes-vous 
intéressée à la sexualité? 
 
1 
2 
3 
4 
 
260. 
Avez-vous ressenti des douleurs ou 
une gêne lors des rapports sexuels? 
 
1 
2 
3 
4 
 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
 
 
Voir page suivante S.V.P. 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
74 
 
Questionnaire concernant l’expérience du patient 
 
Cher patient, 
Votre avis compte. 
Pour améliorer les soins aux patients atteints d’un cancer du côlon, nous recherchons des 
différentes méthodes de suivi. Par ce questionnaire nous voulons évaluer votre expérience avec ces 
différentes méthodes. Ce questionnaire est traité de manière anonyme. 
Merci pour votre participation. 
L’équipe de recherche de LEAD-IN FOLICOLOR Trial 
 
Question 1 
Lorsque vous repensez au scanner (avec administration d’un produit de contraste par perfusion) 
que vous avez passé, pouvez-vous indiquer avec quelle intensité vous avez ressenti les 
inconvénients suivants: 
Encerclez le nombre qui correspond le plus à votre ressenti (une seule réponse possible):  
 
 
Aucun(e) 
Léger 
(légère) 
Modéré(e) 
Fort(e) 
Très fort(e) 
 
11. Douleur lors de la pose de la 
perfusion  
1 
2 
3 
4 
5 
12. Sensation de chaleur, d’envie 
d’uriner après l’administration du 
produit de contraste 
1 
2 
3 
4 
 
5 
13. Sensation générale de malaise 
après l’administration du produit 
de contraste 
1 
2 
3 
4 
5 
14. Goût 
désagréable 
après 
l’administration du produit de 
contraste 
1 
2 
3 
4 
5 
15. Anxiété lors du scan 
1 
2 
3 
4 
 
5 
 
 
Voir page suivante S.V.P. 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
75 
 
 
 
 
Aucun(e) 
Léger 
(légère) 
Modéré(e) 
Fort(e) 
Très fort(e) 
 
16. Sensation de claustrophobie dans 
le scanner 
1 
2 
3 
4 
 
5 
17. Sentiment d’isolement, d’être seul 
lors du scan 
1 
2 
3 
4 
5 
18. Position inconfortable dans le 
scanner 
1 
2 
3 
4 
5 
19. Inconfort du fait de la durée trop 
longue du scan  
1 
2 
3 
4 
5 
20. Autre, à préciser S.V.P.: 
1 
2 
3 
4 
5 
……………………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………………………………………… 
 
 
 
 
Question 2 
Lorsque vous vous souvenez de votre expérience de la prise des deux tubes de sang 
supplémentaires pour cette étude en plus de votre test sanguin standard, pouvez-vous 
indiquer avec quelle intensité vous avez ressenti les inconvénients suivants: 
Encerclez le nombre qui correspond le plus à  votre ressenti (une seule réponse possible): 
 
 
Aucun(e) 
Léger 
(légère) 
Modéré(e) 
Fort(e) 
Très fort(e) 
 
4. Aanxiété lors de la prise de 
sang  
1 
2 
3 
4 
5 
5. Douleur lors de la prise de 
sang 
1 
2 
3 
4 
5 
6. Autre, à préciser S.V.P.: 
1 
2 
3 
4 
5 
……………………………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………………………………………… 
 
 
 
 
Voir page suivante S.V.P. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
76 
 
Question 3 
Supposons que les méthodes de suivi reprises ci-dessous soient équivalentes et tout aussi efficaces, 
laquelle choisiriez-vous? 
Cochez la case de votre choix (une seule réponse possible). 
 Suivi de votre maladie sur base d’une tomodensitométrie (CT-scan) avec administration d’un 
produit de contraste par perfusion toutes les 8 semaines (ce qui est le traitement de 
référence actuel) 
 Suivi de votre maladie sur la base d'un prélèvement sanguin toutes les 2 semaines 
Question 4 
Supposons que les méthodes de suivi reprises ci-dessous soient équivalentes et tout aussi efficaces, 
laquelle choisiriez-vous? 
Cochez la case de votre choix (une seule réponse possible). 
 Suivi de votre maladie sur base d’une tomodensitométrie (CT-scan) avec administration d’un 
produit de contraste par perfusion toutes les 8 semaines (cequi est le traitement de 
référence actuel) 
 Suivi de votre maladie sur la base d'un prélèvement sanguin toutes les 4 semaines 
 
Question 5 
Supposons que les méthodes de suivi reprises ci-dessous soient équivalentes et tout aussi efficaces, 
laquelle choisiriez-vous? 
Cochez la case de votre choix (une seule réponse possible). 
 Suivi de votre maladie sur base d’une tomodensitométrie (CT-scan) avec administration d’un 
produit de contraste par perfusion toutes les 8 semaines (cequi est le traitement de 
référence actuel) 
 Suivi de votre maladie sur la base d'un prélèvement sanguin toutes les 8 semaines 
 
Question 6 
Supposons qu'un suivi par tomodensitométrie (CT-scan) et un suivi par prélèvement sanguin soient 
deux méthodes de suivi équivalentes et que l’une soit aussi efficace que l’autre pour les patients 
atteints 
d’un 
cancer 
colorectal, 
laquelle 
préféreriez-vous?  
Cochez la case de votre choix (une seule réponse possible). 
 Suivi de votre maladie sur la base d’un CT-scan avec administration d’un produit de 
contraste par perfusion, quelle que soit la fréquence passez à la question 7 
 Suivi de votre maladie sur la base d’un prélèvement sanguin, quelle que soit la fréquence 
 passez à la question 8 
 
 
Voir page suivante S.V.P. 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
77 
 
Question 7  
Pourquoi choisissez-vous d'être suivi par tomodensitométrie (CT-scan) avec administration d’un 
produit de contraste par perfusion? Vous pouvez cocher plusieurs réponses. 
 Cette méthode me fait moins peur 
 Cette méthode est moins douloureuse 
 Je trouve cette méthode plus agréable et plus confortable 
 Cette méthode m’inspire plus confiance 
 Je devrai me rendre souvent à l'hôpital 
 Je devrai passer moins de temps à l'hôpital 
 Autre, à préciser S.V.P.: 
……………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………… 
Question 8  
Pourquoi choisissez-vous d’être suivi par prélèvements sanguins réguliers?  
Vous pouvez cocher plusieurs réponses.  
 Cette méthode me fait moins peur 
 Cette méthode est moins douloureuse 
 Je trouve cette méthode plus agréable et plus confortable 
 Cette méthode m’inspire plus confiance 
 Je devrai me rendre moins souvent à l'hôpital 
 Je devrai passer moins de temps à l'hôpital 
 Autre, à préciser S.V.P.: 
……………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………… 
 
Si vous avez des remarques, vous pouvez nous en faire part ci-dessous?  
……………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………
……………………………………………………………………………………………………………………………………………………
………………………………………………………………………………………………………… 
  
Merci d’avoir rempli ce questionnaire! 
L’équipe de recherche de LEAD-IN FOLICOLOR Trial 
 
 

Protocol Number: v.3.0 
Date: 11 August 2020 
                               
78 
 
 
RECIST guideline (version 1.1) 
 

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