EMBRAVE: IntErnational Observational Study on Primary Chemoradiotherapy and iMage-based Adaptive BRAchytherapy for Vaginal cancEr
Conditions: Vaginal Neoplasms
Sponsor: Erasmus Medical Center

EMBRAVE  
 
 
IGABT for vaginal cancer 
 
 
 
 
 
EMBRAVE 
IntErnational observational study on 
primary (chemo)radiotherapy and 
iMage-based adaptive BRAchytherapy 
for Vaginal cancEr 
 
 
 
 
 
 
RESEARCH PROTOCOL 
Version 2.0 
28-01-2025 
 
 
 
 
 
 

EMBRAVE  
 
 
IGABT for vaginal cancer 
 
 
 
PROTOCOL TITLE ‘International observational study on primary (chemo)radiotherapy and 
image-based adaptive brachytherapy for vaginal cancer’ 
Protocol ID 
Short title 
EMBRAVE 
EudraCT number  
not applicable 
Version 
2.0 
Date 
28-01-2025 
Principal Investigator 
 
Project leader 
Remi A. Nout MD PhD 
Erasmus Medical Center 
Henrike Westerveld MD PhD 
Erasmus Medical Center 
 
Co-investigators:  
Erasmus Medical Center, Rotterdam, the Netherlands: 
 
Jérémy Schiphof-Godart  
 
Sofia Spampinato 
 
René Vernhout 
Aarhus University Hospital, Aarhus, Denmark:  
 
Simon Buus (local PI)  
 
Steffen Hofland  
Amsterdam University Medical Center, Amsterdam, 
the Netherlands:  
 
Bradley Pieters (local PI) 
 
Colette van den Broek 
 
Danique Barten 
 
Jan Wiersma 
Gustave Roussy Cancer Campus (Villejuif) and 
University Hospital Pitié Salpêtrière (Paris), France:  
- 
Sophie Espenel (local PI) 
- 
Isabelle Dumas 
- 
Cyrus Chargari 
Leiden 
University 
Medical 
Center 
Leiden, 
the 
Netherlands:  
- 
Laura Velema (local PI) 
- 
Ellen Kerkhof 
Medical University of Vienna, Vienna, Austria: 
- 
Maximilian Schmid (local PI) 
- 
Nicole Eder-Nesvacil 
 
 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
Erasmus Medical Center, Dept. of Radiotherapy 
Subsidizing party 
None 

EMBRAVE  
 
 
IGABT for vaginal cancer 
 
 
 
Independent expert (s) 
None 
Laboratory sites <if applicable> 
Not applicable  
 
Pharmacy <if applicable> 
Not applicable 
 
 

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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
7 
2. SUMMARY 
9 
3. BACKGROUND AND RATIONALE 
12 
3.1 Background 
12 
3.1.1 Primary vaginal cancer 
12 
3.1.2 Vaginal recurrences 
12 
3.2 Current evidence 
13 
3.2.1 Primary vaginal cancer 
13 
3.3 Rationale 
14 
4. STUDY AIMS 
15 
5. STUDY DESIGN 
16 
5.1 Design 
16 
5.2 Data 
17 
5.3 Endpoints 
19 
6. STUDY POPULATION 
21 
6.1 Population (base) 
21 
6.2 Inclusion and exclusion criteria 
21 
6.4 Sample size calculation 
22 
6.5 Patient accrual and study period 
23 
7. EXTERNAL BEAM RADIOTHERAPY TREATMENT 
24 
7.1 Introduction and aims 
24 
7.2 Preparation for treatment planning 
24 
7.3 Definition of EBRT target and fields 
25 
7.4 Organs at risk and reference points: definitions and contouring 
28 
7.5 Dose and fractionation 
28 
7.6 Planning aims for targets and organs at risk 
29 
7.7 Technique and procedures for EBRT including daily image-guidance 
30 
8. BRACHYTHERAPY 
32 
8.1 Introduction 
32 
8.2 Preparations for brachytherapy 
32 
8.3 Imaging for brachytherapy 
33 
8.4 Applicator reconstruction and dose points for OARs 
35 
8.5 Contouring for brachytherapy 
36 
8.6 Treatment planning for brachytherapy 
40 
8.7 Planning aims & constraints for target and OAR 
40 
8.8 Dose and volume reporting 
41 
9. SYSTEMIC THERAPY 
43 
9.1 Introduction and aims 
43 
9.2 Concomitant chemotherapy 
43 
10. METHODS 
44 
10.1 Establishing a reference for clinical outcomes of vaginal cancer 
44 
10.2 Identification of prognostic parameters for clinical outcomes 
45 

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10.3 Development of evidence-based recommendations for radiotherapy treatment46 
10.4 Evaluation of the use of concurrent systemic therapy 
47 
11. QUALITY ASSURANCE 
49 
11.1 Entry requirements for study phase I 
49 
11.2 Eligibility questionnaire and dummy run 
49 
11.3 Accreditation for study phase II 
50 
11.4 Quality Assessments procedures 
50 
11.5 Safety evaluations 
50 
12. ETHICAL CONSIDERATIONS 
51 
12.1 Regulation statement 
51 
12.2 Patient identification 
51 
12.3 Informed consent and patient enrolment procedure 
51 
12.4 Benefits and risks for patient 
52 
12.5 Insurance of study participants 
52 
13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
53 
13.1 
Handling and storage of data and documents 
53 
13.2 
Monitoring and Quality Assurance 
55 
13.3 
Public disclosure and publication policy 
55 
14. REFERENCES 
56 
15. APPENDICES 
61 
15.1 APPENDIX 1: WHO classification of tumors of the vagina, ICD-O coding 
61 
15.2 APPENDIX 2: Overview of vaginal cancer stage classifications 
63 
15.3 APPENDIX 3: EORTC QLQ Questionnaire 
64 
15.4 APPENDIX 4: Clinical drawings of the vagina with and without uterus 
68 
 
 
 
 

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1. LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
18F-FDG   
Fluorine 18 - Fluorodeoxyglucose 
2/3/4D  
Two/Three/Four-dimensional 
ABS 
 
American Brachytherapy Society 
ACT  
 
Addenbrooke’s Contouring Tool 
ATRAB   
Applied and Translational Radiobiology (Medical University Vienna) 
AUC  
 
Area Under the Curve 
BL 
 
Baseline 
BT  
 
Brachytherapy 
CBG 
 
Canadian Brachytherapy Group 
CBCT  
 
Cone beam computed tomography 
CHT 
 
Chemotherapy 
COP  
 
Coverage Probability 
CR  
 
Complete Remission 
CRF  
 
Case Report Form 
CRT  
 
Conformal Radiotherapy 
CSS  
 
Cancer Specific Survival 
CT  
 
Computed Tomography 
CTCAE   
Common Terminology Criteria for Adverse Events 
CTV  
 
Clinical Target Volume 
CTVHR  
High risk clinical target volume 
CTVIR 
 
Intermediate risk clinical target volume 
 
CuSO4   
Copper sulphate 
D90  
 
The isodose that includes 90% of the target 
D100  
 
The isodose that includes 100% of the target 
D2cm3  
 
Minimum dose in the most exposed 2 cm3 of an OAR 
DFS  
 
Disease Free Survival 
DNA  
 
Deoxyribonucleic acid 
DVH  
 
Dose Volume Histogram 
EANM   
European Association of Nuclear Medicine 
EBRT  
 
External Beam Radiotherapy 
EMBRACE  
The European and International study on MRI-guided Brachytherapy in locally Advanced 
Cervical Cancer 
EORTC   
European Organisation for Research and Treatment of Cancer 
EoT 
 
End of Treatment 
EPID  
 
Electronic Portal Imaging Device 
ER 
 
Oestrogen Receptor 
ESTRO   
European SocieTy for Radiotherapy and Oncology 
EQD2  
 
Equivalent dose in 2 Gy fractions 
FIGO  
 
Fédération Internationale de Gynécologie et d’ Obstétrique 
FTE  
 
Full Time Equivalent 
Fx  
 
Fraction 
G  
 
(Morbidity) Grade 
GEC  
 
Groupe Européen de Curiethérapie 
GFR  
 
Glomerula Filtration rate 
GI  
 
Gastro-Intestinal 
GTV  
 
Gross Tumour Volume 
Gy  
 
Gray 
HDR  
 
High Dose Rate 
HPV  
 
Human Papilloma Virus 
HR  
 
High Risk 
IC  
 
Intracavitary 
ICH  
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICRU  
 
International Commission on Radiation Units and Measurements 

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IGABT 
 
Image-guided Adaptive Radiotherapy 
IGRT 
 
Image Guided Radiotherapy 
IMRT  
 
Intensity Modulated Radiotherapy 
IR  
 
Intermediate Risk 
IS  
 
Interstitial 
ITV  
 
Internal Target Volume 
IV  
 
Intravenous 
kV  
 
Kilovoltage 
LACC  
 
Locally Advanced Cervical Cancer 
LC 
 
Local Control 
LN  
 
Lymph Nodes 
LR  
 
Low Risk 
MMRd  
Mismatch repair deficiency 
MRI  
 
Magnetic Resonance Imaging 
MVCT   
Megavoltage Computed Tomography 
N0/N-   
Lymph Node Negative 
N1/N+   
Lymph Node Positive 
OAR  
 
Organs at Risk 
OS  
 
Overall Survival 
OTT  
 
Overall Treatment Time 
p53abn  
p53 abnormal 
PAN  
 
Para-Aortic Lymph Nodes 
PDR  
 
Pulsed Dose Rate 
PET-CT   
Positron Emission Tomography- Computed Tomography 
PFS  
 
Progression Free Survival 
PI  
 
Principal Investigator 
PIBS 
 
Posterior-Inferior Border of Symphysis 
POLE 
 
DNA polymerase epsilon 
PTV 
 
Planning Target Volume 
QoL  
 
Quality of Life 
RT  
 
Radiotherapy 
SD  
 
Standard Deviation 
SIB  
 
Simultaneous Integrated Boost 
SPSS  
 
Statistical Package for Social Sciences 
SUVmax   
Maximum Standardized Uptake Value 
TNM  
 
Tumour (Lymph)Nodes Metastasis 
TPS 
 
Treatment Planning System 
TRAK  
 
Total Reference Air Kerma 
uCR  
 
Uncomplete Remission 
US  
 
Ultrasound 
VMAT   
Volumetric Modulated Arc Therapy 
WHO  
World Health Organization 
 
 
 

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2. SUMMARY 
 
Background/Rationale 
Primary vaginal cancer is a rare gynaecologic cancer, constituting approximately 3% of gynaecological 
malignancies, with the vast majority being of squamous or adeno(-squamous) histology. Due to its 
rareness, the optimal treatment strategy for vaginal cancer is mainly based on experience from the 
treatment of locally advanced cervical cancer with which it shares many similarities. 
Radio(chemo)therapy with image-guided adaptive brachytherapy (IGABT) is the current standard 
treatment for locally advanced cervical cancer. The first clinical experiences in limited numbers of 
patients showed that IGABT for vaginal cancer was feasible, and promising clinical results were 
reported. However, there were distinct differences with cervical cancer, in particular with regard to 
anatomy and brachytherapy applicator systems, and a common concept for brachytherapy target 
volume and dose reporting was lacking. For this purpose, the GYN GEC-ESTRO task-group developed a 
target concept for primary vaginal cancer, in which different target volumes were defined for 
brachytherapy.  
While the majority of primary vaginal cancers has a squamous or adeno(-squamous) histology, there 
are few rare histological subtypes (e.g. clear cell carcinoma, neuroendocrine carcinoma of the vagina) 
that may be treated in accordance to the aforementioned target concept. In addition, there are rare 
clinical scenarios (primary vaginal cancer stage I <2cm; vaginal carcinoma in situ), that in selected cases 
may be treated with IGABT alone. Contemporary clinical evidence to guide treatment decision making 
in these situations is sparse. This study, offers a parallel registration cohort for these rare histological 
subtypes and treatment with IGABT alone, with the aim to gather prospective clinical outcomes in a 
multicentre setting. 
The clinical management of vaginal recurrences from other cancers of the female genital tract (e.g. 
endometrial cancer, cervical cancer) with IGABT is also considered an appealing approach. For this 
reason, a consensus target concept for treatment with radio(chemo)therapy and IGABT for vaginal 
recurrences of other cancers of the female genital tract (e.g. endometrial cancer, cervical cancer) was 
developed by a joint effort of GYN GEC-ESTRO, ABS and CBG. This target concept shows great similarity 
to that of primary vaginal cancer.  
The target concepts for primary vaginal cancer and vaginal recurrences need clinical validation as the 
uptake, feasibility and oncological outcomes including morbidity and quality of life are yet unknown. 
The rationale for this study is the need for an evidence-based treatment for primary and recurrent 
vaginal cancer. Now targets concept have been developed, they should be implemented and evaluated 
in a multicentre setting to advance treatment.  
 
Objective and hypothesis 
The general aim is to improve clinical outcomes of patients with vaginal cancer treated with definitive 
radio(chemo)therapy and IGABT. Specific aims are to develop evidence-based recommendations for 
IGABT and to identify prognostic parameters for oncological outcomes, morbidity and quality of life. 
Parallel registration cohorts for rare histological subtypes and treatment with IGABT alone are aimed 
to provide contemporary multicentre prospective clinical outcomes in these rare conditions. 
Furthermore, the study aims to create possibilities for future fundamental and/or translational studies 
by asking study participants permission for the storage and use of tumour tissue, imaging and 
treatment plans. 
Study design:  
The study is a prospective, observational, international multi-centre cohort study on the treatment of 
vaginal cancer with radio(chemo)therapy and IGABT. This design offers parallel registration of cohorts 
for rare histological subtypes and treatment with IGABT alone. This cohort study is designed as a 
continuous international registry, since vaginal tumours are rare malignancies for which international 
prospective data collection is needed.  

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Study population:  
Adult patients with primary vaginal cancer (FIGO stage I-IVA) or vaginal recurrences (without distant 
metastases) who are treated with curative intent by primary radio(chemo)therapy and MRI based 
image-guided adaptive brachytherapy according to the abovementioned target concept for vaginal 
cancer are eligible to participate in this study. Rare histological subtypes including carcinoma in situ 
and treatment with IGABT alone are eligible for registration in a parallel cohort within this study. 
Treatment of study population:  
Patients included in this registration study receive the same treatment and have the same follow-up 
as patients who do not participate. Study participants will give informed consent for the prospective 
collection of their clinical and treatment data (including DICOM imaging and DICOM-RT treatment 
data). Furthermore, they will have the opportunity to participate in the observational morbidity and 
quality of life study, for which questionnaires will need to be filled out on a regular basis. Finally, they 
will have the opportunity to give permission for the storage and use of tumour material for future 
fundamental or translational studies. 
Quality assurance:  
This study will have two study phases: in the first phase only 6 institutions (Aarhus University Hospital, 
Amsterdam UMC, Leiden UMC, Erasmus MC, Medical University of Vienna and Gustave Roussy) will 
open for inclusion. These institutions were involved in the development of the GEC-ESTRO target 
concept for vaginal cancer and already treat vaginal cancer with the most up-to-date treatment 
equipment and techniques. Based on the experience of these 6 centres during the first year, 
accreditation and quality assessment procedures are refined for new centres. New centres should 
already be experienced with the treatment of cervical cancer by MRI-based IGABT and should 
complete a dummy run (to ensure adherence to the target concept, methodology for dose reporting, 
and study logistics) to obtain accreditation. In addition, quality assessment (QA) procedures will be 
performed for every participating centre after the first year to ensure continuous adherence to the 
protocol. Centres will be given feedback on their performance, and additional QA's will be planned if 
necessary.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
The current study is a longitudinal observational study with registration of clinical outcomes after 
standard care with radio(chemo)therapy and IGABT for vaginal cancer. As such, there are no 
experimental interventions performed in this study. Hence, there is no potential benefit or risk for the 
patients participating in this study. The aim of this study is to collect data in order to optimize and 
improve treatment of vaginal cancer. 
Main study outcome measures:  
This study is an observational, prospective registration study, wherein neither an experimental 
treatment is compared to the standard treatment, nor groups of patients are compared. As a result, 
this study has no classical primary study endpoint.  
Nonetheless, the following endpoints are defined to ascertain proper effectuation:  
1) Oncological events (disease control; disease-free, disease-specific and overall survival) at 2 and 5 
years of follow-up. 
2) Acute and late morbidity events (urogenital, gastrointestinal, bone and general toxicity) at 2 and 5 
years of follow-up. 
3) Uptake of the target concept recommendations. 
4) Feasibility of concurrent systemic therapy (% completion, prevalence of reasons for non-
completion). 
Sample size and data maturity: 
This observational cohort study is designed as a registry for vaginal cancer. As such there is no 
predefined maximal number of patients that can be included in the registry. At the inclusion of 100 
patients, the overall incidence of the clinical outcomes (oncological evens and morbidity) can be 

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estimated. Furthermore, a descriptive analysis of prescribed doses and a validation of the target 
concept can be conducted.  
At the inclusion of 300 patients, multivariable analyses can be performed to determine the 
independent effect of predictors on clinical outcomes. However, estimates will become more accurate 
and conclusions more reliable, if more patients can be included. 
It is expected that the first 100 patients with vaginal tumours will be included during the first 3 years 
and the first 300 patients during the first 8 years. Henceforth, the first analyses which require 100 
patients, and that don’t require follow-up after treatment could be done in the 3rd year. First analyses 
using oncological outcomes will require a follow-up and are expected to be performed in the 6th year. 
The analyses that require at least 300 patients and use clinical outcomes could be performed at earliest 
in the 11th year of the study.  
 

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3. BACKGROUND AND RATIONALE 
 
3.1 Background 
3.1.1 Primary vaginal cancer 
Primary vaginal cancer is a rare gynaecologic cancer, constituting approximately 3% of 
gynaecological malignancies, with the vast majority being of squamous or adeno(-squamous) 
histology. 1 Radiotherapy including brachytherapy is the treatment of choice for the majority of 
patients as organ-sparing surgery with negative resection margins is difficult to achieve.2 Due to 
its rareness, the treatment strategy for primary vaginal cancer has been based on experience from 
the treatment of locally advanced cervical cancer with which it shares many similarities. Therefore, 
a combination of external beam radiotherapy (EBRT) (45-50Gy with 1.8-2Gy per fraction) and a 
brachytherapy-boost up to a total dose of 70-80Gy in combination with concomitant weekly 
cisplatin-based chemotherapy is currently considered standard of care.3-7 
Due to the anatomy, primary vaginal cancer is an optimal target for brachytherapy. Traditionally 
vaginal cylinders or vaginal mould applicators allowing for a stable geometry within the vagina 
were used as intracavitary applicators for the brachytherapy sources. In case of more extensive 
residual disease after EBRT combined intracavitary/interstitial techniques were considered. First 
conceptual ideas on a target volume concepts for vaginal cancer brachytherapy date back from 
the era before the use of volumetric 3-dimensional imaging. These concepts were related to the 
application technique and dose prescription according to institutional experience. The concepts 
included: (1) in small well-defined superficial tumours: the gross tumour volume (GTV) with 1-2 
cm margin; (2) in larger tumours after EBRT: either the initial tumour volume with a safety margin 
(mainly related to the tradition of prescribing to the cumulative 60Gy reference isodose), or 
alternatively the GTV at time of brachytherapy with a safety margin to prescribe a higher dose 
(>60Gy).8 Treatment planning and reporting was based on the clinical experience using mainly 
applicator related points, and systems (e.g. the Paris system) in case of interstitial techniques. Dose 
reporting followed the ICRU reports 38 and 58.9,10 Several large institutional radiograph-based 
brachytherapy experiences report local/pelvic control rates ranging from 44-87% (~75%). Pelvic 
control was good for stage I-II (~90%) compared to 40-80% (~60%) for stage III and 0-69% (~45%) 
for stage IV, while severe morbidity was mainly described for the GU and GI tract.3-5,9-18 
 
3.1.2 Vaginal recurrences 
Primary endometrial or cervical cancer can result in recurrences in the vagina. Endometrial cancer 
recurrences commonly arise in the post-hysterectomy surgical scar, but can also develop at other 
sites in the vaginal wall.19-23 Multifocal spread can also be observed in case of extensive lymph 
vascular space involvement (LVSI) or more aggressive histologies.24 The prognosis is associated 
with the original risk-group classification.19 Evidence suggests to consider also molecular risk 
factors (i.e. p53 or mismatch repair deficient).25 Central recurrences for cervical cancer are 
observed after radical hysterectomy with risk factors including size of the primary tumour, depth 
of invasion, presence of LVSI, and nonsquamous histologies.20,21 
Clinical management of vaginal recurrences is challenging, as the location in central pelvis can 
result in significant symptoms and treatment-related toxicities. Organ-preserving approaches 
combining EBRT with BT represent an attractive option, especially with the advent of image-guided 
brachytherapy (IGABT). 
Small institutional studies reported favourable local control and acceptable toxicity levels in 
treating vaginal recurrences with primary radiotherapy including IGABT. While local control rates 
range from 80% to 90%, there is considerable variability in disease-free and overall survival and 
toxicity outcomes because of the heterogeneity of patients, variations in dose specification, 
treatment volumes, and total dose 26-37. 
 

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3.2 Current evidence 
Recent developments in the field IGABT for cervical cancer appear also attractive for vaginal 
cancer. The principle of IGABT for cervical cancer is to apply repetitive three-dimensional (3D) 
volumetric imaging to visualize both the targets and organs at risk in relation to the applicator. 
During dose planning the dose is shaped according to the individual target volumes, taking tumour 
regression during radio(chemo)therapy into account. Due to the superior soft tissue contrast, MRI 
is the recommended imaging modality for target delineation. Various steps within the treatment 
chain of IGABT for cervical cancer has been elaborated and published as recommendations (target 
volume delineation, dose reporting, applicator reconstruction, imaging) by the GYN GEC-ESTRO 
working group.38-41 Standardization of target volume and dose reporting has greatly facilitated 
multicentre evaluation of these concepts. Subsequent studies have demonstrated the superiority 
of IGABT in comparison to conventional point-A based treatment planning; showing improved local 
control with a simultaneous reduction of treatment related morbidity.42-46 Finally, these concepts 
have now been implemented in the most recent ICRU report 89, which in addition includes 
concepts and terminology for EBRT.47 
Due to the similarities between cervical cancer and vaginal cancer, IGABT was a logical next step. 
Indeed, first clinical experiences in a limited number of patients showed the feasibility of IGABT 
for vaginal cancer and promising clinical results were reported.7,37,48-50 However, there are also 
distinct differences with cervical cancer, in particular in regard to anatomy and applicator systems, 
and a common concept for target volume and dose reporting was lacking. 
To address this issue, two parallel international efforts provided new recommendations for IGABT 
target definitions for primary vaginal cancer and vaginal recurrences. These target concepts needs 
clinical validation. The uptake, feasibility and oncological outcomes including morbidity and quality 
of life are yet unknown. Moreover, there is in general lack of good evidence regarding the optimal 
treatment of vaginal cancer. 
 
3.2.1 Primary vaginal cancer 
In 2013 a task group within the Gynaecological Groupe Européen de Curiethérapie and the 
European Society for Radiotherapy & Oncology (GYN GEC-ESTRO) was established with the aim to 
introduce IGABT concepts. The report published in 2020  summarizes the GYN GEC-ESTRO 
concepts and recommendations for target volume definition in IGABT for primary vaginal cancer.51 
While the majority of primary vaginal cancers have a squamous or, adeno(-squamous) histology, 
there are few rare histological subtypes (e.g. clear cell carcinoma, neuroendocrine carcinoma of 
the vagina) that may be treated in accordance to the aforementioned target concept. In addition, 
there are rare clinical scenarios (primary vaginal cancer stage I <2cm; vaginal carcinoma in situ), 
that may be treated with IGABT alone13,52. Contemporary clinical evidence to guide treatment 
decision making in these situations is sparse. This study, offers a parallel registration cohort for 
these rare histological subtypes and treatment with IGABT alone, with the aim to gather 
prospective clinical outcomes in a multicentre setting. 
 
3.2.2 Vaginal recurrences 
To develop international consensus recommendations, representative members from GEC-ESTRO, 
American Brachytherapy Society (ABS), and the Canadian Brachytherapy Group (CBG) convened to 
establish definition for IGABT clinical target volumes at the time of brachytherapy for recurrent 
endometrial/ cervical cancers in the vagina53. This international effort addressed the variability in 
target volume definition found in literature, and the specific considerations that should be 
considered for vaginal recurrences compared with primary vaginal cancer. There are some 
differences between primary vaginal and recurrent endometrial/cervical vaginal lesions: 1) 
histology, with different natural histories and related patterns of infiltration and spread, 2) and 
post-hysterectomy issues associated with the surgical scar and bowel sitting superior to the vaginal 
cuff.54 

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3.3 Rationale  
The rationale for this study is the need for an evidence-based treatment for vaginal cancer. Now a 
target concept has been developed, it should be implemented and evaluated to advance 
treatment. This should be done in the setting of a carefully designed prospective study. More 
specifically, in a prospective registration study of state-of-the-art treatment for vaginal cancer. This 
will ensure systematic prospective data collection of treatment and outcome parameters and 
minimize registration bias. With the data that this study will generate, evidence-based 
recommendations for planning aims & constraints for radiotherapy targets and OAR can be 
developed. This will further harmonize treatment delivery across different centres, optimize 
oncological outcomes and limit morbidity. 
 

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4. STUDY AIMS 
The general aim of this study is to improve clinical outcomes of patients with primary vaginal cancer 
or vaginal recurrences treated with definitive chemoradiation and MRI based IGABT. Specific aims of 
this study are to develop evidence-based recommendations for the treatment of vaginal cancer and to 
identify prognostic parameters for oncological outcomes, morbidity and QoL. Parallel registration 
cohorts for rare histological subtypes and treatment with IGABT alone within this study are aimed to 
provide contemporary multicentre prospective clinical outcomes in these rare conditions. 
Furthermore, the study aims to create possibilities for future fundamental and/or translational 
research of this rare cancer by asking study participants permission for the storage and use of tumour 
tissue, imaging and treatment planning data. 
 
1. Establishing a reference for clinical outcomes with state-of-the-art treatment of vaginal cancer 
 
Estimate the incidence of treatment failure 
 
Estimate the incidence of acute and late treatment-related morbidity 
 
Estimate the impact of treatment on patient reported symptoms and quality of life 
 
2. Identification of prognostic parameters for clinical outcomes 
 
Identification of risk factors for disease recurrence and death 
 
Identification of risk factors for morbidity and reduced quality of life 
 
3. Development of evidence-based recommendations for radiotherapy treatment 
 
Evaluation of the uptake of the target concepts for vaginal cancer 
 
Evaluation of the variation in radiation doses delivered to treatment targets and organs at risk  
 
Determining the relation between radiation dose in the OAR and morbidity and quality of life 
 
Determining the relation between radiation doses in the targets and oncological outcomes 
 
Developing radiotherapy planning aims & constraints for dose to targets and OAR 
 
4. Evaluation of the use of concurrent systemic therapy 
 
Evaluation of the feasibility of completing systemic therapy 
 
Evaluate the impact of chemotherapy reduction or withholding of chemotherapy on clinical 
outcomes 
 
 
5. Creating possibilities for future fundamental or translational research 
 
Informed consent for the storage and use of FFPE tumour material, imaging and treatment 
planning data  
 
 
 

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5. STUDY DESIGN 
 
5.1 Design 
The proposed study is a prospective, observational international multi-centre cohort study on the 
treatment of vaginal cancer by radio(chemo)therapy and MRI-based IGABT. This design offers 
parallel registration of cohorts for rare histological subtypes and treatment with IGABT alone. This 
cohort study is designed as a continuous international registry, since vaginal cancer is a rare 
malignancy for which no international prospective data collections exist yet.  
The study has first opened first for inclusion in a limited number of institutions; based in Aarhus, 
Amsterdam, Leiden, Rotterdam, Vienna and Villejuif. These institutions were involved in the 
development of the GEC-ESTRO target concept for vaginal cancer and already treat vaginal cancer 
with the most up-to-date treatment equipment and techniques, and have initiated this study. 
Based on the experience of these 6 centres during the first year, the study procedures and data 
collection were further optimized. In addition, accreditation and quality assessment procedures 
have been refined for other centres that will start including after the first year.  
Patients who will be included in this registration study will receive the same treatment and have 
the same follow-up as patients who do not participate in the study. However, patients that 
participate will give informed consent for the prospective collection of their clinical and treatment 
data (including DICOM imaging and DICOM-RT treatment data). Furthermore, they will have the 
opportunity to participate in the observational patient reported morbidity and quality of life 
study, for which questionnaires will need to be filled out on a regular basis. Finally, they will have 
the opportunity to give permission for the storage and use of tumour material in future 
fundamental or translational studies. 
After inclusion, patients’ baseline data (clinical characteristics, pre-treatment morbidity and QoL) 
will be registered before the start of treatment. Treatment will be performed according to the 
local treatment protocols. However, the treatment targets and OAR will have to be defined 
according to the common MRI-based target concepts for vaginal cancer as defined in the 
published recommendations51,53 and the doses delivered to targets and OAR will have to be 
registered in a uniform way. At the end of treatment (EoT) morbidity will be assessed and patients 
who consented to participate in the morbidity and quality of life study will be invited to fill out 
the respective questionnaires. According to the standard of care, after treatment, patients are 
normally invited for follow-up assessments at the hospital at a regular basis by their treating 
radiation oncologist for at least 5 years. The follow-up assessments are expected to be scheduled 
around 3, 6,  12, 18, 24, 36, 48 and 60 months after end of treatment and will be performed 
according to the local standard practice. At each follow-up visit, the treating physician will perform 
a detailed anamnesis and physical and gynaecological examination to assess the disease status 
and morbidity. Radiological tumour evaluations (MRI pelvis and 3D imaging of thorax/abdomen) 
will be performed according to local standard practice, at a minimum MRI pelvis should be 
performed at 3 months. At the follow-up visits patients who consented to participate in the 
morbidity and quality of life study will be invited to fill out the respective questionnaires. An 
overview of the different assessments at baseline and during follow-up is provide in Table 5.1.  
 
 
 

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Table 5.1. Overview of assessments at baseline and during follow-up 
 Follow-up 
(months): 
baseline EoT 
morbidity
3 6 
 
12 18 24 36 48 60 At 
recurrence 
Clinical assessments  
Physical exam 
x 
x x 
x x x x x x x 
Gynaecological exam x 
x x 
 
x x x x x x x 
Pelvic MRI 
x 
x 
 
 
 
 
 
 
 
 
x 
3D imaging chest/abd x 
  
  
  
  
  
  
  
  
  
x 
Morbidity and QoL assessments 
CTCAE v5.0 
x 
x 
x x 
x x x x x x no 
EORTC QLQ* 
x 
x 
x x 
x x x x x x no 
Permission for storage and use of: 
FFPE material 
x 
 
 
 
 
 
 
 
 
 
optional 
* EORTC QLQ-C30 and selection of questions from the CX24, EN24 and the VU34 modules. 
Collection of questionnaires is optional at all the time points. 
 
5.2 Data 
Patient and tumour characteristics 
Assessment of the baseline parameters must take place before the start of radiation therapy. A 
detailed description of the baseline variables are provided in chapter 13. In short, relevant patient 
and tumour characteristics, such as age and performance status at diagnosis, tumour histology 
(according to WHO classification55, appendix 1) and stage (according to FIGO and TNM, appendix 
2) will be registered. 
 
Treatment parameters 
Data on the different aspects of the treatment will be prospectively registered using dedicated 
web-based CRFs (detailed description in chapter 13). This concerns the following treatments: 
 External beam radiotherapy 
 Systemic treatment 
 Brachytherapy 
 Treatment of recurrences 
Data collection of dose and treatment volume parameters will be extensive (including full DICOM 
imaging and DICOM-RT treatment data) as one of the study objectives is to develop a radiotherapy 
dose planning aims and constraints.  
 
 
Oncological outcomes 
If there is, at any time after inclusion, suspicion of disease recurrence or metastasis, a complete 
patient work-up should be performed. This includes a gynaecological examination (preferably 
under general anaesthesia), pelvic MRI, CT thorax-abdomen or a full-body (PET-)CT. Procedures 
to obtain material for pathological examination, such as biopsies of local recurrences or US-guided 
fine needle aspiration in case of suspected lymph nodes, are recommended. 
 
 

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The following events (definitions provided in chapter 10) will be registered at the date of diagnosis 
of the recurrence, which can be at any moment after inclusion in the study: 
 Local failure 
 Lymph node failure 
 Distant failure 
 Disease-related death 
To be able to perform survival analysis of the oncological outcomes the following additional data 
will be registered if applicable: 
 Death due to any other cause(s) 
 Date of last follow-up examination 
 Date lost to follow-up 
If patients are diagnosed with a recurrence or metastasis, they will be treated at the discretion of 
their physician according to the local treatment practices. The primary salvage or palliative 
treatment will be registered in the study database. 
 
Physician-reported morbidity 
At baseline and every scheduled follow-up visit (Table 5.1) the absence or presence of physician-
assessed treatment-related morbidity in the relevant organs at risk (definition in chapter 13) will 
be prospectively registered according to the CTCAE v5.0.56 This entitles that the physician will 
register whether the morbidities are present or not; and will grade the severity of the toxicity 
according to predefined criteria. For this study a selection of CTCAE v5.0. Items has been made to 
cover all relevant morbidities of the treatment of vaginal cancer:  
• Genital morbidity: vaginal haemorrhage, vaginal discharge, vaginal stricture, vaginal 
inflammation (this includes ulceration under grade 2 and 3), dyspareunia. 
• Urinary morbidity: haematuria, urinary frequency, urinary urgency, urinary incontinence, 
urinary tract obstruction. 
• Gastro-intestinal morbidity: abdominal pain, diarrhoea, faecal incontinence, rectal 
haemorrhage, proctitis, enterocolitis, small intestine stenosis. 
• Skin morbidity: radiation dermatitis (this includes necrosis under grade 3) 
• Bone morbidity: fracture  
 Lymph oedema 
 Fistula 
 Fatigue 
 
Patient-reported morbidity and quality of life 
At baseline and every scheduled follow-up visit (Table 5.1) quality of life will be scored by the 
patient herself using validated questionnaires of the EORTC.57 As there is no specific QLQ vaginal 
cancer module, questions from the modules for cervical cancer, endometrial cancer and vulvar 
cancer have been selected with permission from the EORTC item bank to cover all relevant 
disease- and treatment-related morbidities and problems surrounding sexual activity. The 
following items of the EORTC QLQ modules1 will be used (the complete questionnaire can be found 
in Appendix 3): 
 EORTC QLQ-C30, which is of general use for all cancer sites and consists of five functional scales 
(physical, emotional, social, role and cognitive functioning), a global health status/QoL scale 
and several symptom scales commonly reported by cancer patients.40 All questions of the C30 
module are used in this study. 
                                               
1 The Item Library is an online platform comprised of more than 900 individual items from over 60 EORTC 
questionnaires, some of which have been translated into over 100 languages. The item bank can be used to 
create custom-made item lists (https://www.eortc.be/itemlibrary/) 

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 EORTC QLQ-CX24, which is a cervical cancer module that covers typical disease and treatment-
related symptoms and items regarding sexuality.58 From this module a selection of 15 of the 
24 questions has been made: 4 questions that constitute the sexual and vaginal functioning 
scale, 4 single items on urinary morbidity, 1 single item on rectal haemorrhage, 1 single item 
on leg oedema, 1 single item on hot flushes, 1 single item on peripheral neuropathy and 3 
questions on sexual activity and enjoyment. 
 
EORTC QLQ-EN24, which is an endometrial cancer module that covers typical disease and 
treatment-related symptoms and items regarding sexuality.59 From this module a selection of 
5 questions has been made from the gastro-intestinal symptom scale. 
 EORTC QLQ-VU34, which is a vulvar cancer module that covers disease and treatment-related 
symptoms and items regarding sexuality. From this module a selection of 4 questions has been 
made: 1 single item on vaginal discharge, 1 single item on genital pain, 1 single item on irritated 
genital skin and 1 single item on genital oedema. 
 
Creating possibilities for future fundamental or translational research 
There is increasing knowledge of the impact of biomarkers and molecular classification in the 
context of primary endometrial (e.g. POLE, MMRd, p53abn and ER status) and cervical cancer 
(PDL-1, p16 status) and their potential impact on patient managment (refs TCGA endometrial and 
cervical cancer; ESGO ESTRO ESP endometrial cancer; BioEMBRACE and Keynote A18). However, 
knowledge of the impact and role in recurrent disease is limited. C A small number of studies have 
been conducted on retrospective series (no. of included patients 7 to 77). These small series hint 
that there a probably a number of biomarkers relevant for the patient’s prognosis: HPV60,61, MIB-
1 index62, p1663 and p53.63,64 Due to the rarity of vaginal cancer none of these single centre studies 
could include sufficient number of patients, which resulted in underpowered comparisons in all 
studies.  
The EMBRAVE registry study is an unique opportunity to ask informed consent for the use of tissue 
in a cohort that is homogenous for treatment and prospectively registers data on oncological 
outcomes. Hence, the EMBRAVE study could yield the data and the tissue to finally have sufficient 
events to discover and validate biomarkers related to disease recurrence.  
Summarizing, translational research on tumour material of vaginal cancers collected in this cohort 
may have an impact on the treatment of vaginal cancer in the future. Therefore, all patients of 
this study will be asked to consent for the storage and use of tumour material. This will concern 
rest-material of the biopsies (as formalin-fixated, paraffin-embedded tumour block(s)) that were 
obtained to diagnose and classify vaginal cancer. The choice of the patient, whether or not they 
give permission will be stored in the database. No physical tissue repository will be built until a 
meaningful number (>150) of patients have given informed consent for the storage of tissue. At 
that time, a separate research proposal for a translational study with this tissue will be written 
and presented to the involved medical-ethical committees. 
 
5.3 Endpoints 
This study is an observational, prospective registration study, wherein neither an experimental 
treatment is compared to the standard treatment, nor groups of patients are compared. As a 
result, this study has no classical primary study endpoint. Nonetheless, endpoints are defined for 
the first 3 aims of this study to ascertain proper effectuation. 
 
Aim 1: Establishing a reference for clinical outcomes with optimized treatment of vaginal cancer 
 
Oncological events 
 
The following oncological outcomes will be evaluated at 2 and 5 years after treatment: 
 Local control 
 Regional control 
 Distant control 

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 Disease-free survival 
 Disease-specific survival 
 Overall survival 
Definitions of these oncological events are provided in chapter 10. 
 
Acute morbidity  
All acute treatment-related morbidities (<3 months after treatment) will be evaluated, both for the 
scoring by the physician and by the patient at EoT and the 3-month follow-up visit. Acute treatment-
related toxicities of the following types are considered most relevant as endpoints: 
 Genital 
 Urological 
 Gastro-intestinal 
 Skin 
 Lymph oedema 
 Fatigue 
 
Late morbidity 
All selected late treatment-related morbidities (≥3 months after treatment) will be evaluated at 2 
and 5 years after treatment; both for the scoring by the physician and by the patient. Late 
treatment-related morbidities of the following types at risk are considered most relevant as 
endpoints: 
 Genital 
 Urological 
 Gastro-intestinal 
 Bone 
 Lymph oedema 
 Fatigue 
Aim 3: Development of evidence-based recommendations for radiotherapy treatment 
After the treatment of the first 50 and 100 patients has been completed, the uptake of the target 
concepts recommendations will be evaluated, based on available information on clinical tumour 
extension, available MRI imaging and DICOM structures. Results of this evaluation will be reported 
back to the GYN GEC-ESTRO to discuss and promote further development of the target concept if 
applicable. 
Once sufficient data on oncological outcomes and morbidity to the organs at risk has accrued, the 
study group will develop recommendations for dose planning priorities, aims and constraints to 
optimize local tumour control and aims and constraints for organs at risk to limit treatment 
morbidity.  
 
Aim 4: Evaluation of the use of systemic therapy 
 
Percentage of patients that completed the scheduled systemic therapy 
 
Prevalence of reasons for not completing systemic therapy 
 
Prevalence of disease recurrences with and without systemic therapy 
 
 

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6. STUDY POPULATION 
 
6.1 Population (base)  
This study is conducted within the GEC-ESTRO GYN network (Groupe Européen de Curiethérapie 
and the European Society for Radiation Therapy and Oncology) by the established EMBRACE 
research group. The EMBRACE research group has been initiated in 2008 with the aim to improve 
the clinical outcomes of cervical cancer (www.embracestudy.dk). This study group consists of 
European institutions with pioneering technical and clinical experience in the radiotherapeutic 
treatment of gynaecological cancers. The EMBRACE group has successfully conducted the world’s 
three largest international multi-centre cohort studies on cervical cancer; the RetroEMBRACE, 
EMBRACE, and EMBRACE II studies.23 These studies have generated scientific output leading to 
improvement in the treatment of cervical cancer and adoption of IGABT as the state-of-the-art 
brachytherapy treatment as reflected by ICRU report 89.  
Initially, six institutions (Aarhus, Amsterdam, Leiden, Rotterdam, Vienna and Villejuif) were 
involved in developing the target concept for vaginal cancer, and the initiation of this study. After 
a start-up phase, other centres are expected to obtain accreditation (procedure described in 
chapter 11.3) and start including patients as well. 
  
6.2 Inclusion and exclusion criteria 
Patients who are suspected of having primary or recurrent vaginal cancer should undergo the 
following diagnostic procedures before the start of treatment: 
 Gynaecological examination (preferably under general anaesthesia), including a schematic 
drawing (appendix x). 
 Histological biopsy of the tumour 
 Pelvic MRI (preferably with intravaginal gel) 
 3D imaging of abdomen and chest (CT, MRI or PET-CT); in patients with (suspicion of) nodal 
involvement or those presenting with recurrent disease PET-CT is suggested. 
 For primary vaginal cancer: staging according to the FIGO 2018 and TNM (IUCC 8th Edition) 
classification systems, appendix 2 
 
Patients who fulfil all of the inclusion criteria and have none of the exclusion criteria are eligible 
for participation in this study and should be asked informed consent. 
 
Inclusion criteria 
 
Age ≥ 18 years 
 
Histologically proven primary vaginal cancer, vaginal carcinoma in situ (VAIN) or vaginal 
recurrence, per WHO classification38 (appendix 1) 
 
Histological proven primary vaginal cancer:  
 
squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the vagina  
 
 other epithelial carcinoma’s and carcinoma in situ 
 
Histological proven vaginal recurrence from any gynaecological cancer for whom curative 
treatment is envisioned that includes image guided adaptive brachytherapy according to the 
target concept. 
 
Primary vaginal cancer: stage I-IVA  
 
Para-aortic lymph node metastasis below L1-L2 interspace are allowed 
 Macroscopic visible tumour present on MRI and/or gynaecological examination at 
diagnosis. 
 
Planned IGABT treatment with MRI-guided adaptive brachytherapy (at least the 1st fraction 
contouring and planning on MRI; CT for later fractions is allowed): 

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 
External beam radio(chemo)therapy followed by IGABT 
 
IGABT alone for stage I <2cm or carcinoma in situ 
 
Treatment with curative intent 
 
Written informed consent 
 
Exclusion criteria 
 
Primary vaginal cancers with involvement of the ostium of the cervix or vulva (these should be 
classified as cervical cancer or vulvar cancer, respectively)  
 
Metastatic disease beyond para-aortic region L1-L2 interspace 
 
Sarcomas and melanomas. 
 
Treatment only by external beam radiotherapy without brachytherapy to boost the primary 
disease 
 
Primary vaginal cancer: treatment by primary surgery or debulking surgery 
 
Vaginal recurrences: treatment by primary surgery or debulking surgery 
 
Treatment with neo-adjuvant chemotherapy followed by surgery 
 
Treatment with radiotherapy followed by surgery 
 
Previous pelvic or abdominal radiotherapy 
 
Pregnancy 
 
Treatment with concurrent systemic therapy is regarded standard care, but no concurrent therapy 
or concurrent hyperthermia instead of systemic therapy is allowed and not causing ineligibility for 
this observational study. Furthermore, use of (neo-)adjuvant systemic therapy is currently not 
recommended as standard of care in this patient population. In selected cases with very extensive 
disease this may be considered to render a patient suitable for curative radiotherapy. Given the 
ongoing research for optimal treatment strategies in locally advanced cervical cancer and 
endometrial cancer, additional systemic therapy may be considered in the near future in selected 
patients. For these reasons in this observational study this will not cause ineligibility, and we will 
register its use. 
 
6.4 Sample size calculation 
This observational cohort study is designed as a registry for vaginal cancer. As such there is no 
predefined maximal number of patients that can be included in the registry. The minimal number 
of patients required to answer the different research questions of this study will be estimated 
hereafter in order of increasing numbers. If the study is successful and includes substantially more 
than 100 patients, more advanced statistical analyses can be performed which will yield better 
understanding of the disease and its response patterns to treatment. 
N ≈ 100 
For study aim 1 (described in chapter 4), the incidence of the clinical outcomes (oncological events 
and morbidity) need to be estimated. This can be done by using estimated basic statistical 
methods, such as Kaplan-Meier analysis, and will give reasonably accurate estimations (95% 
confidence intervals ranging from -7.5% to +7.5% around the estimate) with approximately 100 
patients. Of course, estimates will become more accurate with more patients, especially for 
subgroup analysis. 
 
N ≥ 300 
For study aim 2, 3 and 4 (described in chapter 4) multivariable analyses need to be performed to 
determine the independent effect of predictors (such as dose and tumour characteristics) on 
clinical outcomes (tumour recurrence, morbidity). For a meaningful multivariable regression 

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analysis at least 10 outcome events are required per predictor. The number of predictors in the 
analyses of all endpoints cannot be defined beforehand, as these will be determined by the 
predictive value to the candidate predictors in the univariable analyses (detailed description of 
statistical methods in chapter 10). It is common to have 3-6 predictors in a multivariable model.  
This implies that at least 30-60 outcome events are required. The number of patients that is 
required for analyses will depend on the incidence of the different outcomes. For example, based 
on a retrospective study this study group conducted, the incidence of local tumour recurrence is 
estimated to be 20% at 3 years of follow-up.67 For this example, this would imply that one would 
need 1/0.20*60 = 300 patients for this analysis. Again, for these types of analyses, estimates will 
become more accurate, and conclusions more reliable with more patients in the analyses. 
 
6.5 Patient accrual and study period 
The institutions of the EMBRACE research group have investigated how many primary vaginal 
cancer patients they have been treating with radio(chemo)therapy and IGABT on average per year; 
which was 5 or 5-10.6  
During the first year of the study, only 6 institutions will open for inclusion, as described at 6.1. 
Based on the aforementioned data6, about 40 patients are expected to be treated for primary and 
recurrent vaginal cancer in these centres during the first year. It is expected that half to two thirds 
of the patients will give informed consent for participation; based on the experience of the 
research group with the registration studies on cervical cancer. Besides, the majority of the 
patients who consent to participate are expected to consent for the morbidity and quality of life 
study and the storage and use of tumour tissue as well. Thus, inclusion of about 27 patients in the 
first year seems a realistic goal.  
After the first year, the 6 centres will continue to include about 30 patients (primary and recurrent 
vaginal cancer) per year and the study will open for inclusion at other centres. It is expected that 
eventually at least 10 other centres will start including patients during the second and third year. 
Thus, the inclusion rate is expected to increase from 30 patients per year to 100 patients per year 
in the 3rd year of the study. The expected cumulative accrual over time is presented by the solid 
orange line in Figure 6.1. 
 
 Figure 6.1. Expected cumulative accrual over time 
 
0
100
200
300
400
500
600
700
800
0
1
2
3
4
5
6
7
8
9
10
NUMBER OF INCLUDED PATIENTS
YEARS SINCE START STUDY
Expected accrual
Primary vaginal cancer
Any vaginal cancer

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Based on these assumptions, it is expected that the first 100 patients will be included during the 3rd 
year and the first 300 patients during the 8th year.  
Henceforth, the first analyses which requires only about 100 patients (see 6.4), and that doesn’t 
require follow-up after treatment (such as analysis of variations in radiotherapy dose and volumes and 
feasibility of concurrent systemic therapy) could be done in the 3rd year. Analyses that require a follow-
up of only 3 months (such as tumour response evaluations and analysis of acute morbidity) may also 
be performed in the 3rd year of the study. Analyses using oncological outcomes will require a follow-
up of at least 3 years, because most of the disease recurrences are diagnosed in the first 2-3 years68,69, 
and are expected to be performed in the 6th year. The analyses that require at least 300 patients (see 
6.4) all use clinical outcomes and will therefore require a follow-up of at least 3 years. This would imply 
that these analyses could be performed at earliest in the 11th year of the study. The study period with 
this study design will be at least 11 years. 
The analyses on the relation between the radiotherapy doses and morbidity and QoL for vaginal 
recurrences could be added to the group of patients with primary vaginal cancer. For the analyses on 
oncological outcomes, the groups will be analysed separately, as recurrences of other gynaecological 
cancers might behave different than primary vaginal cancers. 
7. EXTERNAL BEAM RADIOTHERAPY TREATMENT 
 
7.1 Introduction and aims 
State of the art treatment for vaginal cancer consists of external beam radiotherapy (EBRT) with 
concurrent systemic therapy and a radiotherapy boost with MRI-based image-guided adaptive 
brachytherapy. In the participating centres, EBRT treatment is standardized and performed 
according to the protocol of the EMBRACE II study.48  
Briefly, patients are treated with 45 Gy in 25 fractions of 1.8 Gy, 5 times per week. In case of 
endometrial vaginal recurrence, EBRT schedules of 23 fractions of 2.0 Gy or 27 fractions of 1.8 Gy, 
5 times per week, are also allowed. Image guided Radiation Therapy (IGRT) with daily imaging 
(recommended cone beam CT) is delivered using intensity modulated radiation therapy (IMRT), 
volumetric modulated arc therapy (VMAT) or tomotherapy. Maximal overall treatment time 
including external beam radiotherapy, concurrent systemic therapy and brachytherapy is 50 days. 
The aim of external beam radiotherapy is to obtain regional and nodal tumour control, and to 
achieve initial regression of the primary tumour. EBRT provides a homogenous dose to which the 
steep dose gradient of the brachytherapy boost dose is added to achieve the high dose that is 
needed to obtain local control of the primary tumour.  
 
7.2 Preparation for treatment planning 
A gynaecological examination, preferably under general anaesthesia, must be performed. Local 
tumour extension should be documented by using the specifically developed cartoons (see Figures 
8.1 and 8.2).  
Imaging should minimally consist of: 1) a diagnostic T2-weighted pelvic MRI (preferably in 
treatment position in three orthogonal planes; from the aortic bifurcation to the whole vulva with 
a slice thickness ≤ 5 mm and intra-vaginal gel); 2) a PET-CT is recommended, especially in node 
positive patients, but optional; and 3) a treatment planning CT in treatment position. Slice 
thickness of the treatment planning CT scan should be ≤ 3 mm. The use of intravenous and oral 
contrast media for the treatment planning CT is optional but use is recommended to ease 
identification of structures of interest. The choice for immobilization devices is according to the 
clinical routine of the individual institutes.  

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It is recommended, to perform an empty bladder scan on top of the comfortably filled bladder 
scan. Full and empty bladder scans give information about the range of internal motion of the 
target volumes, and this can be exploited when defining an individualized ITV. Bladder is intended 
to be comfortably filled on the treatment planning CT scan and throughout the treatment. 
Therefore, a drinking protocol is mandatory with specifications on 1) timing of voiding and 2) 
timing and volume of fluid intake. An acceptable drinking protocol would be that the patients are 
asked to void 1 hour before imaging and each EBRT fraction, then drink 300-500 ml of water/clear 
fluid and try not to void before treatment delivery. 
The rectum and sigmoid should be as empty as possible. The patient is asked to empty the stools 
before scanning and treatment. If significant gas or filling is discovered while scanning for 
treatment planning (diameter of gas or filling in rectum > 4 cm maximum extension in any 
direction), the patient should be asked to empty the rectum or deflation with a catheter or 
postponing the treatment planning CT to another day could be considered.  
 
 
7.3 Definition of EBRT target and fields 
The definition of the EBRT targets, as defined by the GYN GEC-ESTRO Vaginal cancer working 
group, is provided in Table 7.1, and should be used in this study. The same definitions apply for 
vaginal recurrences. 
 
Table 7.1 GEC-ESTRO definitions of EBRT targets for vaginal cancer51 
 
GTV-Tinit 
The initial macroscopic (gross) 
tumour volume at time of diagnosis 
as described by clinical examination 
and/or imaging 
Characterized by a hyperintense signal 
intensity on T2 weighted MRI. Due to 
the limited soft tissue contrast of CT in 
the lower pelvis, the GTV-Tinit can only 
be adequately delineated using MRI in 
combination with information from 
clinical gynaecological examination. 
CTV-TLR 
The low risk clinical target volume 
consists of the GTV-Tinit, vagina, 
paravaginal 
space, 
paracolpia, 
parametria, and cervix.   
It is generally recommended to include 
the whole vagina in the CTV-TLR. For 
small (<2cm) stage I tumours located in 
the upper third, the upper two-thirds 
should be minimally included. 
CTV-E 
The elective clinical target volume 
contains 
lymph 
node 
regions 
according 
to 
the 
anatomical 
extension of the primary tumour 
and the presence of lymph node 
metastasis.  
See also PTV, any internal organ 
motion related to lymph node 
regions will be included in the CTV-
E. 
In patients with tumours in the upper 
two thirds of the vagina, delineation of 
nodal areas follows the same principle 
as in patients with cervical cancer 
(internal, external and common iliac, 
obturator and pre-sacral regions). In 
case of involvement of the lower third 
of the vagina the inguino-femoral nodes 
should be included in addition (as is 
done in vulvar cancer), however then 
omission of the common iliac area can 
be 
considered 
in 
node 
negative 
patients. In patients with multiple 
lymph node metastases including the 
common iliac region, the para-aortic 
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should be considered as part of the CTV-
E. In case of para-aortic lymph node 
metastasis the para-aortic region with 
margin 
above 
the 
most 
cranial 
pathologic lymph node should be 
included in the CTV-E.  
GTV-Nx / CTV-Nx Nodal gross tumour volume / 
related clinical target volume, with 
‘x’ specifying prescribed dose (e.g.) 
GTV-N57.5 
Additional sub volumes for EBRT by 
simultaneously boost to pathological 
lymph nodes if applicable.  
ITV-T 
Internal target volume related to 
the for the primary tumour volume 
Further margins from CTV-TLR to derive 
the ITV-T are based on available 
treatment 
planning 
imaging 
(e.g. 
planning-CT 
with 
full and 
empty 
bladder). 
PTV 
Planning target volume 
The PTV margin needs to accommodate 
random and systematic geometrical 
errors that are among others caused by: 
internal 
organ 
motion 
(here 
accommodated in ITV-T for primary 
tumour and CTV-E for nodal regions) 
and geometrical errors in positioning 
during the course of EBRT for the 
tumour and lymph node related CTVs 
(set-up errors). 
 
 
The definition of the elective nodal clinical target volume (CTV-E) depends on the location of the 
tumour in the vagina and the presence of pathological lymph nodes and risk of lymph node micro-
metastasis.  
Criteria for categorizing a lymph node as pathologic are: 
 
FDG-PET positive and/or 
 
Short axis ≥ 1 cm on CT or MRI and/or 
 
Short axis 0.5-1 cm on MRI with pathological morphology: irregular border, high signal 
intensity and/or round shape 
 
Histological / cytological proof of tumour spread to the lymph node(s) 
 
It is recommended to obtain cytological confirmation in case of suspicious inguinal lymph 
nodes. 
 
Using these criteria, tumour location and Table 7.2 allow to determine which lymph nodes areas 
should be included in the CTV-E.  
In case the patient has already undergone a complete (diagnostic) lymph node dissection at 
baseline and none of the removed lymph nodes were involved with tumour, the definition of the 
CTV-E may be adjusted accordingly at the discretion of the treating radiation oncologist.  
 
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It is recommended to use an ITV-T that accommodates target motion and to use daily IGRT to 
evaluate whether the target is being treated adequately. Margins for ITV-T are based on the 
available (pre-)treatment planning imaging (e.g. planning-CT with full and empty bladder) and 
possibilities for image-guidance during EBRT (IGRT, e.g. daily cone beam CT). 
 
PTV 
The total CTV-T to PTV-T margin needs to accommodate random and systematic geometrical errors 
that are among others caused by: internal organ motion (ITV-T) (e.g. rectum, bladder filling status) 
and geometrical errors in positioning during the course of EBRT for the tumour and lymph node 
related CTVs (set-up errors).  
The PTV margin is based on the available treatment planning imaging (e.g. planning-CT with full 
and empty bladder) and possibilities for image-guidance during EBRT (IGRT, e.g. daily cone beam 
CT). When daily soft tissue imaging (cone beam CT) is used (recommended) an isotropic of 5 mm 
margin from the combined ITV-T and CTV-E to PTV45 should be applied. 
For the involved nodes, PTV-Nx is CTV-Nx with an isotropic margin of 5 mm. Each individual 
pathologic node will have an individual PTV-Nx, with the x specifying the total EBRT dose to the 
node.  
 
Table 7.2 Definition of CTV-E 
 
CTV-E 
Lymph 
node 
involvement at baseline 
Inguino-
femoral LN 
int. iliac, ext. iliac, 
obturator,  
pre-sacral LN 
com. iliac LN 
PAO LN  
up to the 
renal vein 
Tumours involving only lower 1/3rd of the vagina 
Node negative 
yes 
yes 
no 
no 
Inguinal 
yes 
yes 
no 
no 
Pelvic below com. iliac 
yes 
yes 
yes 
no 
Common iliac  
yes 
yes 
yes 
yes 
Para-aortal 
yes 
yes 
yes 
yes, with ≥ 3 cm 
margin above most 
cranial pathological 
LN 
Tumours involving only upper 2/3rd of the vagina 
Node negative 
no 
yes 
yes 
no 
Pelvic below com. iliac 
no 
yes 
yes 
no 
Common iliac  
no 
yes 
yes 
yes 
Para-aortal 
no 
yes 
yes 
yes, with ≥ 3 cm 
margin above most 
cranial pathological 
LN 
Tumours involving the lower 1.3rd and the upper 2/3rd of the vagina 
Node negative 
yes 
yes 
yes 
no 
Inguinal 
yes 
yes 
yes 
no 
Pelvic below com. iliac 
yes 
yes 
yes 
no 

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Common iliac  
yes 
yes 
yes 
yes 
Para-aortal 
yes 
yes 
yes 
yes, with ≥ 3 cm 
margin above most 
cranial pathological 
LN 
 
 
7.4 Organs at risk and reference points: definitions and contouring 
The outer contour of the following organs should be delineated separately: 
Bladder  
 
Whole organ including the bladder neck 
Urethra 
 
From the bladder to the ostium urethra 
Rectum  
 
From the ano-rectal sphincter to the recto-sigmoid junction 
Anal canal 
 
From the external anal orifice to the ano-rectal junction 
Sigmoid  
 
From the recto-sigmoid junction to the left iliac fossa 
Bowel  
 
Bowel-bag: outer contour of bowel loops including the mesentery (no 
individual loops) 
Femoral heads  
Both femoral head and neck to the level of the trochanter minor 
For para-aortic irradiation in addition: 
Kidneys  
 
Outer contour excluding renal pelvis 
Spinal cord  
 
Outer contour 
Optional (if para-aortic RT above L1 is applied): 
Duodenum   
Whole organ 
Pancreas 
 
Whole organ 
Liver 
 
Whole organ 
In case of ovarian transposition: 
Ovary  
 
Outer contour 
 
7.5 Dose and fractionation 
Standard fractionation involves 1 fraction per day, 5 fractions per week. Hyper-fractionation is not 
allowed. All beams and segments involved in a given part of the treatment must be treated at each 
fraction. 
Unplanned treatment breaks (>2 consecutive treatment days) should be compensated by two daily 
EBRT fractions spaced by at least 6 hours. This compensation should only be performed once per 
week. To minimize the risk of consequential late damage the dose accumulation of EBRT it must 
not exceed 10.8-12 Gy per week. 
 
PTV45 
The planning aim dose and fractionation schedule for PTV45 is 45 Gy delivered in 25 fractions of 
1.8Gy, 1 fraction per day and 5 fractions per week. In case of an endometrial vaginal recurrence, 
EBRT schedules of 23 fractions of 2.0 Gy or 27 fractions of 1.8 Gy with a simultaneous boost (SIB) 
of 2.2 Gy or 2.3 Gy, 5 times per week, are also allowed. 
The dose to the PTV45, or PTV46 or PTV48.6, should be homogenous, with at least 95% of the PTV 
covered by the 95% prescription isodose, and dose maximum less than 107% of the prescribed 
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Special attention is needed for the OAR irradiation in close proximity to the GTV-Tinit where the 
high BT dose will be delivered. To ensure even less dose variation in this region, where summation 
of EBRT and BT dose is critical, a helper contour with a margin of 10 mm generated around the 
GTV-Tinit (GTV-Tinit +10mm) is recommended. The dose within this helper contour should be less 
than 103% of 45Gy to avoid hotspots in OAR walls which are likely to also receive considerable BT 
dose. 
 
PTV-Nx 
All pathological nodes are contoured (GTV-Nx, CTV-Nx). The ‘x’ denominates the boost dose level, 
e.g. PTV-N55Gy. Nodal boosting of all pathological lymph nodes by use of a simultaneous integrated 
boost (SIB), with a total number of fractions of 25 is recommended to a dose of 55-60 Gy. In case 
of an endometrial vaginal recurrence, a SIB with a total number of fractions of 27 to a physical 
dose of 59.4-62.1 Gy is allowed. Biological equivalence calculations are performed by use of the 
linear-quadratic formulation assuming that the alpha/beta value is 10 Gy for tumour effects. Dose 
attribution from brachytherapy is to be taken in account.  
Total dose to PTV-Ns of about 60 Gy EQD2 can be achieved with the following fractionation 
schedules: 
 PTV-N55Gy EBRT with SIB 25 x 2.2Gy = 55 Gy physical dose. This schedule is equivalent to 56 Gy 
EQD2 EBRT and should be use when an additional 3-4 Gy EQD2 is expected from brachytherapy 
which results in a total dose of ~60 Gy EQD2. 
 PTV-N57.5Gy EBRT with SIB 25 x 2.3 Gy = 57.5 Gy physical dose. This schedule is equivalent to 
~59 Gy EQD2 and BT dose contribution is negligible. 
 
In the study database, the local investigators will register whether boosting for suspicious or 
positive lymph nodes has been applied and which dose level(s) has been used. More detailed 
information on the DVH parameters surrounding nodal boosting can be extracted from the 
separately collected DHV and imaging data. 
 
7.6 Planning aims for targets and organs at risk 
With a prescription dose of 45 Gy to PTV45, and 55-57.5 Gy to PTV-Nx(s) if applicable, delivered in 
25 fractions, the dose volume constraints for organs at risk (OAR) summarized in table 7.3 need to 
be met. In case of other EBRT schedules (23x2 Gy or 27x1.8 Gy with/without SIB), constraints 
should be recalculated in EQD2 according to the EBRT schedule used. 
 
Table 7.3. Summary of planning aims for OAR and target 
  
  
Hard dose constraints 
Soft dose constraints 
Targets 
  
  
  
PTV45 
V95% > 95% 
Dmax<107%*  
  
ITV45 
Dmin> 95% 
  
PTV-Nx 
D98% > 90% of 
prescribed LN dose   
Dmax < 107% of 
prescribed LN dose  
  
CTV-N 
  
D50% > 102% 
Help 
contour 
GTV-Tinit 
+10mm 
  
Dmax < 103%  
OAR 
  
  
Bowel 
Dmax < 105% (47.3Gy)* 
When no lymph node boost: 
- V40Gy < 100cm3**  
- V30Gy < 350cm3**  

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*In case that lymph nodes are not boosted        
**Soft constraints which can be used as optimization constraints as they are not based on clinical 
evidence. The constraints are not supposed to be fulfilled by all patients, but rather by ~70-80% of 
the patients. 
 
 
7.7 Technique and procedures for EBRT including daily image-guidance 
IMRT, VMAT or tomotherapy based on inverse treatment plan optimization should be used to 
optimize EBRT dose distributions and to minimize the dose to OAR delivered with EBRT.  
Irradiation is given with high-energy photons. As pointed out in the introduction the dose 
contribution from EBRT has to be homogenous within this study, at least for the volume 
representing the GTV-Tinit and the CTV-TLR and the small volumes in the adjacent OAR. If this 
homogeneity is not achieved it will compromise the evaluation of dose volume effects of BT on 
local control and on morbidity.   
It is recommended to use coverage probability (CoP) dose planning principles for lymph node 
boosting as used in the EMBRACE-II study. With CoP planning principles it is assumed that the CTV-
Nx is more often occupying the central region of the PTV-Nx than the edge region. According to 
this, it is aimed to generate a heterogeneous dose across the PTV-Nx in such a way that the central 
dose >100% and the edge dose is decreased down to 90%. In case of large lymph nodes, it is 
possible to escalate the central part of the GTV-Nx to e.g. D50 > 102%, while respecting an upper 
limit of 107%. 
Daily 2D (MV or kV) or recommended 3D (CBCT or MVCT) IGRT is mandatory. The daily imaging is 
used for fusion and position verification on bony anatomy. Couch correction must be performed 
daily before treatment delivery according to the bony fusion between the on-board imaging and 
the treatment planning CT. Couch alignment should take soft tissue into account. Soft tissue 
verification (evaluation of the position of CTV-TLR) based on CBCT can be performed, but is not 
  
  
  
  
  
  
When lymph node boost or para-aortic 
irradiation:  
- V40Gy < 250cm3**  
- V30Gy < 500cm3**  
Dmax < 57.5Gy 
Sigmoid 
Dmax < 105% (47.3Gy)* 
Dmax < 57.5Gy  
Bladder 
Dmax < 105% (47.3Gy)* 
V40Gy < 75%**  
V30Gy < 85%**  
Dmax < 57.5Gy  
 
 
Rectum 
Dmax < 105% (47.3Gy)* 
V40Gy < 85%**  
V30Gy < 95%**  
Dmax < 57.5Gy  
Anal canal 
Dmax < 105% (47.3Gy)* 
V30Gy < 50% 
Urethra 
Dmax < 105% (47.3Gy)* 
 
Spinal cord 
Dmax < 48Gy 
  
Femoral heads Dmax < 50Gy 
  
Kidney 
Dmean < 15Gy 
Dmean < 10Gy  
Body 
Dmax < 107%* 
  
Optional  
 
 
  
Duodenum48 
 
V55Gy<15cm3 

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mandatory. With soft tissue verification it is possible to evaluate if the daily position is significantly 
different from expected and this knowledge can be used to decide that a new treatment plan 
would be beneficial.   
In case that 3D soft tissue verification imaging and monitoring shows that significant parts of CTVs 
are repeatedly outside the 95% isodose volume, the following should be considered:  
 Additional tattoos at the level of L2 
 Additional planning CT scan for re-planning 
 Redefining the ITV, taking the information acquired with CBCT into account. 
 Adjustment of the PTV margin (see the section on angulation of the pelvis in relation to the 
lumbar spine. 
 
Angulation of the pelvis in relation to the lumbar spine 
With para-aortic radiation, flexing of the thoracolumbar spine in relation to the pelvis can be a 
concern considering the tight PTV margin. In case of repeated residual misalignment of more than 
5mm despite daily correcting to match on bony anatomy the following procedures should be 
considered: check if immobilization device is used optimally; consider additional tattoos at the 
level of L2; consider an additional planning CT scan; a last step would be to consider to expand the 
PTV margin in the para-aortic region where the residual set-up error persists. 
 
7.8 Dose and volume reporting 
For clinical purposes the following dose and volume parameters are recorded. 
 
Volume (nomenclature)  
 
Dose and volume parameters  
GTV-Tinit (cm3)   
 
 
Volume  
CTV-TLR (cm3)   
 
 
Volume  
ITV-T (cm3, Gy)   
 
 
Volume, D98  
PTV45 (cm3, Gy)  
 
 
Volume, D98  
GTV-Nx volume (cm3)  
 
Volume  
CTV-Nx  (Gy)  
 
 
 
Volume, D98  
PTV-Nx (Gy)  
 
 
 
D98  
Bowel (cm3)   
 
 
 
V15Gy  
Bowel (cm3)  
 
 
 
V30Gy  
Bowel (cm3)  
 
 
 
V40Gy  
Bowel (cm3)  
 
 
 
V50Gy  
Sigmoid (%)  
 
 
 
V30Gy  
Sigmoid (%)  
 
 
 
V40Gy  
Sigmoid (%)  
 
 
 
V50Gy  
Bladder (%)  
 
 
 
V30Gy  
Bladder (%)  
 
 
 
V40Gy  
Bladder (%)  
 
 
 
V50Gy  
Rectum (%)  
 
 
 
V30Gy  
Rectum (%)  
 
 
 
V40Gy  
Rectum (%)  
 
 
 
V50Gy  
Body (cm3)*  
 
 
 
V43Gy  
Body (cm3)*  
 
 
 
V50Gy  
Body (cm3)*  
 
 
 
2cc 

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* Total volume (including PTV and entire body). Depending on planning system a helper structure might be 
necessary (e.g. Monaco) 
 
For research purposes, full DHV data will be stored (DICOM imaging and treatment data). 
 
 
 
 
8. BRACHYTHERAPY 
 
8.1 Introduction  
With the publication of the GEC-ESTRO recommendations for three-dimensional (3D) and adaptive 
(4D) target brachytherapy (BT) in locally advanced cervical cancer, IGABT has been introduced in 
gynaecological BT.38,40,67 The GEC-ESTRO target concept has proven useful in cervical cancer and 
clinical studies have shown improvements in local control without additional late morbidity.42-46  
Based on the results on IGABT in cervical cancer, small mono-institutional studies have been 
conducted on IGABT in primary vaginal cancer37,50,70 and vaginal recurrences. When these studies 
are compared with previous studies using X-ray based BT there seem to be an improved local 
control rate associated with IGABT, especially in larger tumours. 
So far, systematic MRI-based BT dose planning has been limited to single centre experience, but 
based on the initial promising monocentric results a cooperative group within the GEC-ESTRO was 
formed in 2013 aiming to explore and introduce (4D) adaptive BT in vaginal cancer. During the last 
years the group has held regular meetings and conducted a retrospective multicentre study on 
IGABT in vaginal cancer. This study included 148 patients treated in 5 European centres and 
showed that 4D IGABT in vaginal cancer was associated with a good local control rate and limited 
morbidity.6 The group has introduced a new GYN GEC-ESTRO target concept for IGABT in primary 
vaginal cancer. This target concept has now been evaluated and accepted for publication.51 Few 
years later, an aligned consensus for target definitions was also published for recurrent 
endometrial and cervical tumours in the vagina treated with IGABT53. Target definitions in this 
protocol are according to these concepts and recommendations. 
 
8.2 Preparations for brachytherapy 
Treatment planning for BT is based on gynaecological examination and MRI performed with the 
BT applicator in place. This can be supported by CT, especially for the process of applicator 
reconstruction. Before placement of the BT applicator a clinical assessment of the tumour 
extension is performed describing tumour dimensions and possible paravaginal involvement, as 
well as involvement of OAR. The clinical examination is documented by drawings by use of 
standard cartoons (see Figures 8.1 and 8.2 and Appendix 4). Using these drawings a clockwise 
definition of the tumour spread at upper, middle and lower third, the length of the tumour along 
the vaginal axis, the thickness perpendicular to the vaginal axis and the left-right (laterolateral) 
width of the tumour including any paravaginal extension are recorded. Due to the potential 
deformation of the vagina by the tumour, the expected tumour regression during 
radio(chemo)therapy and the possibility to stretch the vagina during the examination, tumour-free 
distances from the apex to the cranial border of the tumour (proximal) and from the caudal border 
of the tumour to the level of the introitus should be systematically reported (both at time of 
diagnosis and at time of BT). The external urethral ostium, the posterior commissure, the portio, 
the fornices (if present) and the anus represent important anatomical landmark reference 
structures. 

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Bowel preparation should be used to ensure an empty rectum and sigmoid colon. Supportive 
treatment such as low molecular weight heparin, antibiotics and analgesics are given according to 
individual patient needs and institutional practice. A Foley catheter is placed in the bladder. Each 
participating department should define standard rules for bladder filling which should be followed 
both during MRI acquisition and the subsequent BT treatment.  
The choice of MRI compatible applicator type and interstitial needles are up to the decision of each 
centre. Use of an individual mould or other customized procedures is allowed for fixation of the 
applicator according the practice of the participating institution.  
For brachytherapy, the choice of applicator and implant procedures should follow the usual 
standard of the individual department. After applicator insertion, the patient is transferred to the 
MRI scanner to obtain appropriate images with the applicator in situ.  
 
8.3 Imaging for brachytherapy 
MR images should be obtained with applicator in situ and the patient in the supine treatment 
position. To ensure a reliable reconstruction of the applicator the slice thickness of MRI should be 
≤ 5 mm (preferably ≤ 3 mm) with no interslice gap. For high field MRI (i.e. 1.5 Tesla) the 
reconstruction of the applicator can be eased by placing catheters containing water, oil, CuSO4 or 
other substances in the channels of the applicator. Transverse images perpendicular to the 
orientation of the vagina / applicator are recommended for optimal target volume / tumour 
depiction. The application of intravaginal gel should be considered for any MRI before or during 
EBRT (if no applicator is in place). An additional (“pre-planning”) MRI before brachytherapy with a 
provisional applicator (e.g. vaginal cylinder only) can help to plan the type of application (combined 
intravaginal and interstitial vs intravaginal alone) and facilitate later contouring in case of an 
extensive interstitial component which may cause additional oedema and or haemorrhaging. 
These images can also be used to generate a full pre-plan, where the required needle positions in 
relation to the target volumes can be defined upfront.71 The intraoperative use of a transrectal / 
transvaginal ultrasound can help to identify the target volume, correlate it with clinical findings 
and support the application and delineation.72 MRI compatible markers might be used for the 
identification of the maximum tumour dimensions, and support applicator position verification. 
 
Figure 8.1 Clinical drawing of vagina  
 
 

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a. With intact uterus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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b. Without uterus 
Left:  
Speculum view: from centre to periphery: cervical os, portio, fornixes (grey area 
surrounded by thick dashed line), upper third, middle third, lower third (all separated by 
thin dotted lines), hymnal remnants marking the lower vaginal boundary (grey thick 
dashed line); u = urethra; for clockwise “3D” tumour delineation 
Right:  
Sagittal view (top) with reference structures including uterus, cervical os, portio, fornixes, 
upper third, middle third, lower third (all separated by thin dotted lines) of the vagina, 
ostium urethrae, anus; for longitudinal tumour delineation 
Coronal view (below) with reference structures including uterus, cervical os, portio, 
fornices, upper third, middle third, lower third (all separated by thin dotted lines) of the 
vagina, parametria, paravaginal space; for longitudinal tumour delineation 
 
 
8.4 Applicator reconstruction and dose points for OARs 
Uncertainties of at least half the slice thickness can be present in applicator reconstruction. Great 
care should therefore be exercised when the applicator is reconstructed in the dose planning 
system. Each centre must ensure that the applicator reconstruction can be performed with an 
uncertainty of < 3 mm. Applicator reconstruction on MRI may be supported by additional CT. 
 

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Figure 8.2 Clinical drawing axial view 
Axial view in the upper third (left), middle third (middle) and lower third (right) of the 
vagina including parametria / paravaginal space; for clockwise tumour delineation 
 
8.5 Contouring for brachytherapy 
For each application, contouring for both tumour and OAR is performed on T2 weighted MRI 
sequences on transverse images perpendicular to the orientation of the vagina / applicator in a 
dedicated 3D brachytherapy dose-planning system. In case of fractionated HDR treatment with the 
applicator remaining in place, a CT with the applicator in situ may be used, aided by the MRI from 
the first fraction, to verify applicator position and target volume and OAR relation which may lead 
to adjustment of the treatment plan. However, full MRI-based IGABT is recommended. 
Applicator movements may be observed in intravaginal brachytherapy, in particular if the uterus 
has been removed, and in combined intravaginal/interstitial (perineal) brachytherapy. Techniques 
using only an intravaginal component (e.g. vaginal cylinder) may show rotations and cranio-caudal 
shifts. In combined intravaginal/interstitial techniques the applicator is fixed to the target volume 
and rotations are less likely but there may be cranio-caudal shifts due to insufficient applicator 
fixation and/or swelling due to oedema/haemorrhage. A caudal shift of the applicator appears to 
be the most critical movement leading potentially to a substantial unplanned dose reduction in 
the respective cranial parts of the target volume (and to a significant dose increase in the adjacent 
caudal region). Therefore, strategies to reduce or outweigh applicator movements are essential 
and clinical monitoring and / or repetitive imaging is recommended. This is especially the case for 
patients undergoing multi-fractionated treatments within one application. Use of markers, re-
imaging, re-positioning, re-planning and optimization of fixation should be prioritized, but 
uncertainties likely remain especially for PDR and fractionated HDR schedules lasting for a longer 
time period.  
Vaginal cancer is associated with substantial shrinkage during radio(chemo)therapy in the majority 
of patients, which needs to be taken into account for brachytherapy boost treatment planning. 
This implies the definition of different (response-related) brachytherapy target volumes according 
to the expected different cancer cell densities. Based on the expected cancer cell densities 
(decreasing with distance from the GTV) and routes of microscopic tumour extension different 
target volumes can be defined and adapted according to regression during the course of treatment 
(Figure 8.3). For IGABT the target volumes are related to the vaginal tumour and are detailed in 
table 8.1 (primary) and 8.2 (recurrences) 
 
The following targets should be contoured according to target concept recommendations51,53: 
 

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Table 8.1 Target volume concept for IGABT in primary vaginal cancer. 
GTV-Tres 
The macroscopic gross residual 
tumour volume at the time of 
brachytherapy as described by 
clinical 
examination 
and/or 
imaging. 
Clinically this is the remaining visible and palpable residual 
macroscopic tumour during gynaecological examination. 
On T2-weighted MRI this is visualised as a remaining mass 
with hyperintense to isointense signal intensity, within the 
initial tumour extension at diagnosis, GTV-Tinit. There is 
usually considerable shrinkage of GTV-Tinit, resulting in small 
GTV-Tres. This underlines the importance of proper 
documentation using clinical drawings of GTV-Tinit at time of 
diagnosis and at time of BT. 
CTV-THR 
The high risk clinical target 
volume includes the GTV-Tres 
and areas of pathologic tissue 
This includes the GTV-Tres and any abnormal thickened or 
irregular vaginal wall within the initial tumour extension 
before EBRT (GTV-Tinit). On T2-weighted MRI the thickened 
or deformed wall typically has a more hypointense 
appearance. In case of tumours infiltrating the paravaginal 
or parametrial space at diagnosis, so called ‘‘grey zones” 
can be observed, and are included in the CTV-THR. In 
accordance to cervical cancer grey zones are considered as 
signs of tumour regression in terms of conversion of tumour 
cells into fibrotic tissue and are defined as areas with hypo-
isointense signal intensity on T2-weighted MRI occurring 
within the initial tumour extension in the paravaginal or 
parametrial space. 
CTV-TIR 
The intermediate risk clinical 
target volume should include all 
significant microscopic disease 
adjacent to the CTV-THR 
The CTV-TIR should minimally encompass the initial tumour 
extension at diagnosis (GTV-Tinit), adapted to the 
anatomical situation at brachytherapy. At present, a safety 
margin of minimal 0.5 cm in tissue around the CTV-THR 
should be applied, limited by previously unaffected 
anatomical borders/compartments: e.g. pubic bone, pelvic 
wall, pelvic floor musculature, bladder, urethra, mesorectal 
fascia, rectum, anal sphincter. 
 
Table 8.2 Target volume concept for IGABT in vaginal recurrences. 
GTV-Tres 
Macroscopic gross tumor that 
remains 
at 
the 
time 
of 
brachytherapy as documented 
by clinical examination and/or 
imaging 
Has similar clinical and imaging characteristics as the initial 
GTV at diagnosis; on T2-weighted MRI this is the remaining 
mass with hyperintense to isointense signal intensity. 
CTV-THR 
Includes the GTV-Tres and areas 
on imaging and/or clinical 
examination 
that 
are 
concerning 
for 
harbouring 
macroscopic 
pathologic 
disease. On clinical examination 
this 
should 
include 
any 
abnormal thickened or irregular 
fibrotic vaginal mucosa/wall 
within the initial tumour extent. 
Has different clinical and imaging characteristics compared 
with 
GTV-Tres. 
On 
T2-weighted 
MRI 
pathologic 
abnormalities of thickened or deformed vaginal walls have 
a more hypointense fibrotic appearance and should also be 
included. In cases where tumours infiltrated the 
paravaginal or parametrial space at the time of diagnosis, 
after some regression during external beam radiation these 
areas may appear as “grey zones” and should also be 
included in the CTV-THR target volume. 
CTV-TIR 
Includes at a minimum the 
initial extent of disease at the 
time of diagnosis (GTV-Tinit), and 
should encompass a minimal 
safety margin of 0.5 cm added 
When including the original extent of disease at diagnosis 
or applying the minimal 0.5 cm safety margin in tissue, this 
expansion should be limited by the previously unaffected 
anatomic borders (eg, pubic bone, pelvic wall, pelvic floor 

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to the CTV-THR. In cases of high-
risk histologies (eg, serous 
cancer) known extensive LVSI, 
or multifocality, a larger margin 
can be added along the vaginal 
wall in the craniocaudal and 
circumferential directions. In 
the case of a complete response 
to EBRT both on imaging and 
clinical examination, only a CTV-
TIR is defined. This would 
include the original extent of 
disease in the superior and 
inferior direction and the full 
thickness of the vaginal wall to 
0.5 cm tissue depth. 
musculature, bladder, urethra, mesorectal fascia, rectum, 
and anal sphincter). 
 
 
The macroscopically normal vagina is per definition part of the CTV-TLR for EBRT but may be OAR 
at time of IGABT. Therefore, the dose to the vagina, excluding CTV-THR, will be evaluated both using 
α/β=10Gy and α/β=3Gy.  
In case of partial involvement of cervix (but without involvement of the cervical ostium) the target 
delineation for IGABT should be based in addition on the recommendations for cervical cancer.38 
This implies that the CTV-THR should always include the whole cervix in addition to the GTV-Tres and 
areas at high risk for significant residual disease in the parametrial and paracolpic space.    
In case of macroscopic residual tumour at time of brachytherapy inside the urinary bladder, 
rectum, urethra or anal canal should be contoured as GTV-Tres and included into the CTV-THR. In 
case of infiltration of these organs before EBRT and no residual infiltration at brachytherapy, only 
the initially involved organ wall without the lumen should be included in the CTV-TIR. Initially 
expansive tumour parts inside the lumen which resolved at the time of brachytherapy should not 
be included. 
 
 

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Figure 8.3 Schematic representation of the IGABT target concept32 
 
 
Schematic representation of IGABT target concept.  
 
The following OAR should be contoured:  
 
Vagina: outside CTV-THR  contouring of organ wall 
 
Bladder: The outer bladder wall is contoured 
 
Urethra: The outer urethral wall is contoured 
 
Anal canal: The outer wall of the anal canal is contoured from the anal verge to the level of 
the anal sphincter  
 
Rectum: The outer rectal wall is contoured from above the anal sphincter to the level of 
transition into the sigmoid 
 
Sigmoid: The outer sigmoid wall is to be contoured from the recto-sigmoid flexure to well 
above the parametria and the uterus (at least 2 cm) 
For all these organs the outer wall/boundary should be contoured. The outer contours of bladder, 
rectum and sigmoid are contoured systematically on each slice where the organ is represented 
from at least 2 cm below the CTV-TIR to 2 cm above the uterus. 
 
The following dose points should be defined: 
 
ICRU bladder point 
The reference points are defined according to ICRU 38.9  
 
 

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An example of target and OAR delineation according to the GEC-ESTRO target concept51 is provided 
in Figure 8.4. 
 
It should be kept in mind that these target concepts are not based on broad clinical evidence but 
represents an international agreement for an unambiguous method of recording and reporting. 
The clinical evaluation of these concepts is one of the aims of the present study. The results 
obtained may then be used to further develop these concepts for evidence based target definition 
and dose prescription for future IGABT in vaginal cancer. 
  
Figure 8.4 Example of target and OAR delineation 
 
   
 
Target delineation and OAR based on the recommended structures: GTV-Tres (white), CTV-THR (red), 
CTV-TIR (blue), vagina outside CTV-THR  (light blue), urinary bladder (yellow), rectum (light brown), 
sigmoid(green), bowel (olive), urethra (lilac), anal canal (dark brown).  
 
8.6 Treatment planning for brachytherapy 
It is mandatory that BT treatment planning of the first fraction is based on MR imaging according 
to the target concepts for vaginal cancer.51 Treatment planning for each BT fraction must always 
be based on information from MRI. It is allowed to administer more than one BT fraction by use of 
the same implant. In this case, it is allowed to do the actual dose-planning of subsequent fractions 
on CT as long as the target has been defined by incorporating information from MRI conducted at 
time of BT.  
The intention is to treat the remaining residual tumour and pathologic tissue at the primary site, 
at time of BT (high risk-clinical target volume, CTV-THR) and a safety margin that includes the 
original tumour extent at time of diagnosis (intermediate risk-clinical target volume, CTV-TIR) with 
a dose according to the general practice in the institution. 
The dose level chosen for the CTV-THR or CTV-TIR and the DVH constraints for the OAR is to follow 
the individual departmental practice. Hence, there is no general dose prescription and DVH 
constraints demanded by this study; in accordance with the observational design of this study. 
 
8.7 Planning aims & constraints for target and OAR 
Due to the rareness of vaginal cancer, there are currently no evidence-based recommendations 
for planning aims and constrains for the targets and the organs at risk.  
For primary vaginal cancer, the study of Hiniker et al.73, found a cumulative total dose >70Gy as 
independent prognostic factor for improved locoregional control and overall survival. In the 
retrospective study of this research group on the treatment of primary vaginal cancer using image-
based brachytherapy, there seemed to be an advantage in oncological outcome for patients 

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treated with a dose to the target of >80Gy, keeping in mind that no uniform target concept was 
used.6 The American Brachytherapy Society recommends to treat patients with vaginal cancer in 
the upper vagina with a total dose of 70-85Gy.74 For disease involving the distal vagina in close 
proximity to the vulva or rectovaginal septum however, caution should be exercised and 
consideration should be given to a lower total dose of 70-75 Gy and/or a lower dose per fraction 
to reduce the probability complications.74 Patients who have had poor response to EBRT or have 
large residual disease may benefit from higher total dose of 80-85 Gy.67 However, it should be 
stated that the ABS dose recommendations are not accompanied by a uniform, defined target 
volume definition. This illustrates the lack of data to support well defined dose planning aims and 
constraints, which this study aims to provide.  
With regard to organs at risk, the EMBRACE study has demonstrated dose-effect relationships for 
late morbidity to several organs at risk: amongst others bowel75, vagina76, rectum77 and bladder.78 
Based on these dose-effect relationships planning aims and limits for the doses to several OAR 
were defined for the treatment of cervical cancer in the EMBRACE II study67 using D2cc EQD2: 
Bladder aim <80Gy, limit <90Gy; Rectum aim <65Gy, limit <75Gy; Sigmoid aim <70Gy, limit <75Gy; 
Bowel <70Gy, limit <75Gy; ICRU rectovaginal point aim <65Gy, limit <75Gy. 
Based on the EMBRACE studies it would be possible to formulate dose aims and limits for vaginal 
cancer. However, because there hasn’t been any prospective registration study yet, it is not known 
whether application of the aims and limits for cervical cancer is feasible and if they apply in the 
treatment of vaginal cancer. Since vaginal cancers may be localized lower in the vagina than 
cervical cancers, and may have a different pattern of growing into the surrounding organs (such as 
urethra, bladder, rectum and anal canal), the dose distributions needed to treat the cancer 
effectively may induce a different dose distribution in the organs at risk, compared to cervical 
cancer. It is one of the objectives of this study to get an overview of the dose distributions in the 
targets and OAR. Once this overview has been obtained dose aims and limits can be developed 
more specifically for vaginal cancer. Importantly, these will also include the urethra and anal canal 
due their anatomic proximity.   
Concluding, in the current study it is expected that the participating centres follow the individual 
departmental practice during brachytherapy dose planning and optimisation. Only centres 
experienced in performing MRI-based IGABT will be included, and it is expected that the doses to 
the OAR are kept as low as reasonably achievable while optimally covering the targets. 
 
8.8 Dose and volume reporting 
For clinical purposes, the following dose and volume parameters are recorded. Recording and 
reporting follows the recommendations of ICRU Report 89 for cervical cancer, where all 
parameters included in level 1 and level 2 of the reporting standards are included: The physical 
absorbed doses will be registered, EQD2 doses may be calculated at a later stage by the research 
group for statistical analysis. 
 
Volume (nomenclature)  
 
Dose and volume parameters  
GTV-Tres  
 
 
 
Volume, D98 
CTV-THR  
 
 
 
Volume, D98, D90, D50 
CTV-TIR  
 
 
 
Volume, D98, D50 
Bladder  
 
 
 
D0.1 cm³, D2 cm³ 
Urethra 
 
 
 
D0.1 cm³, D1 cm3 
Rectum  
 
 
 
D0.1 cm³, D2 cm³ 
Anal canal  
 
 
D0.1 cm³, D2 cm³ 
Sigmoid  
 
 
 
D0.1 cm³, D2 cm³  
Bowel  
 
 
 
D2 cm³  

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ICRU bladder point  
 
Point dose 
Vagina outside CTV-THR 
 
D0.1 cm³, D98, D50 
TRAK 
 
 
 
total, intracavitary component, interstitial component 
For research purposes, full DICOM-RT (imaging and treatment data) will be stored.  
Data on the planning and execution of the brachytherapy procedure that cannot (easily) be 
deducted from the DICOM data will be registered in the database by the local investigators. 
 
 

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9. SYSTEMIC THERAPY 
 
9.1 Introduction and aims 
There are no randomized data that address the use of chemotherapy concomitant to RT of vaginal 
cancer. Weekly Cisplatin is recommended based on data from cervical cancer79 and a large 
population study in vaginal cancer72, suggesting an additional survival benefit of concomitant 
radiochemotherapy compared to radiotherapy alone. 
 
9.2 Concurrent chemotherapy 
Chemotherapy is given according to the meta-analysis on the added value of concurrent cisplatin 
to radiation therapy in cervical cancer. Cisplatin is to be given intravenously at a dose 40 mg/m2 
once a week for a total of preferably 5-6 cycles according to institutional practice. While cisplatin is 
the preferred radiation sensitizer, other combination systemic therapies are also allowed during 
radiotherapy. Treatment with Cisplatin should be withheld at the discretion of the centre. Several 
guidelines on chemo-radiation protocols exist for cisplatin withhold.80-82 Leucocytes and 
granulocyte numbers are used as constraints for withhold of cisplatin. Guidelines for withhold vary 
for leucocytes counts around 2.500 or for granulocytes counts between <1,5 to 1.0 X 109 cell/L. For 
platelets institutional guidelines for cisplatin dose reduction should be followed and cisplatin can 
be resumed in the next cycle once the blood counts exceed these limits.  
The dose of Cisplatin should be reduced if two consecutive cycles of chemotherapy have been given 
at dose zero. Cisplatin dose should also be reduced in case of neutropenic fever. Cisplatin should 
be totally discontinued if blood tests remain unacceptable or neutropenic fever recurs despite dose 
reduction. Cisplatin should also be abandoned in case significant auditory problems (tinnitus, 
deafness) or neuropathies > grade 2 develop. 
Measurement or calculation (Cockroft-Gault) of GFR is performed before/during treatment. 
Treatment with Cisplatin is abandoned if GFR < 50 ml/min. Haemoglobin should be monitored 
during treatment. Corrections by transfusion according to institutional guidelines are allowed. 
 
Recommended agent  
dose/day  
Route   
Frequency  
Cisplatinum  
 
 
40mg/m2 
 i.v. in 3 hours  Weekly for 5-6 cycles 
 
 
9.3 Use of (neo)adjuvant systemic treatments 
Currently, use of (neo)adjuvant systemic treatment for downsizing of the tumour in vaginal and 
cervical cancer is used. Research is ongoing regarding the use of neoadjuvant chemotherapy in 
patients with high risk feature, or the use of other systemic treatments (e.g. immunotherapy) in 
cervical or endometrium cancer based on specific molecular profile classification. 
Given the current evolution of application of other systemic treatments in the context of vaginal 
cancer and vaginal recurrences of cervical and endometrial cancer, the use of these treatments, 
despite not being the current standard of care, will be register in the EMBRAVE database. These 
patients will be evaluated for response after the neo-adjuvant systemic treatment, and at this 
moment will be eligible for inclusion in the study if planned to receive primary radiotherapy 
according to the EMBRAVE protocol including EBRT followed by an IGABT boost. 
 
 
 

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10. METHODS 
This is an international registration study of patients with vaginal cancer that aims to improve clinical 
outcomes after curative treatment. Several aims and endpoints were defined to ascertain proper 
effectuation of the study. Below the procedures and statistical methods are described per research 
aim. 
 
10.1 Establishing a reference for clinical outcomes of vaginal cancer 
If there is, at any time after inclusion, suspicion of disease recurrence or metastasis a complete patient 
work-up should be performed according to local standard practice. This preferably includes a 
gynaecological examination, pelvic MRI, CT thorax-abdomen or a full-body (PET-)CT. Procedures to 
obtain material for pathological examination, such as biopsies of local recurrences or US-guided fine 
needle aspiration in case of suspected lymph nodes, are recommended. Imaging at time of recurrence 
if available will be collected as part of this study protocol. 
 
 
Definitions 
 
‘Local failure’ is defined as: a new, recurrent or progressive residual tumour within the external 
beam low-risk clinical target volume (CTV-TLR). This also applies to local failures in the area that 
retrospectively should have been included in the CTV-T-LR at diagnosis. E.g. distal vaginal 
recurrences outside the CTV-T-IR in patients with a proximal tumour at diagnosis.  
 
‘Regional failure’ is defined as: a new, recurrent or progressive residual tumour within the 
clinical target volume of the external beam radiotherapy (CTV-E) and/or the area that should 
have been treated with EBRT; which is not a local failure. 
 
‘Locoregional failure’ is defined as: a recurrence that is either a local recurrence, or a regional 
recurrence, or both. 
 
‘Distant metastasis’ is defined as: one or more new tumour localization(s) outside the clinical 
target volume of the external beam radiotherapy (CTV-TLR and CTV-E) and/or the area that 
should have been treated with EBRT. 
 
‘Disease control’ is defined as absence of: a local, regional, locoregional failure or distant 
metastasis, or a combination of these events. 
 
‘Disease-specific death’ is defined as: death directly or indirectly due to vaginal cancer, 
including fatal treatment-related morbidities. 
 
‘Death’ is defined as: death due to any cause, including disease-specific death. 
 
Definitions of the survival times for the oncological outcomes: 
 
Local-, regional-, locoregional-control and distant control times are all defined to start at the 
first day of radiotherapy. These survival times are defined to end, for patients with the event 
of interest, at the date of diagnosis of the failure event. For patients who died without the 
failure event of interest, the endpoint of survival time is defined as the date of death. For 
patients who are alive without diagnosis of the failure event of interest, the endpoint of 
survival is the date of the last follow-up examination. For patients who got lost to follow-up, 
without a known status of the failure event of interest, the endpoint of survival is also the date 
of the last follow-up examination, or the date of the last treatment day in patients who are 
lost to follow-up before their first follow-up examination. 
 
Disease-free survival is defined to start at the first day of radiotherapy and to end at the date 
of diagnosis of the first failure event, which may be local, regional, locoregional failure or 
distant metastasis. For patients who died without any of these events, the endpoint of survival 
time is defined as the date of death. For patients who are alive without diagnosis of any of 
these events, the endpoint of survival is the date of the last follow-up examination. For 

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patients who are lost to follow-up, without a known diagnosis of any of the events, the 
endpoint of survival is the date of the last follow-up examination, or the date of the last 
treatment day in patients who got lost to follow-up before their first follow-up examination. 
 
Disease-specific and overall survival time are defined to start at the first day of radiotherapy 
and to end at the date death. For patients lost-to-follow-up, survival time ends at the date of 
lost to follow-up. For patients who are alive, survival time ends at the last date that is was 
known that they were alive; this may be the date of the last follow-up examination, but this 
may also be the last date they had contact with any health care provider, or the last date they 
are known to be alive according to (national) registries. 
 
Definitions for morbidity outcomes: 
 
Relevant morbidity (definition in chapter 13) will be assessed by the physician and the severity 
will be graded (from 0 ‘absent’ to 5 ‘lethal’) according to the CTCAE v5.0 system, which is a 
validated and internationally established system developed by the National Cancer Institute.56 
 
Patient-reported morbidity and quality of life will be assessed using the EORTEC QLQ-C30 and 
additional items  from 3 EORTC QLQ modules (defined in chapter 13).57  
 
Acute treatment-related morbidity is defined as any morbidity event occurring after start of 
treatment (first fraction of EBRT) and ≤3 months since completion of treatment. In patients 
with morbidity before start of treatment (at baseline), morbidity will be considered treatment-
related if the grading increases compared to baseline.  
 
Late treatment-related morbidity is defined as any morbidity event persisting over or occurring 
> 3 months after completion of treatment. 
 
For actuarial analysis, the most severe (highest graded) morbidity event per organ at risk will 
be considered for analysis. In case of multiple equally high graded morbidity events in one 
OAR, the earliest event will be considered for analyses. 
 
Morbidity will be censored in patients with disease recurrence 3 months before the date of 
diagnosis of the recurrence. 
Statistical methods 
Tumour response to therapy will be described as crude percentages of the different response 
categories. For any subgroup analysis, the significance of the difference between groups will be 
assessed using the Chi2 or Fisher’s exact test, depending on the numbers available for analysis. 
Statistical significance will be defined as a p-value <0.05. 
For all oncological outcomes, mean and median survival times and the percentage of patients that 
is still event-free at 2 and 5 years of follow-up will be calculated using Kaplan-Meier’s 
methodology. For any subgroup analysis, the significance of the difference between groups will be 
assessed using the log-rank test and/or univariable regression analysis using Cox proportional 
hazard models. Statistical significance will be defined as a p-value <0.05. 
For all morbidity outcomes, the prevalence at listed time points will be calculated and the 
cumulative incidence of the various morbidity events will be estimated at 2 and 5 years of follow-
up using Kaplan-Meier’s methodology. For any subgroup analysis, the significance of the difference 
between groups will be assessed using the log-rank test. Statistical significance will be defined as 
a difference with a p-value <0.05.  
In addition, morbidity will be also evaluated by a specific methodology developed within the 
EMBRACE I study for evaluating late, persistent, substantial, treatment-related symptoms 
(LAPERS).83 
 
10.2 Identification of prognostic parameters for clinical outcomes 
Identification of prognostic parameters is essential to understand disease behaviour and to guide 
future treatment decisions. The final selection of the relevant outcomes and candidate predictors 

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will be made when sufficient data has accrued based on the incidence and severity of the 
oncological and morbidity events.  
Concerning the clinical outcomes, these are expected to include: 
 Local. regional and distant control at 2 and 5 years 
 Disease recurrence at 2 and 5 years 
 Overall survival at 2 and 5 years 
 Overall grade 3-5 morbidity at 2 and 5 years 
 Substantial and persistent morbidity as defined by the LAPERS method69 
 Summary score of the QLQ-C30 over time 
 Functional and/or symptom scales or items from the EORTC questionnaires over time 
 Concerning candidate predictors, they are expected to include: 
 
Radiotherapy dose 
 
Completion of (a substantial part of) concurrent systemic therapy 
 
Tumour histological type, size and stage 
 
Response to external beam radio(chemo)therapy as assessed at time of brachytherapy 
 
Tissue and/or imaging based biomarkers 
Cumulative radiotherapy dose of external beam radiotherapy and brachytherapy will be calculated 
as biologically equivalent dose in 2 Gy per fraction (EQD2) of these two treatments using the linear-
quadratic model with a α/β = 10 Gy for targets and α/β = 3 Gy for late normal tissue damage. The 
repair half time is assumed to be 1.5 hrs. 
 
Statistical methods 
Cox proportional hazards models will be used to identify prognostic parameters for time-
dependent events with a single occurrence (such as the oncological outcomes and occurrence of 
severe morbidity). Initially, the uncorrected prognostic value of a-priori defined candidate 
predictors (such as tumour stage and radiotherapy dose) will be estimated by univariable 
regression analyses. Thereafter, the candidate predictors that had a p-value <0.10 in univariable 
analysis, will be entered together in a multivariable regression analysis. Multivariable models 
consisting of only independent prognostic predictors will be built using a step-wise backward 
elimination procedure of variables with p-values ≥0.05. If necessary, corrections will be made for 
multiple testing by lowering the latter cut-off for the p-value to ≥0.01. 
Linear mixed models (LMM; for continuous outcomes) or generalized estimated equations (GEE; 
for categorical outcomes) will be used to identify prognostic parameters for outcomes that 
regularly measured during follow-up; such as morbidity and QoL. The exact set-up of these 
analyses will depend on the eventually selected outcomes and candidate predictors. Patients will 
be included as random effects in the analysis and time as fixed effect. Independent predictors of 
will be identified by subsequent univariable and multivariable analyses with corrections for 
multiple testing if necessary.  
 
10.3 Development of evidence-based recommendations for radiotherapy treatment 
The recommendations for the radiotherapy dose planning will be determined by consensus of the 
research group. Optimized dose aims & constraints for targets and organs at risk will be defined. 
The doses will be chosen based on the balance between the chance to reach tumour control and 
the risk of radiation-induced morbidity.   
 
Statistical methods 
To determine the relation between radiation dose in the targets and oncological outcomes, 
univariable Cox regression analysis (described in chapter 10.2) will be conducted with the array of 

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DVH parameters. To determine the relation between radiation dose in the OAR and late morbidity, 
univariable Cox regression analysis (described in chapter 10.2) will be conducted with the array of 
DVH parameters and the a-priori defined morbidity outcomes of the appurtenant OAR. 
Based on radiobiological principles, it is expected that these analyses will show a consistent pattern 
between dose and tumour response on the one hand and a relation between dose in the OAR and 
late morbidity. Hence, dose-effect curves will be deducted from the estimates of the analyses.  
Once the dose-response relationships of both tumour control and late morbidity are known and 
can be presented graphically to leading clinical experts, consensus meetings to determine 
optimized dose aims and constraints can be organized. 
 
10.4 Evaluation of the use of systemic therapy 
The use of systemic concurrent treatment will be evaluated based on the following evidence from 
this study: 
 
Feasibility of completing current systemic therapy 
 
Prevalence of systemic-therapy-related morbidities limiting completion of concurrent 
chemotherapy 
 
Use of (neo)adjuvant systemic therapies 
 
Estimated benefit of systemic therapy, compared to radiotherapy alone 
 
Definitions 
 
Concurrent systematic therapy is defined to be completed if the patient has received (an 
equivalent of) the prescribed dose at start of therapy. The most commonly prescribed systemic 
therapy is expected to be Cisplatin. Patients who have received at least 5 cycles of Cisplatin 
dosed at 40mg/m2 during radiotherapy are defined to have completed their treatment. Other 
types of radio-sensitizing concurrent (systemic) therapies will be registered.  
 
(Neo)adjuvant systemic therapy refers to any systemic therapy that is regarded as part of the 
complete curative intent therapy either preceding or following (chemo)radiotherapy and 
brachytherapy. 
 
Morbidity events (defined in chapter 13) will be scored by the physician (from 0 ‘absent’ to 5 
‘lethal’) according to the CTCAE v5.0 system developed by the National Cancer Institute.56 In 
addition, physicians will register the reason for not completing systemic treatment; e.g. 
haematological morbidity, reduced kidney function, hearing deficits, nausea/vomiting etc. 
 
Statistical methods 
The feasibility of completing concurrent systemic therapy will be described by the mean and/or 
median received dose and cycles. In addition, the percentage of patients that completed a full 
concurrent systemic therapy course will be described as a crude percentage.  
Prevalence of reasons for not completing systemic therapy will be reported as crude percentages. 
For any subgroup analysis, the significance of the difference between groups will be assessed using 
the Chi2 or Fisher’s exact test, depending on the numbers of events. Statistical significance will be 
defined as differences with a p-value <0.05. 
Estimation of the added value of concurrent systemic therapy compared to radiotherapy alone in 
this observational study is expected to be biased due to confounding by indication. Nonetheless, 
an attempt will be made to produce a reliable estimate (corrected for confounding) because there 
will probably never be a randomized controlled trial on the added value of chemotherapy as 
vaginal cancer is such a rare malignancy. The difference in the hazard of having a disease 
recurrence between treatment with or without systemic therapy will be estimated using a Cox 
proportional hazard model. A multivariable model will be built with this variable and the significant 
prognostic parameters identified in chapter 10.2. The model’s estimate of the hazard ratio will give 
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and disease recurrence, but it should be interpreted with caution. If the numbers of events suffice, 
analysis will also be performed stratified by disease stage at diagnosis. To assess whether patients 
at high risk of disease recurrence, benefit more from systemic therapy than those with a low risk 
of recurrence. 
 
 
 
 
 

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11. QUALITY ASSURANCE 
 
This study will have two study phases: in the first phase only 6 institutions (Aarhus, Amsterdam, Leiden, 
Rotterdam, Vienna and Villejuif) will open for inclusion. In the second study phase, other institutions 
are expected to obtain accreditation and open for inclusion as well.  
 
11.1 Entry requirements for study phase I 
The first 6 institutions (Aarhus University Hospital, Amsterdam UMC, Leiden UMC, Erasmus MC, 
Medical University of Vienna and Gustave Roussy) have their usual care for vaginal cancer patients 
protocolled in accordance with the entry criteria: 
 
Diagnostic work-up as described in chapter 6.2. 
 
External beam radiotherapy as described in chapter 7. 
 
Brachytherapy as described in chapter 8. 
 
Concurrent systemic treatment as described in chapter 9. 
 
Follow-up as described in chapter 5.1. 
In addition, the centres will provide the central data manager with (proof of) the following: 
 
Signed research contract (details in chapter 13.3). 
 
Permission from the local authorities to conduct the study, such as an institutional medical 
ethics committee, the Board of Directors, departmental science committee or department 
head 
 
Names and contact details (including direct phone numbers and email addresses) of the local 
principal investigator, other investigators and research nurses or assistants.  
 
Choice for either the paper or the digital procedure for the data collection of patient-reported 
outcomes (described in chapter 13.1) and proof of having put in place the means to follow the 
appurtenant procedure in. 
 
The local responsible for data entry should have read the instructions and will receive a training 
on data-entry in the e-CRF system. 
Confirmation of accreditation for study phase I will be given by a letter of principal investigator to 
the local investigator. 
 
11.2 Eligibility questionnaire and dummy run 
An eligibility questionnaire will be administered to new centres that express interest in being 
included in the study. The questionnaire is intended to verify that the centre meets the minimum 
requirements of the protocol. If not, the centre will receive detailed feedback and the accreditation 
will not continue further. If the screening is positive, the centre will be invited to continue the 
accreditation to the study with a dummy run focused on brachytherapy contouring according to 
the new target definitions. The  dummy run procedure is based on the experience of the 6 main 
study centres. In general, new centres should be experienced with the treatment of cervical cancer 
IGABT to get accreditation for participation in study phase II. The aim of the dummy run is to ensure 
that all participating institutes adhere to the brachytherapy target concept contouring as described 
by the protocol. The coordinating group will provide the candidate centres with an (anonymous) 
patient case and imaging data. The candidate centres have to simulate contouring for 
brachytherapy targets and organs at risk. Centres will be given the opportunity to improve their 
contouring and perform another dummy run in the case the first attempt is not successful. 
Confirmation of a successful dummy run will be given by a letter from principal investigator to the 
local investigator.  
 
 

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11.3 Accreditation for study phase II  
Other institutions that aim to get accreditation for participation will need to successfully complete 
a dummy run for brachytherapy contouring (described at 11.2). Further, they will need to provide 
the central data manager (based in Erasmus MC) with (proof of) the following to obtain 
accreditation for participation in study phase II: 
 
Confirmation that local usual care for vaginal cancer patients is protocolled in accordance with 
the entry criteria: 
o Diagnostic work-up as described in chapter 6.2. 
o External beam radiotherapy as described in chapter 7. 
o Brachytherapy as described in chapter 8. 
o Systemic treatment as described in chapter 9. 
o Follow-up as described in chapter 5.1. 
 
Signed research contact (details in chapter 13.3). 
 
Permission from the local authorities to conduct the study, such as an institutional medical 
ethics committee, departmental science committee or department head 
 
Names and contact details (including direct phone numbers and email addresses) of the local 
principal investigator, other investigators and research nurses or assistants.  
 
Choice for either the paper or the digital procedure for the data collection of patient-reported 
outcomes (described in chapter 13.1) and put in place the means to follow the appurtenant 
procedure. 
 
The local responsible for data entry and will receive a training on data-entry in the e-CRF. 
Confirmation of accreditation for study phase II will be given in writing by the principal investigator 
to the local investigator. 
 
11.4 Quality Assessments procedures 
During the first phase of the study, the Quality Assessment (QA) procedure will be developed based 
on the experience of the 6 main study centres. In general, a QA procedure will be performed of 
every participating centre after the first year of opening the study. The first patient included by the 
centre will be evaluated to verify that to the brachytherapy contouring as described by the protocol. 
Contouring will be compared to the concept recommendations32,addrecurrences Dose planning will be 
compared to the accepted dose ranges. Centres will be given feedback on their performance, and 
additional cases will be reviewed if necessary. Confirmation of a successful QA will be given by a 
letter from principal investigator to the local principal investigator. 
 
11.5 Safety evaluations 
As this is an observational study, no independent DSMB will be installed.  
 
 
 

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12. ETHICAL CONSIDERATIONS 
 
12.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (last 
amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013).84 and in 
accordance with the Medical Research Involving Human Subjects Act (WMO)85and the General 
Data Protection Regulation of the EU (GDPR)86 This study protocol will be approved by the local 
Research Ethics Committees in each of the participating centres, in accordance with national 
legislation and guidelines, before start of the study. This trial is already registered at the registry 
www.clinicaltrials.gov with identification number NCT06514235.. 
 
12.2 Patient identification 
As this study will be conducted in accordance with the General Data Protection Regulation86, 
directly identifiable patient data will not be processed in this study. Instead, patient data will be 
handled in a coded fashion. Each patient consenting to participate in the study will get a unique 
study number. All data that will be entered in the central study database is stored in a record 
identifiable by this study number. The data that will be entered in the central study database will 
not be directly identifiable. Hence, directly identifiable data such as names, date of birth or 
identification number of the local hospital will not be stored centrally. Moreover, only the local 
data managers and local investigators will be able to link the study number to the identity of the 
patient. The key file containing the link between the study number and the identity of the patient 
is stored at a safe location at the recruiting centre and will only be accessible for the local study 
team. Data protection procedures will be put in place according to local legislations and guidelines. 
Once the link between the study number and the identity of the patient is no longer necessary 
according to applicable laws and regulations the key file will be deleted. 
 
12.3 Informed consent and patient enrolment procedure 
If a patient with vaginal cancer is diagnosed in or referred to one of the participation hospitals, the 
local investigator will check whether she is eligible to participate in this study (in- and exclusion 
criteria described in chapter 6.2).  
If the patient is eligible, the patient will be informed by her treating radiation oncologist or 
(research) nurse about the possibility to participate in this study. All patients will be informed 
about the aims of the study and its observational design. It will be emphasized that participation 
in this study is voluntary and that their treatment will not be influenced by the decision to 
participate or not participate in the study. Patients will be asked to participate in all aspects of the 
study; however, patients may decline participation in the quality of life questionnaire study and/or 
decline permission for the storage and use of tumour tissue at any time point in the future. 
Relevant aspects of the handling of their data will be communicated. The patient information 
folder of this study will be used to guide the communication of the information and will be 
provided to the patient to reflect on the information afterwards. The informed consent document 
will be also be explained and provided to the patients.  
Thereafter, patients will be given a reasonable period of time to reflect on the information and to 
take an informed decision on participation. Written informed consent must be obtained before 
patients can be included in the study and registered in the central study database. Informed 
consent must be dated and signed by the patient, or its legal representative, before inclusion in 
the study. In addition, patients who consent to participate in the morbidity & quality of life study 
should fill out the baseline morbidity and QoL questionnaires before start of treatment. After 
inclusion in the study, patients always have the right to withdraw from the study. At any moment, 

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patients have the right to ask questions and to be informed about the study by local investigator 
or an independent person. 
 
12.4 Benefits and risks for patient 
The current study is an observational study wherein clinical outcomes of usual care for vaginal 
cancer patients, provided in accordance with local treatment guidelines, are registered. As such, 
there are no experimental interventions performed in this study. Hence, there is no potential 
benefit or risk for the patients participating in this study. However, the aim of this study is to collect 
data in order to optimize treatment of vaginal cancer and improve clinical outcomes of future 
vaginal cancer patients. 
Communication of the potential benefits and risk of the treatment (which is thus not experimental, 
but usual care) is the responsibility of the local treating physician(s). 
 
12.5 Insurance of study participants 
Since this is an observational study, participation does not expose the patients to additional risks. 
Therefore, insurance of study participants is deemed not necessary. 
 
 

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13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
13.1 Handling and storage of data and documents 
Data will be handled and stored in accordance with the regulations stated in chapter 12.1.  
Handling and storage of essential study documents 
The sponsor will store essential documents in the Trial Master File. For each site the essential study 
documents, like the documentation of the local permission procedures and the signed informed 
consents of the locally included patients, will be stored locally. Storage as long as the study is active 
will be at a secured location that is accessible for only authorized personnel. It is each centre’s 
responsibility to arrange this according to the local regulations. At the end of study documentation 
will be moved to the study archive until the legal storage period of 15 years has passed. The 
department heads are responsible for the management of the archive and destruction of the files. 
 
Collection and handling of physician-reported data 
Data will be collected by the local investigators on the following fixed moments during the study 
(which is conform the follow-up schedule in standard care): 
 
Baseline (which is before start of radiotherapy) 
 
End of Treatment (EoT) 
 
3 months of follow-up 
 
6 months of follow-up12 months of follow-up 
 
18 months of follow-up 
 
24 months of follow-up 
 
36 months of follow-up 
 
48 months of follow-up 
 
60 months of follow-up 
And data will be collected by the local investigators on the following events at the moment these 
occur:  
 
Any disease recurrence (defined in chapter 10.1) 
 
Death 
 
Lost to follow-up 
 
Withdrawal (of consent) 
 
A dedicated web-based CRF is designed for each of these moments and events. The local 
investigator will be responsible for the timely and accurate completion of the CRF on the specific 
time points within a reasonable time (i.e. within 3 months after patient visited the hospital).  
 
Collection and handling of patient-reported data 
Morbidity and quality of life questionnaires will be filled out by the patients at all aforementioned 
fixed moments. Each participating centre will be responsible for the distribution and collection of 
patient reported outcome measures (PROMs) for their own patients in the native language of the 
patient conform study protocol. The Dutch participating sites will be offered the opportunity to 
delegate the scheduled digital distribution and collection of questionnaires during follow-up to the 
study team in Erasmus MC. The patients included in these sites should give explicit written consent 
for the transfer of identifying personal data to the Datacentre at Erasmus MC for this purpose. For 
logistic reasons it is recommended to always collect the baseline set of questionnaires on paper 
during a pre-treatment visit at the clinic, to ensure this pre-treatment assessment will not be 
missed for logistical or administrative reasons of any kind in the relative small time window 
between date of written informed consent and start of treatment. The paper baseline 
questionnaire can be entered manually in the e-CRF afterwards by the local investigator or his/her 

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delegate. For the non-Dutch participating centres, the PROMs should be entered manually in the 
e-CRF by the local investigator or his/her delegate.  
Procedure for digital data collection: The local site staff will provide the Datacentre at Erasmus MC 
with the following patient details for the purpose of central distribution and collection of on-line 
questionnaires: patient’s full name, email address, date of birth, telephone number, and 
(expected) date of treatment completion. These identifying patient data will only be transferred 
to the Datacentre after explicit written informed consent has been obtained for this purpose by 
the local site staff (“NAW form”). The identifying data will be stored at Erasmus MC at a secured 
server location. During follow-up, the local investigator is responsible for providing the Datacentre 
with relevant updates in these patient data such as study withdrawal, disease progression, death, 
change of email address or telephone number, change in (expected) date of treatment completion. 
At the Datacentre all questionnaires will be scheduled and distributed according to the study 
protocol using a validated tool for the management of online questionnaires for patients. On 
protocol time points the patients will receive an e-mail containing a secure link to the online 
questionnaires, together with instructions on completion. The Datacentre will monitor the patient 
compliance on a weekly base and remind/contact the patient and/or site staff in case of any non-
response to the scheduled questionnaires. 
 
Procedure for paper data collection: The local investigators will provide the patient with the bundle 
of printed questionnaires (which are all marked at each page with the patients’ study number and 
not with any identifiable data) around each follow-up visit (allowed range: a maximum of 3 weeks 
before or 3 weeks after). Each participating site will put decent procedures in place to ease and 
assure collection of the filled out questionnaires. Examples are: letting patients fill out the 
questionnaires directly at the outpatient clinic at the day of their visit; or handing out (or sending 
by mail) the bundle of questionnaires with addressed and stamped return envelopes combined 
with a protocolled sequence of reminders to non-responders. After the completed questionnaires 
have been retrieved from the patients, the local investigator, or his/her delegate, is responsible 
for entering the data into the database. In addition, they are responsible for monitoring and quality 
assurance of this paper-to-digital data transfer. Finally, the local investigators are responsible for 
safe storage of the questionnaires during the storage period conform applicable laws, regulations 
and institutional policies.  
 
Data storage 
The online database system Castor will be used to collect and store the data. Castor e-CRF is GCP 
(Good Clinical Practice) compliant and has a build-in audit trail. Data storage is compliant with all 
relevant regulations, such as FDA, EMA, GDPR, ICH-GCP, and applicable data practices and security 
standards. The local investigators will only have access to the data of the study participants of their 
centre. The central team of investigators and data managers, based in Erasmus Medical Centre, 
will have access to the data of all study participants. Access to the data may be secured by two-
factor-authentication where needed to comply with (local) information security requirements. A 
detailed description of protection of the participant’s privacy and handling of the key to the code 
is described in chapter 12.2.  
 
Imaging data 
Central storage of pseudonymized DICOM images and dose distributions will be done at a secured 
server at Erasmus MC, using the unique patient study number (12.2) as identifier. DICOM images 
from diagnosis and treatment including dose distributions will be sent or uploaded directly after 
completion of treatment. Follow-up DICOM images will be sent or uploaded within a reasonable 
time period after they have become available. Further logistical details are provided in the most 
recent version of the study manual.   

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Data will be stored during the applicable legal storage period for study data of 15 years after the 
end of the study. 
 
13.2 Monitoring and Quality Assurance 
Data will be monitored on a continuous base by the principal investigator and his  delegates on 
missings, data inconsistencies and protocol deviations. As part of the site activation procedures 
the Sponsor will train the Local Investigator (and his/her team) on study procedures such as 
informed consent, patient enrolment, CRF completion and administration of essential trial 
documents. The Local Investigator should ensure that study related tasks will only be delegated to 
qualified persons who are familiar with the study protocol and applicable procedures. If indicated, 
the Sponsor may decide to perform a monitoring site visit in a participating site. The scope and 
purpose of such a monitoring visit will be communicated with the Local Investigator in the 
announcement letter sent by the independent Monitoring Team that will perform the monitoring 
visit on behalf of the Sponsor.  
 
13.3 Public disclosure and publication policy 
Research contracts need to be signed by each participating centre as part of the accreditation 
procedure (described in chapter 11). Policy concerning public disclosure and publication policy are 
defined in the research contract. 
Briefly, results of this study will be unreservedly (regardless of a favourable or unfavourable 
outcomes) disclosed by publication in peer-reviewed scientific journals. Study participants are 
entitled to public disclosure of the results of the trial, after publication in peer-reviewed scientific 
journals, on the basis of their participation.  
Further, the agreements on publication between the investigators are according to the 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals87 (previously known as the rules of the Vancouver convention) of the 
International Committee of Medical Journal Editors (ICMJE) and the editors' statements of a 
number of authoritative biomedical scientific journals.88 
 
 
 
 

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the EMBRACE studies. Clin Transl Radiat Oncol 2018; 9: 48-60. 
68. Horeweg N, Creutzberg CL, Rijkmans EC, et al. Efficacy and toxicity of chemoradiation 
with image-guided adaptive brachytherapy for locally advanced cervical cancer. Int J 
Gynecol Cancer 2019; 29(2): 257-65. 
69. Yagi A, Ueda Y, Kakuda M, et al. Descriptive epidemiological study of vaginal cancer 
using data from the Osaka Japan population-based cancer registry: Long-term analysis 
from a clinical viewpoint. Medicine (Baltimore) 2017; 96(32): e7751. 
70. Verma J, Sulman EP, Jhingran A, et al. Dosimetric predictors of duodenal toxicity after 
intensity modulated radiation therapy for treatment of the para-aortic nodes in 
gynecologic cancer. Int J Radiat Oncol Biol Phys 2014; 88(2): 357-62. 
71. Fokdal L, Tanderup K, Hokland SB, et al. Clinical feasibility of combined 
intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI 
with a tandem/ring applicator in situ and virtual preplanning of the interstitial component. 
Radiother Oncol 2013; 107(1): 63-8. 
72. Weitmann HD, Knocke TH, Waldhäusl C, Pötter R. Ultrasound-guided interstitial 
brachytherapy in the treatment of advanced vaginal recurrences from cervical and 
endometrial carcinoma. Strahlenther Onkol 2006; 182(2): 86-95. 
73. Hiniker SM, Roux A, Murphy JD, et al. Primary squamous cell carcinoma of the vagina: 
prognostic factors, treatment patterns, and outcomes. Gynecol Oncol 2013; 131(2): 380-
5. 
74. Beriwal S, Demanes DJ, Erickson B, et al. American Brachytherapy Society consensus 
guidelines for interstitial brachytherapy for vaginal cancer. Brachytherapy 2012; 11(1): 
68-75. 
75. Jensen NBK, Pötter R, Kirchheiner K, et al. Bowel morbidity following radiochemotherapy 
and image-guided adaptive brachytherapy for cervical cancer: Physician- and patient 
reported outcome from the EMBRACE study. Radiother Oncol 2018; 127(3): 431-9. 
76. Kirchheiner K, Nout RA, Lindegaard JC, et al. Dose-effect relationship and risk factors 
for 
vaginal 
stenosis 
after 
definitive 
radio(chemo)therapy 
with 
image-guided 
brachytherapy for locally advanced cervical cancer in the EMBRACE study. Radiother 
Oncol 2016; 118(1): 160-6. 
77. Mazeron R, Fokdal LU, Kirchheiner K, et al. Dose-volume effect relationships for late 
rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive 
brachytherapy for locally advanced cervical cancer: Results from the prospective 
multicenter EMBRACE study. Radiother Oncol 2016; 120(3): 412-9. 
78. Fokdal L, Pötter R, Kirchheiner K, et al. Physician assessed and patient reported urinary 
morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally 
advanced cervical cancer. Radiother Oncol 2018; 127(3): 423-30. 
79. Chemoradiotherapy for Cervical Cancer Meta-Analysis C. Reducing uncertainties about 
the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-

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analysis of individual patient data from 18 randomized trials. J Clin Oncol 2008; 26(35): 
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81. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy 
compared with radiation and adjuvant hysterectomy for bulky stage IB cervical 
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with and without cisplatin chemotherapy in patients with advanced squamous cell cancer 
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N Engl J Med 2001; 345(11): 825-6; discussion 6-7. 
 
 
 

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15. APPENDICES 
 
15.1 APPENDIX 1: WHO classification of tumors of the vagina, ICD-O coding 
Tumor 
ICD-0 
subtypes 
Epithelial tumors 
Squamous cell papilloma 
NOS 
8052/0 
Vestibular 
micropapillomatosis; solitary 
vaginal papilloma 
Atrophy 
 
- 
- 
Tubulosquamous polyp 
8560/0 
- 
 
 
Squamous 
intraepithelial 
lesions of the vagina 
8077/0 
Low-grade 
squamous 
intraepithelial 
lesion  
 
Vaginal 
intraepithelial 
neoplasia, grade 1 
8077/2 
High-grade 
squamous 
intraepithelial 
lesion 
Vaginal 
intraepithelial 
neoplasia grade 2 
vaginal 
intraepithelial 
neoplasia, grade 3 
Squamous cell carcinoma, 
HPV-associated 
8085/3  
- 
Squamous cell carcinoma, 
HPV-independent 
8086/3 
- 
Squamous cell carcinoma 
NOS 
8070/3 
- 
Villous adenoma NOS 
8261/0 
- 
Müllerian papilloma 
- 
- 
Vaginal adenosis 
- 
- 
Endocervicosis 
- 
- 
Cysts 
- 
- 
Adenocarcinoma 
8140/3 
Adenocarcinoma 
NOS 
8483/3Adenocarcinoma, 
HPV-associated 
- 
Endometrioid 
adenocarcinoma NOS 
8380/3 
- 
Clear cell adenocarcinoma 
NOS 
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Mucinous 
carcinoma, 
gastric type 
8310/3 
 
Mucinous 
carcinoma, 
intestinal type 
8480/3 
 
Mesonephric 
adenocarcinoma 
9110/3 
 
Carcinosarcoma NOS 
8980/3 
 
Mixed tumour NOS 
8940/0 
 
Carcinoma 
of 
Skene, 
Cowper, and Littré glands 
8140/3 
 
Adenosquamous 
carcinoma 
8560/3 
 
Adenoid basal carcinoma 
8560/3 
 
Mixed epithelial and mesenchymal tumors 
Adenosarcoma 
8933/3 
 
Miscellaneous tumors 
Germ cell tumour NOS 
9064/3 
Yolk 
sac 
tumour, 
pre-
pubertal type 
Mature teratoma NOS 
Dermoid cyst NOS 
 

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15.2 APPENDIX 2: Overview of vaginal cancer stage classifications 
 
FIGO 
2018 
AJCC, 8th Edition 
IUCC, 
8th 
Edition 
Description 
Stage 
Stage 
Grouping 
Stage 
 
0 
 
 
Tis 
N0 
M0 
Carcinoma in situ 
I 
IA 
 
T1a 
N0 
M0 
T1 
N0 
M0 
The cancer is only in the vagina and is no larger than 2 cm (4/5 inch) 
(T1a). 
It has not spread to nearby lymph nodes (N0) or to distant sites (M0). 
IB 
T1b 
N0 
M0 
The cancer is only in the vagina and is larger than 2.0 cm (4/5 inch) 
(T1b). 
It has not spread to nearby lymph nodes (N0) or to distant sites (M0). 
II 
IIA 
 
T2a 
N0 
M0 
 
T2 
N0 
M0 
 
The cancer has grown through the vaginal wall, but not as far as the 
pelvic wall and is no larger than 2.0 cm (4/5 inch) (T2a). 
It has not spread to nearby lymph nodes (N0) or to distant sites (M0). 
IIB 
T2b 
N0 
M0 
The cancer has grown through the vaginal wall, but not as far as the 
pelvic wall and is larger than 2.0 cm (4/5 inch) (T2b). 
It has not spread to nearby lymph nodes (N0) or to distant sites (M0). 
III 
III 
T3 
N0 
M0 
 
OR 
 
T1 to T3 
N1 
M0 
T3 
N0 
M0 
 
OR 
 
T1 to T3 
N1 
M0 
The cancer is growing into the pelvic wall and/or has blocked the flow 
of urine (hydronephrosis) which is causing the kidneys to not work. 
(T3). 
 
 
OR 
The cancer can be any size and might be growing into the pelvic wall 
and/or has blocked the flow of urine (hydronephrosis) which is causing 
the kidneys to not work. (T1 to T3). AND It has also spread to nearby 
lymph nodes in the pelvis or groin (inguinal) area (N1) but not distant 
sites (M0). 
IVA 
IVA 
T4 
Any N 
M0 
IVA 
The cancer is growing into the bladder or rectum or is growing out of 
the pelvis (T4).  
It might or might not have spread to lymph nodes in the pelvis or groin 
(inguinal area) (Any N).  It has not spread to distant sites (M0). 
IVB 
IVB 
Any T 
Any N 
M1 
IVB 
The cancer has spread to distant organs such as the lungs, liver, or 
bones. (M1). It can be any size and might or might not have grown 
into nearby structures or organs (Any T). 
It might or might not have spread to nearby lymph nodes (Any N). 
 
Vaginal cancer staging. Includes tumors with primary site of growth in vagina only; tumors with 
secondary spread to the vagina from other genital (vulva, cervix, endometrium) or extra-genital sites 
should not be included. Staging is mostly clinical; however, information available from pathologic 
evaluation of resection specimens needs to be used 
Based on: 
 
American Joint Committee on Cancer. Vagina. In: AJCC Cancer Staging Manual. 8th ed. New 
York, NY: Springer; 2017:641-647. 
 
Mary K. Gospodarowicz (Editor)and Christian Wittekind (Editor). TNM Classification of 
Malignant Tumours, 8th Edition (UICC) 
 
Tracey Adams and Mauricio Cuello. Cancer of the Vagina. FIGO cancer report 2018 
 
 

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15.3 APPENDIX 3: EORTC QLQ Questionnaire 
 
 
 
 

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15.4 APPENDIX 4: Clinical drawings of the vagina with and without uterus 
15.4.1a Clinical drawing of vagina without uterus 
15.4.1b Clinical drawing of vagina with intact uterus 
Left:  
Speculum view: from centre to periphery: cervical os, portio, fornixes (grey area surrounded by thick dashed line), upper third, middle third, lower 
third (all separated by thin dotted lines), hymnal remnants marking the lower vaginal boundary (grey thick dashed line); u = urethra; for clockwise 
“3D” tumour delineation 
Right:  
Sagittal view (top) with reference structures including uterus, cervical os, portio, fornixes, upper third, middle third, lower third (all separated by 
thin dotted lines) of the vagina, ostium urthrae, anus; for longitudinal tumour delineation 
Coronal view (below) with reference structures including uterus, cervical os, portio, fornices, upper third, middle third, lower third (all separated 
by thin dotted lines) of the vagina, parametria, paravaginal space; for longitudinal tumour delineation 
 
15.4.2 Clinical drawing of vagina with intact uterus, axial view 
 
 

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