ENDORISK Clinical Implementation Study
Phase: NA
Conditions: Endometrial Cancer
Sponsor: Radboud University Medical Center

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Protocol ENDORISK clinical implementation 
study (ENDORISK-I) 
 
 
 
 

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PROTOCOL TITLE ‘ENDORISK clinical implementation study’ 
 
Protocol ID 
NL86300.000.24 (before: NL86300.091.24) 
Short title 
ENDORISK-I 
Version 
4.1 
Date 
03-03-2026 
Coordinating 
investigator/project leader 
Johanna M.A. Pijnenborg, MD, PhD 
Department of Obstetrics and Gynaecology 
Radboud University Medical Center, Nijmegen 
Hanny.MA.Pijnenborg@radboudumc.nl 
 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Johanna M.A. Pijnenborg, MD, PhD 
Department of Obstetrics and Gynaecology 
Radboud University Medical Center, Nijmegen 
Hanny.MA.Pijnenborg@radboudumc.nl 
 
Dorry Boll, MD, PhD 
Department of Obstetrics and Gynaecology 
Catharina Hospital, Eindhoven 
Dorry.boll@catharinaziekenhuis.nl 
Marc Snijders, MD, PhD 
Department of Obstetrics and Gynaecology 
Canisius-Wilhelmina Hospital, Nijmegen  
 
Rahul Samlal, MD, PhD 
Department of Obstetrics and Gynaecology 
Hospital Gelderse Vallei, Ede 
 
Charlotte Lybøl, MD, PhD 
Department of Obstetrics and Gynaecology 
Streekziekenhuis Koningin Beatrix Hospital, 
Winterswijk 
 
Tijmen Bonestroo, MD, PhD 
Department of Obstetrics and Gynaecology 
Rijnstate Hospital, Arnhem 
 
Angèle Oei, MD 
Department of Obstetrics and Gynaecology 
Bernhoven hospital, Uden 
 
Kirsten Smeets, MD 
Department of Obstetrics and Gynaecology 
Slingeland Hospital, Doetichem 
 
Marieke Smink, MD 
Department of Obstetrics and Gynaecology 
Elisabeth-Tweesteden Hospital, Tilburg 
 

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Joris van Esch, MD 
Department of Obstetrics and Gynaecology 
Elkerliek Hospital, Helmond 
 
Brenda Pijlman, MD 
Department of Obstetrics and Gynaecology 
Jeroen Bosch Hospital, Den Bosch 
 
Viola Verhoef, MD, PhD 
Department of Obstetrics and Gynaecology 
Maxima Medical Center, Veldhoven 
 
Dennis van Hamont, MD, PhD 
Department of Obstetrics and Gynaecology 
Amphia, Breda 
 
Channa E. Schmeink, MD, PhD 
Department of Obstetrics and Gynaecology 
St. Anna Hospital, Geldrop 
 
Sub investigators 
 
 
Rosella Hermens, PhD 
Scientific department of IQ Health 
Radboud University Medical Center, Nijmegen 
Rosella.hermens@radboudumc.nl 
 
Nicole P.M. Ezendam, PhD 
Department of Research and Development 
Netherlands Comprehensive Cancer Organisation, 
Eindhoven 
n.ezendam@iknl.nl 
 
Nicole C.M. Visser, MD, PhD 
Department of Pathology 
Eurofins PAMM 
n.visser@pamm.nl 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
Subsidising party 
Dutch Cancer Society (KWF) [10616/2016-2] 
Independent expert 
Bertho Nieboer, MD PhD 
Department of Obstetrics and Gynecology 
Radboudumc, Nijmegen 
Bertho.Nieboer@radboudumc.nl  

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Annemiek Nap, gynaecologist 
 
 
03-03-2026 
Coordinating Investigator/Project 
leader: 
Dr. Hanny Pijnenborg, gynaecologist 
 
 
03-03-2026 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................14 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................15 
5. 
INVESTIGATIONAL PRODUCT ....................................................................................19 
5.1 
Name and description of investigational product(s) ................................................19 
5.2 
Summary of findings from non-clinical studies ........................................................19 
5.3 
Summary of findings from clinical studies ...............................................................19 
5.4 
Summary of known and potential risks and benefits ...............................................19 
5.5 
User interface for ENDORISK ................................................................................21 
6. 
METHODS ....................................................................................................................23 
6.1 
Study parameters/endpoints ...................................................................................23 
6.1.1 
Main study parameters/endpoints....................................................................23 
6.1.2 
Secondary study parameters/endpoints ..........................................................23 
6.1.3 
Other study parameters ...................................................................................24 
6.2 
Randomisation, blinding and treatment allocation ..................................................25 
6.3 
Study procedures ...................................................................................................25 
6.4 
Withdrawal of individual subjects ............................................................................30 
6.5 
Follow-up of subjects withdrawn from treatment .....................................................31 
6.6 
Premature termination of the study .........................................................................31 
7. 
SAFETY REPORTING ..................................................................................................31 
7.1 
Temporary halt for reasons of subject safety ..........................................................31 
7.2 
AEs, SAEs and Device Deficiencies .......................................................................31 
7.2.1 
Adverse events (AEs) (IVDR 2017/746, art 2.60) ............................................31 
7.2.2 
Serious adverse events (SAEs) (IVDR 2017/746, art 2.61) .............................31 
7.2.3 
Device deficiency (IVDR 2017/746, art 2.62) ...................................................32 
7.2.4 
Reportable events (IVDR, art 76, sub 2) ..........................................................32 
7.3 
Follow-up of adverse events ...................................................................................33 
7.4 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................33 
8. 
STATISTICAL ANALYSIS .............................................................................................33 
8.1 
Primary study parameter(s) ....................................................................................33 
8.2 
Secondary study parameter(s) ...............................................................................33 
9. 
ETHICAL CONSIDERATIONS ......................................................................................35 
9.1 
Regulation statement .............................................................................................35 
9.2 
Recruitment and consent........................................................................................35 
9.3 
Benefits and risks assessment, group relatedness .................................................35 
9.4 
Compensation for injury .........................................................................................35 

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9.5 
Incentives (if applicable) .........................................................................................36 
10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................37 
10.1 
Handling and storage of data and documents ........................................................37 
10.2 
Monitoring and Quality Assurance ..........................................................................38 
10.3 
Amendments ..........................................................................................................38 
10.4 
Annual progress report ...........................................................................................38 
10.5 
Temporary halt and (prematurely) end of study report ............................................38 
10.6 
Public disclosure and publication policy ..................................................................39 
11. STRUCTURED RISK ANALYSIS ..................................................................................39 
11.1 
Potential issues of concern .....................................................................................39 
11.2 
Synthesis ...............................................................................................................40 
12. REFERENCES ..............................................................................................................41 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
AUC 
Area under the curve 
CV 
Curriculum Vitae 
DSS 
Disease Specific Survival 
EC 
Endometrial cancer 
ER 
Estrogen receptor 
ESMO 
European Society of Medical Oncology 
FIGO 
International Federation of Gynaecologic Oncology 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
GOCN 
Gynaecologisch oncologisch centrum Nijmegen 
GOCZ 
Gynaecologisch oncologisch centrum Zuid 
HRQoL 
Health related quality of life 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IHC 
Immunohistochemical 
LNM 
Lymph node metastases 
LVSI 
Lymphovascular space invasion 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
NEEC 
Non-endometrioid endometrial cancer 
NCCO 
Netherlands Comprehensive Cancer Organization 
NFU 
Dutch Federation of University Medical Centers  
OS 
Overall survival 
PPV 
Positive predictive value 
PR 
Progesteron receptor 
RFS 
Recurrence free survival 
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
TCGA 
The Cancer Genome Atlas 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 

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WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
Rationale: Preoperative identification of patients at risk for lymph node metastasis (LNM) is 
challenging in endometrial cancer (EC). Therefore, a Bayesian network model called 
ENDORISK was developed and validated in three external cohorts to improve preoperative 
risk stratification. The next step is to implement and evaluate whether use of the model 
improves daily clinical practice. 
Objective: The ENDORISK implementation (ENDORISK-I) study aims to prospectively 
evaluate whether implementation of ENDORISK in daily clinical practice improves preoperative 
risk stratification.  
Study design: A stepped wedge non inferiority study in which two oncology regions will 
consecutively start implementation of ENDORISK with one year interval. The ENDORISK 
model will be filled in and used in preoperative treatment counselling. Results will be compared 
to current standard clinical care which is prospectively evaluated in both regions since March 
2022 in the ‘evaluation of care in endometrial cancer’ study (2021-7400).  
Study population: all consecutive patients recently diagnosed with early stage EC who are 
eligible for surgical treatment, who understand Dutch and/or English and are able to fill in a 
digital or paper questionnaire can be included.  
Main study parameters/endpoints: The ENDORISK implementation (ENDORISK-I) study 
aims to prospectively evaluate implementation of ENDORISK in daily clinical practice by 
investigating: 
• 
The proportion of identified LNM in patients with lymph node staging (positive predictive 
value (PPV)) compared to standard care 
• 
Proportion of patients who decide to have lymph node status assessed in ENDORISK 
care compared to standard care 
• 
Preoperative information provision for patients and shared-decision making with the 
use of ENDORISK compared to standard care 
• 
Patients’ disease- specific-, overall survival, and health-related quality of life compared 
to standard care 
• 
Patients’ and doctors’ use of and experiences with the ENDORISK-model 
• 
Impact of ENDORISK on regional care costs 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: In the ENDORISK-I study, eligible patients will be asked by their treating 
gynaecologist or nurse specialist for participation in this study. Patients are asked to watch a 
short information video and given an optional folder with additional information about 
endometrial cancer and ENDORISK. After inclusion, their treating gynaecologist will fill in the 
ENDORISK model and then use this information for shared-decision making with their patient 
to determine whether their lymph node status needs to be surgically assessed:  
- 
Standard care decisions for type of surgical treatment are based on patient factors (e.g. 
age, comorbidity, diagnostic tests), For example, if a patient has a high CA125 level, 
additional imaging is done in standard care to assess tumor extension beyond the uterus.  
- 
Within the ENDORISK-I study, the results from these diagnostic tests are entered in the 
ENDORISK model, which then calculates a patients’ personal risk of lymph node 
metastases (LNM). ENDORISK care decisions for type of surgical treatment are based on 
standard care in addition to the calculated result from ENDORISK. So, treatment decisions 
should not be made based on the calculations by ENDORISK alone, but in collaboration 

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with the patient and always based on all available patient information by a specialized 
treating clinician. 
 
Currently used risk stratification systems recommended in endometrial cancer guidelines are 
based on tumor grade and have area under the curves (AUC) of 0.69-0.70 for predicting LNM 
[1]. ENDORISK has AUCs of around 0.82 [2-4]. The ENDORISK model was trained on patient 
data from 763 patients from different hospitals in Europe, including several hospitals from the 
Netherlands that will be participating in the ENDORISK-I study [3]. This includes data from a 
variety of hospital laboratories and clinical care paths. External validation was performed on 
three cohorts with similar patient characteristics as the prospective study population [2-4]. 
Patients are informed that although accuracy of ENDORISK is superior, inaccuracies may still 
occur with use of  ENDORISK.  
 
Regardless of study participation, patients with grade 3 EC will all be recommended to be send 
for referral to tertiary hospitals for counseling, as counseling of these patients is already more 
complicated due to other factors and tertiary hospitals have more experience with this.  
 
No additional hospital visits are needed while participating in this study: ENDORISK care 
counselling will be incorporated in routine care. Treatment options are the same as in standard 
care (hysterectomy and bilateral salpingo-oophorectomy with or without determining lymph 
node status by lymphadenectomy or sentinel node procedure). 
 
In addition to the extra information participants receive from ENDORISK during preoperative 
counselling, participants are asked to fill out two questionnaires: one within three months after 
primary treatment and the second one a year after primary treatment. This will take 
approximately 15-30 minutes per questionnaire. 
 
We hypothesize that the use of ENDORISK will mainly add to counselling information and 
quality and risk of suboptimal treatment is expected to be low. 
 

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1. INTRODUCTION AND RATIONALE 
In the Netherlands, endometrial cancer (EC) care is organized within clinical oncology 
networks. Collaborating hospitals discuss all treatment plans of gynaecologic oncology 
patients at regional tumour boards. Standard care for primary surgical treatment of EC consists 
of hysterectomy with bilateral salpingo-oophorectomy which can be performed in all hospitals 
in the Netherlands.  
Treatment decisions are based on the preoperative tumour grade, as outlined in clinical 
guidelines [5]. For women with grade 1-2 tumours (low-risk), the standard approach consists 
of a hysterectomy with bilateral salpingo-oophorectomy, without additional imaging unless 
specific indications are present (Figure 1). Imaging is only performed when clinical suspicion 
of advanced disease arises or when CA125 levels are elevated, as practiced in the GOCN 
(Nijmegen) and GOCZ (Brabant) regions. If imaging does not reveal abnormalities, patients 
continue with the standard surgical treatment.  
 
In contrast, for women with grade 3 tumours (high-risk), which includes high-grade 
endometrioid and non-endometrioid EC (NEEC), tertiary care referral is recommended to 
assess the need for lymph node dissection as part of staging and to evaluate potential adjuvant 
therapies (Figure 1). Treatment decisions for these women are tailored based on their fitness 
and comorbidities, and if a patient is deemed unfit for additional therapy, lymph node removal 
may be reconsidered. 
 
Currently, only high-risk women (grade 3 EC) are informed about the likelihood of lymph node 
metastases [6], while women with low-risk tumours (grades 1-2) do not receive such 
information as part of standard care. Women with advanced-stage EC or those requiring 
surgical lymph node staging are referred to gynaecologic oncology centres for further 
management.  
 
This approach is in line with the current Dutch guidelines and is supported by large meta-
analyses, which found no survival benefit from routine lymph node dissection in women with 
Figure 1: Standard care for primary surgical treatment of endometrial 
cancer. 

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clinical early-stage, low-risk endometrial carcinoma [7]. Internationally, it is recommended that 
sentinel lymph node biopsy may be considered for staging purposes in patients with low-risk 
or intermediate-risk disease, but it can be omitted in cases without myometrial invasion. 
Systematic lymphadenectomy is not recommended in this group [8]. 
 
Lymph node metastasis (LNM) represents one of the strongest prognostic factors in EC, and 
an important indicator for adjuvant therapy [9]. Pelvic and para-aortic lymph node dissection 
(LND) or a sentinel node procedure (SNP) can be performed as part of the primary surgical 
treatment, as histology is still the golden standard for assessment of nodal status [6, 10]. The 
clinical relevance of adjuvant therapy in LNM is underlined by five-year survival rates that are 
approximately 81% in adequately treated patients, compared to 50-60% when untreated and 
even 15% once further metastasized [11-19]. Most EC patients (85%) have no LNM, and LND 
is associated with risk of lymphedema [20-22]. While this risk is much lower in the SNP, the 
SNP fails in up to 20% of patients, for whom side-specific LND could still be needed [23]. 
Therefore, selective lymph node staging requires balancing between surgical-related 
comorbidity on one hand, and the clinical benefit of nodal status information for adjuvant 
therapy on the other hand [6].  
 
Several prediction models in EC were developed combining preoperative histology, serum 
tumour markers and imaging results [24-31]. However, uptake of these models in clinical 
practice is slow and could be addressed to several challenges. Only few prediction models rely 
on preoperative data only allowing pretreatment decisions [30, 32]. So far, none of them have 
been implemented in to clinical practice.  
 
Hormone receptor expression i.e. estrogen receptor (ER) and progesterone receptor (PR) 
have consistently shown to be correlated with LNM and belong to the most validated molecular 
markers in EC [9, 33-36]. Abnormal P53 expression is identified by The Cancer Genome Atlas 
(TCGA) as a biologically distinct molecular subgroup with the poorest prognosis and 
associated with high risk of LNM [37-40]. Talhouk et al. demonstrated that abnormal P53 
expression was present in 89% of the European Society of Medical Oncology (ESMO) high-
risk group but consisted of only 25% of advanced stage (FIGO III-IV) cases, underlining the 
need of additional prognosticators [39]. Molecular profiling may guide future adjuvant therapy 
but does not help surgeons to decide when and how to stage EC [41, 42]. L1CAM has 
repeatedly shown to identify patients with poor outcome and LNM in EC and could further 
stratify EC patients with no specific molecular risk profile [43-45]. Serum cancer antigen 125 
(CA125) has repeatedly been shown to be an important prognostic factor for LNM and 
advanced stage in both low-, and high-grade EC [46-48]. Integrated risk classification systems 
rather than either clinical or molecular seem to result in the best solution [49].  
The introduction of the SNP has reduced surgical-related morbidity compared to LND. 
However, this requires additional surgical expertise and 20-25% of cases fail bilateral mapping 
thus still needing (lateral) LND [50]. 
 

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Within the European Network for Individualized Treatment of Endometrial Carcinoma 
(ENITEC) network a powerful Bayesian network (ENDORISK) predicting LNM and outcome 
was constructed by integrating preoperative clinical, histopathological, molecular and serum 
markers of EC patients [3]. For the prediction of LNM, external validation has shown a good 
diagnostic performance of this ENDORISK model (AUC 0.818) when compared to current risk 
classification (AUC 0.646) [2, 4]. These easily accessible biomarkers were shown to be 
strongly correlated with high-grade, NEEC, LVSI, myometrial- and cervical stromal invasion 
[51]. Even though prediction models have been identified by the National Cancer Institute as 
an area of ‘extraordinary opportunity’, actual prospective implementation studies remain very 
scarce [52]. This kind of evaluation is fundamental to investigate clinical utility, including the 
proper presentation of clinical data in an understandable format, whether it influences doctors’ 
and patients’ decisions, is cost effective, and it actually improves outcome. 
Moreover, as patients with EC are characterized by frailty and comorbidity, surgical lymph 
node staging remains relevant only if the patient is fit and willing to receive adjuvant therapy. 
 
Based on earlier studies, ENDORISK seems better at preoperative risk stratification of patients 
at risk of LNM than standard care. The ENDORISK model will be applied exclusively to the 
low-risk group to calculate the individual probability of lymph node metastases. The decision 
regarding lymph node surgery will then be made through a shared decision-making process, 
involving both the patient and the treating physician.  
 
We hypothesize that using ENDORISK together with all available patient information in clinical 
practice (ENDORISK care) will be at least similar to standard care in stratifying patients at risk 
of LNM, which would result in a similar positive predictive value (PPV) compared to standard 
care (non-inferiority). However, the type of patients stratified could be more optimal, as we 
hypothesize that the use of ENDORISK could contribute to increased information provision 
and therefore better shared-decision making compared to standard care. This could in turn 
improve health related quality of life (HRQoL).  
 
 

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2. OBJECTIVES 
Main outcomes: 
• 
Proportion of patients who decide to have lymph node status assessed in ENDORISK 
care compared to standard care; 
• 
Proportion of patients with LNM within patients undergoing lymph node staging (the 
positive predictive value, PPV) in ENDORISK care, compared with standard care; 
• 
Preoperative information provision for patients and shared-decision making with the 
use of ENDORISK compared to standard care. 
 
Secondary outcomes: 
• 
Patients’ 5-year disease- specific-, overall survival (DSS, OS), and health-related 
quality of life (HRQoL) compared to standard care; 
• 
Experiences of patients and clinicians with the use of ENDORISK in preoperative 
counselling and shared-decision making on treatment; 
• 
Impact of ENDORISK on regional care costs. 
 
3. STUDY DESIGN 
 
We will perform a prospective stepped wedge non-inferiority study to evaluate implementation 
of the ENDORISK model in clinical endometrial care practice. The ENDORISK model will be 
sequentially implemented in two oncological regional networks (1 & 2). For the evaluation,  
‘ENDORISK care’ will be compared to ‘standard care’ for which data has been collected in a 
previous study (evaluation of care in endometrial cancer study, 2021-7400), within the same 
two oncological networks (Figure 2).  
 
 
Figure 2: Stepped wedge study design 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
All patients recently diagnosed with early stage EC in the participating hospitals of the two 
oncological networks in the Netherlands will be requested by an independent nurse (specialist) 
to participate in the prospective study prior to the surgical treatment and informed consent will 
be obtained. The clinical oncology networks involved in the study can be seen as independent 
networks: gynecologic oncologic center Nijmegen (GOCN), with hospitals referring to Radboud 
University Medical Center Nijmegen, and gynecologic oncologic center South (GOCZ), with 
hospitals referring to Catharina hospital in Eindhoven. 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a participant must meet all of the following 
criteria: 
1. Diagnosed with early stage endometrial carcinoma (every grade and stage permitted) 
2. Eligible for primary surgical treatment (neo-adjuvant therapy is permitted) 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 
1. Unable to give informed consent 
2. No understanding of Dutch or English language 
3. Rare types of endometrial cancer, such as endometrial stroma cell sarcoma  
4.4 Sample size calculation 
Sample size calculation is based on the prevalence of LNM within patients undergoing lymph 
node staging (PPV), comparing standard care with ENDORISK care. Switching from standard 
care to ENDORISK care not only changes the probability of detection of LNM in patients 
referred to lymph node staging but might impact the patients referred to oncology centers. 
Therefore, we will discuss first the number of patients and corresponding LNM prevalence in 
standard care and then for the ENDORISK care. 
 
Clinical practice standard care GOCN and GOCZ 
Epidemiologic data on the two oncological networks (GOCN and GOCZ) were obtained from 
the Netherlands Comprehensive Cancer Organization (NCCO) to determine the potential 
inclusion in the participating oncology regions. 
 
Number of patients 
As reported by the NCCO, between 2016-2018 (3 consecutive years), a total of 1,472 patients 
with EC were treated in the GOCN and GOCZ region. Of these 1,472 patients: 368 patients 
were diagnosed with grade 3 EC (25% of total population). Of these 368 patients with grade 3 

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EC, 180 (48.9%) patients underwent lymph node staging, comparable in both regions (47% 
versus 51%). This was verified and comparable with data of the NCCO of 2021-2022 for these 
two regions. As these 1472 patients are the total over 2 regions in 3 years, we conclude that 
there are 245 EC patients per year and per network.  
Thus: 30 patients underwent lymph node staging per oncology network, per year in 
standard care clinical practice. 
 
Probability of detection 
42 of these 180 patients that underwent lymph node staging had lymph node metastases 
(LNM). Thus: detection probability (PPV) is 23% in standard care. 
Side note: We consider that two networks have similar performance. Based on the data of the 
NCCO there was no difference in the clinical practice of lymph node directed surgery between 
2016-2018 in the two oncological networks. The risk of LNM metastasis in grade 3 EC in the 
NCCO is in line with previously reported data of 17-21%, irrespective of histological subtype 
[20, 46, 53, 54]. Lymph node directed surgery seems to be omitted in fewer patients in later 
reports that were requested from the NCCO from 2021-2022 (not yet public data). We are 
unsure what caused this, but hypothesize this could be caused by increased use of the SNP 
which is associated with less morbidity than LND. Therefore, instead of 50%, lymph node 
staging might occur in 50-75% of patients. This would mean standard care detection of LNM 
would be 245x25%x (50-75%) = 30 to 46 patients per region-year in standard care, with 23% 
of those detected with LNM (7-11 patients in total). 
 
ENDORISK care 
The inflow of 245 patients diagnosed with EC, per year, per oncology network will stay the 
same. When ENDORISK is implemented, patients are counseled for lymph node staging with 
additional support of the ENDORISK-model. Similar to standard care, part of the patients will 
not undergo lymph node staging: we assume the group of omitted patients will be smaller in 
the coming years due to further introduction of the SNP in clinical standard care.  
 
Number of patients 
Based on estimated prevalence in the ENDORISK classes, 33% of the patients have a risk of 
LNM as calculated by ENDORISK of ≥10% based on external validation of the ENDORISK 
model [3]. We assume 75% will undergo lymph node staging, as we expect the decrease in 
omission of staging described in standard care to continue, so: 75% x 33% x 245 patients per 
year per region will be included in the ENDORISK care periods. Thus: 60 patients per year 
per oncology network will undergo lymph node directed surgery if a risk cut-off 
calculated by ENDORISK of 10% is recommended. 
 
Probability of detection 
External validations of the ENDORISK model showed PPVs between 24.7% and 35.7% at a 
risk cut-off of 10%[2-4]. The mean detection probability (PPV) of all external validations 
at a risk cut-off of 10% is approximately 30% and was therefore used to calculate the 

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sample size needed. 30% of 60 patients are detected with LNM would result in 18 patients in 
total. 
Non-inferiority 
The non-inferiority margin is set at 7% based on the following two arguments:  
 
First, a non-inferiority margin of 7% (together with an assumed 30% detection in ENDORISK) 
means that the point estimate for PPV of ENDORISK care will be similar or better to that of 
standard care (23%). 
 
Second, with this non-inferiority margin at least as many patients with will be detected by 
ENDORISK as under standard care. To see this: in standard care per region per period (year):  
(i) 
There are 245 EC patients of which 25% have grade 3 and between 50% to 75% 
of those have a resection, so 245 x 25% x (50 to 75)% =30 to 46 patients.  
(ii) 
23% of those are detected with LNM. In conclusion, (23% of 30 to 46, i.e.) 7 to 11 
patients in total are detected with LNM. 
In ENDORISK care: 
(i) 
Of the 245 EC patients, 33% are expected to be at risk of 10% or more and it is 
expected that more of those will be willing to have a resection, therefore taking into 
account 75%. Then 245 x 33% x 75% = 60 patients per region-year in ENDORISK 
care. 
(ii) 
With a non-inferiority margin of 7 percent points, ENDORISK would detect (30-
7)%=23%, so 23% x 60 patients = 14 patients with LNM.  
Thus, with a non-inferiority margin of 7%, ENDORISK detects at least as much patients as in 
standard care.  
 
To estimate power, the number of detected LNM per region per year were generated from a 
binomial probability with the region detection probability and the number of patients having 
lymph node directed surgery. Data were analyzed using a generalized linear mixed model with 
identity link, normally distributed random effect, binomial error distribution, and a fixed effect 
for treatment and fixed effects for region. As no trend in time was observed in the risk of LNM 
metastasis in grade 3 EC, we will assume that there is no time trend.  
 
Based on power simulations and the design with inclusion of the three retrospective 
measurements from the ‘evaluation of care’ study (Table 1), we estimated that power was > 
80% (at α = 0.05). The years 2020 and 2021 will be excluded due to COVID-19 impacting 
healthcare during those years. The numbers in yellow marking could differ based on increased 
lymph node staging in standard care to up to 46 patients if 75% are staged instead of 50%. 
This would actually improve power.  
 Table 1 
Measurement: 
Cluster 
: 
-3  
-2  
-1 
0 
1 (start 
ENDORISK-I 
region 1) 
2 (start 
ENDORISK-I 
region 2) 
Regio 1 
N=30, 
P=23% 
N=30, 
P=23 
N=30, 
P=23% 
N=30, 
P=23% 
N=60 
P=30% 
N=60 
P=30% 
Regio 2 
N=30, 
P=23% 
N=30, 
P=23% 
N=30, 
P=23% 
N=30, 
P=23% 
N=30, 
P=23% 
N=60 
P=30% 

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Conclusion 
Assuming an ENDORISK cut-off of 10%, the aforementioned stepped-wedge design will be  
sufficient to obtain power > 80%, by including: 180 patients retrospectively, 210 patients 
prospectively who underwent lymph node assessment, with a non-inferiority margin of 
7%. To also research the other study endpoints, all patients with EC meeting the inclusion 
criteria will be included. Therefore, 245x 2 years (region 1) + 245 x 1 years (region 2) = up 
to 735 patients could be included in total. If the sample size is not achieved within the 
expected two year inclusion period, this period could be extended for both regions. 
 
 
 

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5. INVESTIGATIONAL PRODUCT  
5.1 Name and description of investigational product(s)  
The ENDORISK model will be used in a preoperative setting to determine a patients' personal 
risk of LNM. This model is a Bayesian network that assesses the risk of LNM and predicts 
survival. Within this study, the model will only be used to assess the risk of LNM. The model 
will be used as an information tool to provide additional information about a patients' 
personalized risk of LNM within a larger context of patient characteristics. Treatment decisions 
should not be made based on the calculations by ENDORISK alone but always based on all 
available patient information by a specialized treating clinician. As ENDORISK can be used to 
stratify a patients risk of LNM, and thus to stratify disease stage and determine treatment, it is 
classified as a class C in vitro device according to the European In Vitro Device Regulation 
(IVDR, Regulation (EU) 2017/746). 
5.2 Summary of findings from non-clinical studies 
The ENDORISK model has previously been internally validated and thrice externally validated 
with consistent area under the curve’s (AUC) of >0.80 and recently in a fourth external cohort 
of patients that only underwent sentinel node procedure which resulted in a comparable AUC 
(to be published) [2-4]. The benefit of a Bayesian network is that not all variables need to be 
entered as evidence into the model for a reliable calculation.  
 
Within the European Network for Individualized Treatment of Endometrial Carcinoma 
(ENITEC) network a powerful Bayesian network (ENDORISK) predicting LNM and outcome 
was constructed by integrating preoperative clinical, histopathological, molecular and serum 
markers of EC patients [17]. For the prediction of LNM, external validation has shown a good 
diagnostic performance of this ENDORISK model (AUC 0.818) when compared to current risk 
classification (AUC 0.646) [2, 4]. These easily accessible biomarkers were shown to be 
strongly correlated with high-grade, NEEC, LVSI, myometrial- and cervical stromal invasion 
[51]. Even though prediction models have been identified by the National Cancer Institute as 
an area of ‘extraordinary opportunity’, actual prospective implementation studies remain very 
scarce [52]. Prospective evaluation is fundamental to investigate clinical utility, including the 
proper presentation of clinical data in an understandable format, whether it influences doctors’ 
and patients’ decisions, is cost effective, and it actually improves outcome. 
5.3 Summary of findings from clinical studies 
Not applicable. 
5.4 Summary of known and potential risks and benefits 
ENDORISK should not be used on its own but as an additional information tool besides other 
known patient characteristics. Oncological safety is part of preoperative counselling including 
the context of the individual patient, age, comorbidity and willingness to accept side-effects of 
primary and adjuvant therapy. In the Netherlands, the risk of LNM in grade 1-2 EC (8-10%) is 

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currently not discussed, while representing 50% of LNM cases, whereas surgical staging is 
omitted in 50% of NEEC cases. This study does not impose specific treatment plans on 
patients but seeks to investigate the added value of using the ENDORISK model within the 
entire process of preoperative risk stratification by a specialized clinician in shared-decision 
making with their patient. 
 
A 10% threshold will be used as a guiding criterion, based on insights from focus groups with 
clinicians and patients. Additionally, the patient’s comorbidities and overall fitness will be 
considered, particularly regarding the potential implications of additional chemotherapy or 
radiotherapy. Use of the model could lead to more low-grade patients feeling confident in 
omitting this assessment based on the ENDORISK result.  
 
Based on calculations from various validation cohorts, it is estimated that 17% of all low-risk 
patients will have a probability of >10% for lymph node metastases. Given that the low-risk 
group represents 75% of all patients with endometrial cancer, this corresponds to 12.8% of the 
total patient population. 
In standard care, the negative predictive value (NPV) for patients with grade 1–2 endometrial 
carcinoma is 8.5%. This figure is based on data from earlier studies in which all patients 
routinely underwent lymph node dissection (n = 36/423) [9]. The NPV of the ENDORISK model 
at a threshold value of 10% is currently between 3 and 6.9% and requires further evaluation 
[to be published]. 
 
Women in the high-risk group will continue to follow standard care pathways, including referral 
to tertiary care and consideration of lymph node surgery. While relevant clinical variables will 
still be collected for the ENDORISK model in this group, the model’s calculations will not be 
used in clinical decision-making. As in standard care, comorbidities, overall fitness and 
personal preferences will be taken into account when determining whether to proceed with 
lymph node surgery. In these cases, the ENDORISK result could aid these patients in making 
an even more informed decision, and clinicians will decide on an individual patient level 
Figure 3: ENDORISK care for primary surgical treatment of endometrial cancer.

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whether the patient needs treatment in a tertiary centre or their own local hospital, similar to 
standard care. 
5.5 User interface for ENDORISK 
A user interface (UI) for ENDORISK was developed as described in the paper by Kleinau et 
al. (Figure 4 and 5) [56]. 
 
After initial development and publication, the UI was further updated and tested amongst seven 
gynecologists with experience in endometrial cancer care: four from the Netherlands, one from 
Germany and two from Italy using a semi-structured test guide. The UI was iteratively improved 
for both usability and explainability. Tests were recorded and documented to allow for direct 
implementation of changes after each test.  
 
Usability improvements included an enhanced tutorial for novel users, presets for common 
tasks and complete translations in English, Dutch and German. Explanations of model 
predictions were improved by adding new detail views of individual Bayesian Network nodes, 
replacing color-coded percentages with more accurate bar charts and adding support for 
minimizing likelihoods in addition to maximization. 
Users enter evidence items locally via the UI. For each model use, a unique study identification 
number is generated. The evidence items are then sent to the backend for calculations—
without transmitting any user-identifiable information. Simultaneously, the input and output, 
along with the study ID, are automatically exported to a PDF file that must be saved in the 
patient record. The UI logs the study ID, submitted input, and generated results, allowing 
traceability of the input data. No personal patient information is stored or retained in the UI. 
These measures safeguard user privacy and data confidentiality. 
Users are able to request assistance with the UI by clicking on a ‘help’ button. Users are then 
able to send an email to the research-team and are given the option to automatically include 
all information added up to that point in to the UI. This ensures the research team can provide 
proper help and feedback. A research phone number is also available to clinicians in the study 
for more immediate assistance during working hours. 
 
The UI does keep track of what buttons people click on, without cookies and without 
geographical data besides the country and without tracking individual evidence items. These 
measures ensure we will be able to track if users click on the correct buttons (e.g. ‘add 
evidence’, ‘download’, ‘compare’) and we will be able to see which types of explanations they 
use most without logging sensitive information. 
 

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The UI can be accessed through the website https://endorisk.eu and then clicking on the ‘open 
model’ button (Figure 5). The UI is hosted on Github and the backend and the database on 
Heroku. 
 
 
Figure 5: ENDORISK website. 
Figure 4: ENDORISK User Interface. 

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6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 
Main study parameters/endpoints 
• 
Proportion of patients who decide to have lymph node status assessed in 
ENDORISK care compared to standard care 
• 
Proportion of patients with lymph node status assessed and LNM (positive 
predictive value (PPV)) in ENDORISK care compared to standard care 
• 
Information provision score 
o Questionnaire: EORTC QLQ-INFO25 [57], with additional questions 
specific to ENDORISK use, within 12 weeks after primary surgery 
• 
Shared-decision making score 
o Questionnaire: SDM-Q-9 [58], with additional questions specific to 
ENDORISK use, within 12 weeks after primary surgery 
6.1.2 
Secondary study parameters/endpoints  
• 
5-year disease specific survival (DSS): proportion of patients alive 5 years post-
surgery (or died due to endometrial cancer) 
• 
5-year overall survival (OS): proportion of patients alive 5 years post-surgery (or 
died due to any cause) 
• 
Health-related quality of life (HRQoL) 
o Questionnaire: EORTC QLQ-C30 [59] within 12 weeks and 12 months 
after primary surgery  
• 
Treatment-related morbidity 
o Questionnaire: EORTC QLQ-EN24 [60] within 12 weeks and 12 months 
after primary surgery  
o Questionnaire lymphoedema: EORTC IL76 [61] and LYMQOL [62], 12 
months after primary surgery 
• 
Clinicians’ experiences with ENDORISK care 
o Questionnaire at baseline, and 9 months and 18 months after start of the 
inclusion period in their hospital 
o Additional in depth interviews with sample of participating clinicians to 
evaluate user experiences, within 1 year after start of the inclusion period 
in their hospital 
• 
Impact of ENDORISK on regional care costs 

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6.1.3 
Other study parameters 
• 
Health Literacy questionnaire (included with first questionnaires within 12 weeks 
after surgery)  
• 
Charlson-index (included with first questionnaires within 12 weeks after surgery 
as reported by patient and as reported by clinician/researcher from patient 
records) 
 
Applied clinical care:  
Data collection from the NCCO and patient records 
• 
Patients characteristics:  
o Age (at diagnosis) 
o BMI, length and weight 
o Social status  
▪ 
Partner yes/no 
▪ 
Work  
• 
Diagnostics (if performed):  
o Preoperative histology of tumor: grade (1,2 or 3), histology type and biomarker 
staining performed on tissue  
o Preoperative performed blood samples: cancer antigen 125, hemoglobin, 
platelets  
o Imaging: transvaginal ultrasound (TVU), CT, MRI or PET-CT  
▪ 
Lymph nodes suspect for LNM visible on imaging  yes/no 
▪ 
Other suspected metastases on imaging 
▪ 
If TVU of MRI performed: suspected invasion of myometrium 
o PAP-smear: yes/no, KOPAC-B 
▪ 
Endometrial carcinoma cells in PAP-smear yes/no 
• 
Treatment:  
o Type of surgery 
▪ 
Laparotomic surgery or laparoscopic surgery (incl. Robot surgery) 
o Lymphadenectomy yes/no  
o Sentinel lymph node dissection yes/no 
o Additional surgical staging  
o Deviation from guideline recommendations (e.g. :due to comorbidity, patient 
preferences) 
• 
Pathology  

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o Sentinel 
lymph 
node 
positive/negative 
and/or 
lymphadenectomy 
positive/negative 
▪ 
Total number of removed lymph nodes 
o Myometrial invasion (MI) yes/no 
o Lymph vascular space invasion (LVSI) yes (focal or substantial)/no 
o International Federation of Gynecology and Obstetrics (FIGO) stage 
• 
Adjuvant treatment 
o External 
beam 
radiotherapy 
(EBRT), 
vaginal 
brachytherapy 
(VBT), 
chemotherapy (CT), combination chemo- & radiotherapy (CRT) 
o Deviation from guideline recommendations (e.g. :due to comorbidity, patient 
preferences) 
• 
Follow-up at 1 to 5 years after surgery:  
o Outcome: date of last follow-up visit at gynecologist, date of death, cause of 
death (EC related of unrelated)  
o Recurrence: date of recurrence, location  
 
• 
Referral to oncology centre yes/no 
6.2 Randomisation, blinding and treatment allocation 
Not applicable, the starting region is chosen based on which region first reaches enough 
inclusions in the prior ‘evaluation of care’ study to switch to ‘ENDORISK-I’. 
 
6.3 Study procedures 
Training of clinicians 
Prior to start of the inclusion period, clinicians of participating hospitals will be trained in use 
and counseling with the ENDORISK model according to recommendations from prior 
qualitative research (focus groups) which also included clinicians from the current study 
regions (to be published). Researchers will perform site visits to give a demonstration to 
participating clinicians with an overview of the study, the ENDORISK model and a 
demonstration of how to accurately use and counsel with the model. Clinicians will then receive 
an e-learning including a written explanation of the model, a demonstration video of the user 
interface and several test patients' cases which clinicians can use to become familiar with the 
user interface of ENDORISK and to train counseling according to additionally provided use 
and counseling guidelines. These are afterwards discussed with the researcher. Where 
necessary, follow up visits will be done by researchers for additional individual training.  
 

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Screening and inclusion of participants 
Patients will be screened and asked for inclusion after initial diagnosis with endometrial cancer 
(Figure 6). In Radboud UMC this will be done by an independent researcher/research nurse. 
The procedure will be included in the coordination with the participating centers. All patients 
that meet the inclusion criteria are given the study information including the informed consent 
form and are requested to view a counseling video after their diagnosis (consultation). The 
video discusses endometrial cancer and the use of ENDORISK and will aid in providing uniform 
counseling information to patients across all participating hospitals. In previous qualitative 
research in which 18 patients with endometrial cancer were interviewed (to be published), 
patients recommended giving study participants a choice of extent of information provision. 
Therefore, prospective participants are also given a  patient information folder with information 
of the counseling video in writing and including more extensive information about endometrial 
cancer and the ENDORISK model.  
 
Interested patients are given the chance to ask questions regarding the study prior to the next 
consultation, which is usually one to two weeks after their diagnosis consultation. During the 
consultation in which treatment is discussed, patients interested in participating return the 
informed consent form. Patients with grade 3 EC will all be recommended to be send for 
referral to tertiary hospitals (similar to standard care) within the ENDORISK-I study irrespective 
of their calculated risk of LNM by ENDORISK, as counseling of these patients is more 
complicated due to other factors and tertiary hospitals have more experience with this. 
Referring hospitals are responsible for obtaining informed consent for the study prior to 
consultation in the tertiary hospital. 
 
Counseling of participants with the ENDORISK model 
Previous qualitative research (to be published) showed that patients vary in the level of 
information they prefer for shared-decision making on treatment. Therefore, participants are 
asked whether they want to know their personalized risk of LNM as calculated by the 
ENDORISK model which will then be used in standard counseling information to determine 
their preferred treatment. Participants may also choose to not be told the result from the 
ENDORISK model and to only let their clinician be informed by it, this option is explicitly noted 
in the informed consent. Patients in this situation are then told by their clinician which treatment 
their clinicians deem most optimal for their situation (most similar to standard care). Clinicians 
are requested to document the type of counselling of the patient record. 
 
Use of the ENDORISK model 

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Important: the ENDORISK score must only be used in the consultation and shared-decision 
making in low-grade patients (grade 1-2) ≥45 years of age as an aid to diagnose. This is in 
accordance with the intended purpose of this In Vitro Medical Device (IVD), described in the 
Investigator’s Brochure. Patient’s outside this scope, including grade 3 EC patients and 
patients younger than 45 years of age, standard of care must always be the provided, 
independently of the generated ENDORISK score.  
 
The gynecologist enters the participants information into the ENDORISK user interface based 
on the diagnostic tests they perform in the context of standard care. To ensure a minimum 
level of accuracy in the calculation (maintaining an AUC >0.80), a minimal set of variables, 
including the preoperative tumor grade, three out of four biomarkers (ER, PR, p53 and/or 
L1CAM) and CA-125, are made mandatory to submit by the user before generation of a risk 
score is enabled. All of the aforementioned variables are part of standard care. Participants 
are told their personalized calculated risk percentage of lymph node metastases based on 
aforementioned preferences, together with other clinical information deemed relevant by their 
gynecologist or nurse specialist as is currently performed in standard care.  
 
Determining optimal surgical treatment 
According to the Dutch clinical guideline, lymph node staging is recommended in patient with 
clinical early stage, grade 3 endometrial cancer, who have about 20% risk of LNM. As part of 
the preparatory phase for implementing ENDORISK, eight focus groups including 
gynecologists, medical oncologists, pathologists and radiation oncologists from the 
participating hospital regions and several other hospitals in the Netherlands were organized 
resulting in a final consensus of using a cut-off of 10% risk of LNM (to be published). Above 
this cut-off, the clinician can consider to recommend assessment of lymph node status (Figure 
6). Yet, the choice of removing lymph nodes for assessment is entirely up to the patient 
together with their clinician according to current practice irrespective of their individual risk 
percentage. Therefore, the cut-off should only be seen as a background framework for 
clinicians. 

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Figure 6: Clinical workflow. 
Removal of enlarged lymph nodes during surgery that were not preoperatively recognized, or 
in patients with clinical suspicion of advanced stage EC and/or enlarged lymph nodes on 
preoperative imaging is considered as part of standard clinical care in both care models 
(standard & ENDORISK care). 
 
Evaluating ENDORISK implementation in clinical practice 
The main outcome parameter is defined as the proportion of LNM in patients who underwent 
lymph node staging by either SNP and/or LND (PPV) and will be compared to the PPV in 
standard care. As use of the ENDORISK model together with all available patient information 
could lead to patients making more informed choices to consciously omit lymph node staging, 
additional outcome parameters will be proportion of patients who decide to undergo lymph 
node staging compared to guideline recommendations, and preoperative information provision 
and shared-decision making as compared to standard care.   
 
Evaluation of patients’ experiences within ENDORISK care 
Patients receive a set of questionnaires within 12 weeks after surgery and 12 months after 
surgery (Figure 6). Each set of questionnaires takes approximately 20 to 30 minutes to fill in. 
Questionnaires are send either digitally by E-mail via CastorEDC or on paper depending on 
the preferences they indicated during the informed consent procedure.  
 
Information provision and shared-decision making will be evaluated by using the validated 
EORTC QOL-INFO25, and SDM-Q-9 questionnaires [57, 58]. The EORTC QOL-INFO25 
serves for evaluation of information provision and satisfaction about EC treatment. The SDM-
Q-9 is a 9-item questionnaire, in which patients are asked to score different aspects on shared-

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decision making on a six-point scale. These questionnaires will be send within 12 weeks after 
surgery. 
 
For the evaluation of use and experience of patients with the ENDORISK-model, additional 
questions about ENDORISK use during counselling were added to the EORTC QOL-INFO25 
and SDM-Q-9 questionnaires based on earlier qualitative research within the same study 
region (to be published), as the questions fit within the domains of these questionnaires. 
However, they will be analyzed separately from the standardized questionnaires.  
 
Health-related quality of life will be evaluated within 12 weeks after surgery and 12 months 
after surgery by the EORTC QLQ-C30 and QLQ-EN24 [59, 63]. The EORTC QLQC30 contains 
five functional scales on physical, role, cognitive, emotional and social functioning, a global 
health status/QoL scale, three symptom scales on fatigue, nausea and vomiting, and pain, and 
six single items. The EORTC QLQ-EN24 assesses endometrial cancer specific symptoms: 
lymphedema, 
urological 
symptoms, 
gastrointestinal 
symptoms, 
body 
image 
and 
sexual/vaginal symptoms, back/pelvic pain, tingling/numbness, muscular/joint pain, hair loss, 
taste change, sexual interest, sexual activity, and sexual enjoyment. Questions about sexual 
symptoms are not mandatory to answer. In addition, with the questionnaires send 12 months 
after surgery, the questionnaires EORTC IL76 and LYMQOL will be send to evaluate 
complaints of lymphedema [62] [61]. 
Figure 6. study workflow  
 
Evaluation of clinicians’ experiences with the ENDORISK model 
For the evaluation of use and experience of clinicians with the ENDORISK-model, a 
questionnaire and interview guide were developed tailored on the requirements for clinicians 
by earlier qualitative research within the same study region (to be published). The 
questionnaire will be send at baseline and 12 months to evaluate use and experience of 

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clinicians over time. A small sample of clinicians will be invited for additional in depth interviews 
within the first year to evaluate use and experience of ENDORISK in depth. 
 
Data collection 
Data collection will be stored into CastorEDC data management software by members of the 
coordinating research team or by the local researchers. 
 
Patient characteristics (age at diagnosis, BMI, comorbidity (hypertension and DM), 
preoperative tumor characteristics (tumor type, grade and molecular ER, PR, P53 and L1CAM 
status done on tumor tissue), serum markers (CA-125, platelet count), results of PAP smear if 
available, results of imaging if performed, primary surgical procedure (hysterectomy with or 
without lymph node directed surgery), final FIGO stage, and applied adjuvant therapy (VBT, 
EBRT, CT, CRT) will be registered, and follow-up (death, recurrence) will be documented till 5 
years after primary treatment.  
 
As secondary outcome parameters, 5-year disease specific and overall survival (DSS and OS) 
and Health Related Quality of Life (HRQoL) in ENDORISK care will be compared to standard 
care to evaluate the impact of ENDORISK model use on these parameters. In addition, 
patients’ and doctors’ use and experiences with the ENDORISK model will be evaluated and 
an analysis of the impact of ENDORISK on regional care costs will be performed. 
 
Patients’ outcome including recurrence of endometrial cancer and death due to endometrial 
cancer or other causes will be documented till at least 5 years after primary surgery to calculate 
DSS and OS.  
 
Evaluating impact of ENDORISK on regional care costs 
Potential differences in healthcare expenditures across regions will be assessed, focusing 
solely on direct costs, considering variations in referral patterns, treatment approaches, and 
clinical decision-making compared to standard care. Specifically, changes in the number 
and/or type of lymph node assessment. This data will be used to estimate the impact of 
ENDORISK in an oncology network on regional care costs. By comparing these factors, we 
aim to determine whether the implementation of the ENDORISK model influences regional 
healthcare spending regarding lymph node staging in endometrial cancer care. This impact 
analysis will be generated as a series of scenario analyses. Scenarios will be determined 
together with relevant stakeholders. 
6.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. Upon request for withdrawal, participants are asked whether they only wish to 
withdraw from study actions (e.g. filling out a questionnaire) or wish to withdraw completely 
(thus also stopping any further data collection from their medical records by the researchers). 

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Participants are made aware in the study information that study data collected until point of 
withdrawal can be used by researchers.  
6.5 Follow-up of subjects withdrawn from treatment 
Not applicable as no study-specific treatment is given. 
6.6 Premature termination of the study 
No scenario is expected in which premature termination of the study might need to occur. 
7. SAFETY REPORTING 
7.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or safety. 
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision 
by the accredited METC. The investigator will take care that all subjects are kept informed.  
7.2 AEs, SAEs and Device Deficiencies 
7.2.1 
Adverse events (AEs) (IVDR 2017/746, art 2.60) 
Any untoward medical occurrence, inappropriate patient management decision, unintended 
disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in 
subjects, users or other persons, in the context of this performance study.  
 
Only study related AEs will be recorded. This means all AEs related to participation in this 
study protocol, meaning a deviation of standard care for primary treatment due to use of the 
ENDORISK model in preoperative counselling will be recorded. Investigators will record AE’s 
on the Adverse Event form in Castor EDC. All other AEs will not be reported, as no patient 
benefit is expected from this.   
7.2.2 
Serious adverse events (SAEs) (IVDR 2017/746, art 2.61) 
Any adverse event that led to any of the following:  
• 
a patient management decision resulting in death or an imminent life-threatening situation 
for the individual being tested, or in the death of the individual's offspring,  
• 
death,  
• 
serious deterioration in the health of the individual for whom the ENDORISK was used in 
preoperative counseling for treatment decision making that resulted in any of the following:  
i. 
life-threatening illness or injury,  
ii. 
permanent impairment of a body structure or a body function,  
iii. 
hospitalization or prolongation of patient hospitalization,  
iv. 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
v. 
chronic disease  

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An elective hospital admission will not be considered as a serious adverse event. 
 
Our study population has a high risk of complications, including death, which are inherent to 
their vulnerable condition (endometrial cancer) and these are considered unrelated to the 
intervention. Only study related SAEs will be recorded and reported immediately by 
investigators on the Adverse Event form in Castor EDC to the sponsor, in addition to 
notification of the sponsor by phone for death or life-threatening categories and by e-mail for 
other categories. This means all SAEs related to participation in this study protocol, meaning 
a deviation of standard care for primary treatment due to use of the ENDORISK model in 
preoperative counselling, will be recorded and reported, including any new findings in relation 
to any of these SAEs. All other SAEs will not be reported, as no patient benefit is expected 
from this.   
7.2.3 
Device deficiency (IVDR 2017/746, art 2.62) 
Any inadequacy in the identity, quality, durability, reliability, safety or performance of the 
ENDORISK model for this performance study, including malfunction, use errors or inadequacy 
in information supplied by the manufacturer.  
 
Any device deficiency that might have led to a serious adverse event if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less fortunate will 
be recorded by investigators on the Adverse Event form in Castor EDC and reported by the 
sponsor, including any new findings in relation to any of these device deficiencies.  
7.2.4 
Reportable events (IVDR, art 76, sub 2)  
A reportable event is:  
a) any serious adverse event that has a causal relationship with the device, the 
comparator or the study procedure or where such causal relationship is reasonably 
possible;  
b) any device deficiency that might have led to a serious adverse event if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been 
less fortunate;  
c) any new findings in relation to any event referred to in points (a) and (b). 
 
All causality assessments will be done according to section 9 of MDCG 2020-10/1. The period 
for reporting shall take account of the severity of the event. Where necessary to ensure timely 
reporting, the sponsor may submit an initial report that is incomplete followed up by a complete 
report. 
 
The sponsor will report the reportable events using the MDCG 2020-10/2 table through the 
web portal ToetsingOnline to the accredited METC that approved the protocol, 
without undue delay but not later than 2 calendar days (and 2 calendar days for any new follow-
up information) for death and life threatening and 7 calendar days for other categories (and 7 

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calendar days for any new follow up information) after awareness by sponsor of the event/new 
finding to it. 
7.3 Follow-up of adverse events 
All SAEs that fit the aforementioned criteria 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. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol. 
7.4 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
Based on the structured risk analysis as described in chapter 11 and the criteria described by 
the Dutch Federation of University Medical Centers (NFU), this study can be classified as low 
risk. Therefore, no DSMB is needed. 
 
8. STATISTICAL ANALYSIS 
The data of the historical and prospective time periods will be analyzed using a generalized 
linear mixed model with identity link, normally distributed random effect, binomial error 
distribution, and a fixed effect for treatment and fixed effects for region.  
 
Baseline characteristics will be compared between the two study arms using descriptive 
statistics to assess for imbalance. Analysis follow the intention-to-treat principle. Reasons for 
missing data will be collected as much as possible but as primary analysis, missing-at-random 
will be assumed for the outcomes. 
8.1 Primary study parameter(s) 
For the main outcome, identified LNM (PPV) in patients with lymph node staging in these 
patients will in compared between the risk difference between standard care and ENDORISK 
care using the generalized linear mixed model mentioned for the sample size calculation. The 
estimated intervention effects will be reported as the difference in percentage for binary 
outcomes between the intervention and control arms. If the model does not converge, we will 
fall back on a logit link (i.e. logistic regression with a odds ratio as effect measure). The impact 
of ENDORISK care on information provision (EORTC QLQ-INFO25) and shared-decision 
making (SDM-Q-9) will be evaluated with a linear mixed model. 
8.2 Secondary study parameter(s)  
Secondary outcome measurements will be compared between Standard care and ENDORISK 
care. For patients’ outcome measurements we will focus on comparing the health-related 
quality of life between Standard care and ENDORISK care. For these secondary outcomes, 

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mean scores and standard deviations (SD) will be calculated for the multi-item and single-item 
scales according the recommended analysis of the validated questionnaires [57-59, 63]. 
Changes in HR-QoL in the EORTC-QLQ-C-30 and EN-24 between baseline and 12 months 
postoperatively will be calculated and compared between arms using a Linear Mixed Model 
analysis. Follow-up will be documented at 1 year up until 5 years after primary surgery and will 
include recurrence and mortality (overall (OS) and caused by EC (DSS).These outcomes will 
be analyzed using Cox regression with region as strata. The patients’ and doctors’ experiences 
with the ENDORISK model will be described using mean and 95%-CI (as this concerns no 
comparison). Impact on regional care cost will be analyzed based on the scenario’s that will 
be developed with relevant stakeholders. 
 

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9. ETHICAL CONSIDERATIONS 
9.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki, version 
of October 2013.  
9.2 Recruitment and consent 
Patients will be recruited by their treating gynaecologist or nurse specialist after initial diagnosis 
with endometrial carcinoma. The patient folder and counselling video will be distributed to them 
to provide further information on ENDORISK and this study. They will be given until their next 
consult in which they discuss their treatment to consider if they want to participate in the study. 
This time can range from one to two weeks. If patients are referred to a tertiary/academic 
centre, the referring hospital is responsible for obtaining informed consent prior to consultation 
in the referral centre. 
9.3 Benefits and risks assessment, group relatedness 
Current risk estimation of lymph node metastases is based mostly on tumor grade. Patients 
with grade 3 endometrial carcinoma have approximately 20% risk of LNM and are therefore 
recommended by guidelines for lymph node status assessment [6, 20]. However, research 
shows that LNM are prevalent in about 8-10% of grade 1 and 2 patients as well [6, 20]. These 
patients are currently missed with standard care and therefore undertreated. With the SNP, 
risk of lymphedema is low, but for the 20% of patients with bilateral failure, side-specific LND 
might steel be needed [23]. LND leads to lymphoedema in 5-20% of patients which can have 
a large impact on their quality of life [21, 22, 64]. This means that 80% of grade 3 patients are 
at risk of lymphedema without having LNM and are therefore overtreated. The ENDORISK 
model (AUCs >0.80) seems to be more accurate than standard risk estimation of LNM (AUCs 
0.69-0.70) and could therefore reduce undertreatment and overtreatment [1-4]. 
9.4 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
 
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 
 
The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 

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9.5 Incentives (if applicable) 
Patients or clinicians of patients participating in the study will receive additional information 
about their personal preoperative risk of lymph node metastasis by allowing their clinician to 
use the ENDORISK model. Apart from this additional information, there are no incentives for 
patients participating in the study. 

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
10.1 Handling and storage of data and documents 
Data of patient records and patient questionnaires will be pseudo-anonymized for other 
researchers and stored in CastorEDC data management software. 
 
Data will be stored at the department of Obstetrics and Gynaecology, Radboudumc. The non-
anonymized patient records will only be accessible for the treating gynaecologist and 
researcher or research-supporting staff collecting data for the participating centre. Patient 
questionnaires and data collection in Castor will be pseudo-anonymized. The key for patient 
identification will only be accessible for the research team that included the patient. If the 
coordinating research team assisted in the informed consent procedure for a local hospital, all 
identifying information will be transferred to the original hospital and anonymized in the 
database of the coordinating team at the end of the inclusion period. Keyfiles and filled in 
informed consent forms will be archived at the hospital from which a patient was included.  
 
After all eCRFs are locked, a non-adaptable export including an export of the CastorEDC audit 
trail and an empty export of the study structure will be archived together with other 
pseudonymized study files, separate from identifiable study files, on department files with 
access restricted to the research team. This will also include adaptable anonymized files used 
for analysis of study data. The non-adaptable anonymized eCRF export and audit trail export 
will also be send to the participating hospitals for archiving and audit-purposes. 
 
Only anonymized datasets (without patient numbers, date of birth or name) will be shared with 
other people relevant to the study or relevant to additional studies as reported in the patient 
information folder.  
 
Interviews with clinicians are audio-recorded and then transcribed leaving out identifying 
information. Audio recordings will be stored separately from the transcriptions on a restricted 
department file. 
 
Study documents will be archived for 15 years after conclusion of the study period: physical 
source documents in a locked department storage and digital documents in restricted 
department files, all only accessible by the research team of the local hospital.  
 

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10.2 Monitoring and Quality Assurance  
This study will be monitored by a monitor from the team of Clinical Research Monitoring of the 
Radboud university medical center. Based on criteria by the NFU, this study falls in the lowest 
risk class for monitoring. While ENDORISK is a medical device, it is used digitally via an 
internet browser and only used to obtain additional information from diagnostic tests from 
standard care. Therefore, the guidelines for ‘other research’ from the NFU are most applicable 
to this study as opposed to the guidelines for medical guidelines. All centres will remotely be 
visited for monitoring approximately a month after first exclusion except for the Radboudumc 
and Catharina hospital. Two interim visits will be held in the Catharina hospital: one after first 
inclusion and one after the last inclusion. After the first inclusion in the Catharina hospital, an 
interim visit will be held in the Radboudumc to monitor the Trial Master File. In the 
Radboudumc, additional interim visits will be held within a month after first inclusion there and 
the third one after the last inclusion. The separate monitoring plan for this study can be 
observed for additional information.  
10.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
10.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
10.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as the moment that the 5-year follow up data has 
been collected for all included and still participating patients.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 

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Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
10.6 Public disclosure and publication policy 
This study will be registered in a public trial registry before the first patient is recruited. Results 
of the study will unreservedly be published in a peer reviewed journal, and if possible, will be 
published with open access.   
 
11. STRUCTURED RISK ANALYSIS  
11.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
The ENDORISK model has previously been internally validated and thrice externally 
validated with consistent area under the curve’s (AUC) of >0.80 and recently in a fourth 
external cohort of patients that only underwent sentinel node procedure which resulted in a 
comparable AUC (to be published)[2-4]. The benefit of a Bayesian network is that not all 
variables need to be entered as evidence into the model for a reliable calculation. This was 
validated in the original paper by Reijnen et al. and validated on the other external cohorts 
by the research team (to be published)[3]. 
 
The 
ENDORISK 
model 
was 
constructed 
by 
integrating 
preoperative 
clinical, 
histopathological, molecular and serum markers of EC patients [17]. For the prediction of 
LNM, external validations have shown a good diagnostic performance of this ENDORISK 
model (AUCs >0.80) when compared to current risk classification (AUC 0.65-0.70)[1, 2, 4]. 
Biomarkers included in the model were shown to be strongly correlated with high-grade, 
NEEC, LVSI, myometrial- and cervical stromal invasion and all variables in the model are 
already part of standard care are recommended in international guidelines [6, 51]. 
 
b. Study population 
The ENDORISK model was trained on 763 patients from several hospitals in Europe, 
including hospitals in the current study region [3]. It was also validated with comparable 
good results on three external cohorts from Norway, Germany and Czech Republic with 
similar patient characteristics to the prospective study population [2-4]. 
 
c. Interaction with other products 
While on its own, the ENDORISK model already performs well in preoperative prediction of 
LNM, it must be used together with other clinically relevant patient characteristics to 
determine optimal treatment, similar to current practice in standard care. Variables in the 
ENDORISK model have already been in use within standard care for years and are 
recommended for preoperative risk stratification by international guidelines[6]. 
 
d. Predictability of effect 

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All previous external validations resulted in similar AUCs >0.80, with PPV ranging from 24-
35% which are all at least comparable compared to standard care PPV as described by 
published NCCO data.  
11.2 Synthesis 
The ENDORISK model was consistently validated with AUCs >0.80 in study populations 
comparable to the prospective study population. As there is still a risk of error in risk calculation 
by the ENDORISK model, clinicians are recommended to also keep other patient 
characteristics, e.g. comorbidity, age, diagnostic tests not part of the model and patient 
preferences, in consideration when determining optimal treatment together with their patient. 
Based on earlier published results, ENDORISK could be comparable to even superior 
compared to current risk stratification systems. Patients are already exposed to a risk of error 
in preoperative risk stratification in standard care and are therefore currently already at risk of 
under- or overtreatment.  
 
High grade patients in standard care are referred to tertiary centers for preoperative risk 
assessment, as counselling and treatment of these patients is more complex. To ensure safety, 
high grade patients within ENDORISK care will all be referred to tertiary centers as well, 
irrespective of their result from ENDORISK. High grade patients might still choose to omit 
lymph node assessment, however other factors, e.g. comorbidity and therefore less suitability 
for surgery, will be more important in this choice, comparable to current practice in standard 
care. 
 
As ENDORISK is only one of the many factors involving treatment decision, the risk of under- 
or overtreatment is not expected to be larger for participants of the study. Using the model 
could even improve preoperative counselling and therefore patients’ experiences within 
endometrial cancer care. Therefore, we deem the risk of participating in this study acceptable. 
 
 
 

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