Preoperative Radiation Therapy and Immediate Breast Reconstruction, a Phase 3 Randomized Controlled Trial in the Belgian Population
Phase: NA
Conditions: Breast Neoplasms, Breast Carcinoma, Breast Adenocarcinoma, Cancer, Neoplasm
Sponsor: Cancer Research Antwerp

 
CLINICAL 
PROTOCOL 
PRADAIIBE 
 
Protocol no CTO23023GZA 
ClinicalTrials.Gov NCT06739655 
 
Version 4.0 24-DEC-2025 
ZAS vzw 
Kempenstraat 100 
2030 Antwerpen 

Page 1 of 73 
 
Trial title, protocol version and registration 
English title: Preoperative Radiation Therapy and Immediate Breast Reconstruction, a phase 3 
randomised controlled trial in the Belgian population. (PRADAIIBE) 
Dutch title: Preoperatieve bestralingstherapie en onmiddelijke borstreconstructie, een fase 3 
gerandomizeerde gecontrolleerde klinische studie in de Belgische populatie (PRADAIIBE) 
French title: Radiothérapie préopératoire et reconstruction mammaire immédiate, un essai contrôlé 
randomisé de phase 3 dans la population Belge 
Current protocol: Version 4 - 24-DEC-2025 
 
Trial registration 
Registry 
Unique Id 
Date of first registration 
Local trial registry (central IEC) 
CTO23023GZA 
22-APR-2024 
ClinicalTrials.gov 
NCT06739655 
17-DEC-2024 
Statement of compliance 
This study will be conducted in compliance with this clinical study protocol, the current International 
Conference on Harmonization guidelines for Good Clinical Practices (ICH - GCP E6 R3), the principles of the 
Declaration of Helsinki (version 2024) and any applicable regulatory requirements.(1,2) Enrolment at any 
clinical study site may not begin prior to that site receiving approval from the ethics committee of record 
for the protocol and all materials provided to potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment. Reconsent of previously enrolled participants may be necessary 
depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol will not be 
made without prior agreement from the Sponsor and documented approval from the ethics committee of 
record, unless such a change is necessary to eliminate an immediate hazard to the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection and GCP 
Training as outlined by their governing institution. 
Confidentiality Statement 
This document and its contents are the property of and confidential to ZAS vzw. Any unauthorised copying 
or use of this document is prohibited. 

Page 2 of 73 
 
Roles and responsibilities 
Coordinating team and centre (ZAS Augustinus) 
Prof. Dr. Melanie Machiels, Radiation 
oncologist in ZAS – Iridium Netwerk1 
Principal Investigator (PI), involved in Protocol 
development and trial managementa 
Dr. Tom Quisenaerts, Plastic-Reconstructive 
surgery resident and PhD-candidate1 
Sub-investigator (SI), Project manager, involved in 
Protocol development and trial managementa 
Prof. Dr. Philip Poortmans, Radiation 
oncologist in ZAS – Iridium Netwerk1 
Sub-investigator (SI), involved in Protocol development 
and trial oversight  
Ilse Van Der Auwera, Project manager ZAS 
CTO1 
Project manager, involved in Protocol development and 
trial managementa 
Trial sponsor and funding 
Ziekenhuis aan de Stroom (ZAS) vzw, 
represented by CEO Willeke Dijkhoffz2 
Sponsor, delegates trial responsibilities to the PI and their 
delegates 
Kom op tegen kanker (KOTK) vzw, 
represented by CEO David Vansteenbrugge3 
Funder, delegates trial responsibilities to the PI and their 
delegates. Requests annual updates in order to assess 
correct trial conduct and viability. 
Trial Steering Committee (TSC)b 
Prof. Dr. Philip Poortmans, Radiation 
oncologist in ZAS – Iridium Netwerk1 
TSC president 
Prof. Dr. Melanie Machiels, Radiation 
oncologist in ZAS – Iridium Netwerk1 
TSC member 
Prof., Dr. Filip Thiessen, Plastic-
Reconstructive surgeon in ZAS – Clinic12b1,4 
TSC member 
Prof. Thierry Tondu, Plastic-Reconstructive 
surgeon in ZAS – Clinic12b1,4 
TSC member 
Dr. Zainab Amajoud, Surgical Oncologist 
(Gynaecologist) in ZAS1 
TSC member 
Dr. Kevin Punie, Medical Oncologist in ZAS1 TSC member 
Dr. Tom Quisenaerts, Plastic-reconstructive 
surgery resident and PhD-candidate in ZAS1 
TSC member 
Dries Reynders, Senior statistician,  
Stat-Gent – Ghent University5 
TSC member 

Page 3 of 73 
 
Trial writing committee 
Prof. Dr. Melanie Machiels, Radiation 
oncologist in ZAS – Iridium Netwerk1 
Writing of the study report and scientific or public 
disseminations 
Dr. Tom Quisenaerts, Plastic-reconstructive 
surgery resident and PhD-candidate1 
Writing of the study report and scientific or public 
disseminations 
a: Trial management will include overseeing data collection and handling, data analysis (supported by a statistician consultant), 
data interpretation. 
b: The TSC will also take upon itself the role of overseeing end point adjudication and will advise on data management 
1: ZAS Augustinus, Oosterveldlaan 24, 2610 Wilrijk, Belgium; cancertrials@zas.be 
2: ZAS vzw, Kempenstraat 100, 2030 Antwerp, Belgium; medische-directie@zas.be  
3: Kom op tegen kanker, Koningsstraat 217, 1210 Brussel, Belgium; info@komoptegenkanker.be  
4: Clinic12b, Beukenlaan 10 B, 2020 Antwerpen; info@clinic12b.be  
5: Stat-Gent, Ghent University Krijgslaan 281 - S9, 9000 Gent, Belgium; statgent@ugent.be  
Contact for general inquiries: Dr. Tom Quisenaerts; cancertrials@zas.be   
Funding 
This clinical trial is financially funded by “Kom op tegen kanker vzw” (KOTK), providing a grant covering 
all direct study related expenses. This grant results from the KOTK “Call for proposals 2022 - Clinical 
trials”. KOTK is a non-profit organisation focused on supporting patients with cancer and research in the 
field of oncology.   
The indirect/overhead costs such as the functioning of the ZAS Augustinus clinical trial office, and 
additional (unforeseen) costs will be covered by “Iridium network vzw” and “Ziekenhuis aan de Stroom 
vzw” (ZAS).  
 

Page 4 of 73 
 
Sponsor’s Approval 
Protocol title: Preoperative Radiation Therapy and Immediate Breast Reconstruction, a phase 3 randomised 
controlled trial in the Belgian population. (PRADAIIBE)  
Version number and date: 4.0 24-DEC-2025 
 
The design of this study as outlined by this protocol has been reviewed and approved by the Sponsor’s 
responsible personnel as indicated below. 
 
Sponsor Representative: 
Signature:  
Date: 
 
Name: 
Willeke Dijkhoffz 
CEO ZAS Ziekenhuizen 
Kempenstraat 100, 2030 Antwerp 
Phone: +32(0)34433990 
Fax: +32(0)34433129 
www.zas.be 
 
Study responsible physician:  
Signature:  
Date: 
 
Name: 
Dr. Melanie Machiels 
Radiotherapist ZAS Ziekenhuizen 
Oosterveldlaan 24, 2610 Wilrijk (Antwerp) 
Phone: +32(0)34433759 
E-mail: cancertrials@zas.be  
 
 
 

Page 5 of 73 
 
Investigator Agreement 
Protocol title: Preoperative Radiation Therapy and Immediate Breast Reconstruction, a phase 3 randomised 
controlled trial in the Belgian population. (PRADAIIBE)  
Version number and date: 4.0 24-DEC-2025 
 
I have read the protocol, appendices, and accessory materials related to the “Preoperative Radiation 
Therapy and Immediate Breast Reconstruction, a phase 3 randomised controlled trial in the Belgian 
population. (PRADAIIBE)” clinical trial and agree to the following: 
• 
To conduct this study as described by the protocol and any accessory materials 
• 
To protect the rights, safety, and welfare of the participants under my care 
• 
To provide oversight to all personnel to whom study activities have been delegated 
• 
To conduct the study in accordance with all applicable local and national regulations, the requirements 
of the ethics committee of record for my clinical site, and Good Clinical Practices as outlined by ICH 
E6(R3) 
• 
To obtain approval for the protocol and all written materials provided to participants prior to initiating 
the study at my site 
• 
To obtain informed consent – and updated consent in the event of new information or amendments 
– from all participants enrolled at my study site prior to initiating any study specific procedures or 
administering investigational products to those participants 
• 
To maintain records of each participant’s participation and all data required by the protocol 
 
 
Signature:  
Date: 
 
Name: 
 
 
 
 
 
 

Page 6 of 73 
 
Table of Contents 
Trial title, protocol version and registration ................................................................................................. 1 
Statement of compliance .............................................................................................................................. 1 
Confidentiality Statement ............................................................................................................................. 1 
Roles and responsibilities .............................................................................................................................. 2 
Funding .......................................................................................................................................................... 3 
Sponsor’s Approval ........................................................................................................................................ 4 
Investigator Agreement................................................................................................................................. 5 
Table of Contents .......................................................................................................................................... 6 
List of In-text Tables and Figures ................................................................................................................. 11 
List of Attachments ..................................................................................................................................... 11 
List of Abbreviations .................................................................................................................................... 12 
Amendments ............................................................................................................................................... 14 
Synopsis ....................................................................................................................................................... 15 
Schedule of Events ...................................................................................................................................... 23 
1. 
Introduction ......................................................................................................................................... 27 
1.1 
Background .................................................................................................................................. 27 
1.2 Rationale for Use of Preop-RT to improve IBR outcomes ................................................................. 27 
1.3 Benefit-risk assessment ..................................................................................................................... 28 
1.3.1 Complication rates ..................................................................................................................... 28 
1.3.2 Oncological outcomes ................................................................................................................ 29 
1.4 Concluding the introduction .............................................................................................................. 29 
2. 
Objectives and Endpoints .................................................................................................................... 30 
3. Overall Study Design ................................................................................................................................ 35 
3.1 General Scheme of Study Design ...................................................................................................... 35 
3.2 Study Duration, Enrolment and Number of Sites .............................................................................. 38 
3.2.1 Duration of Study Participation .................................................................................................. 38 
3.2.2 Total Number of Study Sites/Total Number of Participants Projected ...................................... 38 
4. Population ............................................................................................................................................... 39 
4.1 Definitions ......................................................................................................................................... 39 
4.2 Participant Inclusion Criteria ............................................................................................................. 39 
4.3 Participant Exclusion Criteria ............................................................................................................ 40 
4.4 Study Restrictions .............................................................................................................................. 40 

Page 7 of 73 
 
4.4.1 Contraceptive Requirements...................................................................................................... 40 
4.4.2 Other Lifestyle Considerations and Study Restrictions .............................................................. 41 
4.4.3 Prior and Concomitant Therapies ............................................................................................... 41 
4.5 Screen Failures .................................................................................................................................. 41 
5. Study Conduct ......................................................................................................................................... 42 
5.1 Study Procedures............................................................................................................................... 42 
5.1.1 Recruitment ................................................................................................................................ 42 
5.1.2 Assignment of the Participant Identification Number ............................................................... 42 
5.1.3 Screening Period ......................................................................................................................... 43 
5.1.4 Study participant randomisation ................................................................................................ 43 
5.1.5 Treatment period ....................................................................................................................... 44 
5.1.6 Follow-up Period ........................................................................................................................ 45 
5.1.7 End of Study................................................................................................................................ 45 
5.1.8 Unscheduled Visits ..................................................................................................................... 45 
5.1.9 Early Termination ....................................................................................................................... 45 
5.2 Discontinuation or Withdrawal ......................................................................................................... 46 
5.2.1 Individual participants ................................................................................................................ 46 
5.3 Study Termination ............................................................................................................................. 47 
5.4 Study Assessments ............................................................................................................................ 47 
5.4.1 Demographics ............................................................................................................................. 47 
5.4.2 Medical History........................................................................................................................... 47 
5.4.3 Clinical Assessment .................................................................................................................... 47 
5.4.4 BREAST-Q questionnaire ............................................................................................................ 48 
5.4.5 European Quality of Life 5 Dimensions, 5 Levels (EQ-5D-5L) questionnaire ............................. 49 
5.4.6 Digital Photographs of the Breasts ............................................................................................. 50 
5.4.7 Disease baseline characteristics ................................................................................................. 52 
5.4.8 Assessment of (S)AEs and Surgical AEs ...................................................................................... 53 
5.4.9 Treatment duration .................................................................................................................... 53 
5.4.10 Assessment of Pathological Tumour Response and resection specimen pathology TNM ...... 53 
5.4.11 Collection of Data on oncological survival ............................................................................... 54 
6. Study Intervention ................................................................................................................................... 55 
6.1 Radiation Therapy ............................................................................................................................. 55 
6.1.1 Timing ......................................................................................................................................... 55 

Page 8 of 73 
 
6.1.2 Patient Positioning and Imaging ................................................................................................. 55 
6.1.3 Target Volume Definition ........................................................................................................... 55 
6.1.4 Treatment Planning .................................................................................................................... 55 
6.1.5 Dose ............................................................................................................................................ 55 
6.1.6 Use of Bolus ................................................................................................................................ 55 
6.2 Oncological breast Surgery ................................................................................................................ 56 
6.3 Breast Reconstruction surgery .......................................................................................................... 56 
6.5 Treatment Characteristics, Compliance and Adherence ................................................................... 56 
6.5.1 Radiation therapy characteristics ............................................................................................... 56 
6.5.2 Surgery characteristics ............................................................................................................... 57 
6.5.3 Systemic treatment characteristics ............................................................................................ 57 
7. Safety Monitoring .................................................................................................................................... 58 
7.1 Definition of Adverse Events (AEs) .................................................................................................... 58 
7.2 
Definition of Adverse Reaction (AR) ............................................................................................ 58 
7.3 
Definition of Unexpected Adverse Reaction (UAR) ..................................................................... 58 
7.4 
Definition of Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR) ........................ 58 
7.5 
Severity or Intensity of an Adverse Event ................................................................................... 60 
7.6 
Causal Relationship or Relatedness of an Adverse Event ........................................................... 60 
7.7 
Outcome ...................................................................................................................................... 61 
7.8 
Method of Detecting Adverse and Serious Adverse Events ........................................................ 62 
7.9 
Recording of Adverse and Serious Adverse Events ..................................................................... 62 
7.10 
Follow-up of Adverse and Serious Adverse Events ..................................................................... 62 
7.10.1 
Period and Frequency for Collecting AE and SAE Information ............................................ 62 
7.11 
Regulatory Reporting Requirements for Serious Adverse Events ............................................... 63 
7.11.1 
Annual Safety Report ........................................................................................................... 63 
7.12 
Clinical Laboratory Findings ......................................................................................................... 63 
8. Statistical Considerations ........................................................................................................................ 64 
8.1 Justification of Sample Size ............................................................................................................... 64 
8.2 Analysis Populations .......................................................................................................................... 65 
8.3 Statistical Methods for Analysing Primary, Secondary, and Tertiary Outcomes .............................. 65 
8.3.1 Primary Endpoint ........................................................................................................................ 65 
8.3.2 Secondary Endpoints .................................................................................................................. 66 
8.3.3 Tertiary Endpoints ...................................................................................................................... 67 

Page 9 of 73 
 
8.4 Interim Analyses ................................................................................................................................ 67 
8.5 Handling of Missing Data ................................................................................................................... 67 
9. Study Management ................................................................................................................................. 68 
9.1 Regulatory and Ethical Considerations .............................................................................................. 68 
9.1.1 Regulations and Guidelines ........................................................................................................ 68 
9.1.2 Independent Ethics Committees (IEC) ........................................................................................ 68 
9.1.3 Insurance .................................................................................................................................... 68 
9.2 Informed Consent .............................................................................................................................. 68 
9.3 Participant Identification, Enrolment and Screening Logs ................................................................ 69 
9.4 Quality Control and Assurance .......................................................................................................... 69 
9.4.1 Data Monitoring ......................................................................................................................... 69 
9.4.2 Audits .......................................................................................................................................... 70 
9.4.3 Protocol Amendments................................................................................................................ 70 
9.4.4  Protocol Deviations ................................................................................................................... 70 
9.4.5 Records ....................................................................................................................................... 70 
9.5 Data management plan ..................................................................................................................... 72 
9.6 Study Termination or Study Site Closure .......................................................................................... 72 
10. Clinical Study Report ............................................................................................................................. 73 
11. Publication Policy .................................................................................................................................. 73 
References ..................................................................................................................................................... 1 
Appendices .................................................................................................................................................... 7 
Appendix 1: Eastern Cooperative Oncology Group Performance Status Assessment .............................. 7 
Appendix 2: BREAST-Q questionnaire ....................................................................................................... 8 
BREAST-Q – Preoperative scale (universal) ........................................................................................... 8 
BREAST-Q – Postoperative scale (Reconstruction module) ................................................................ 10 
BREAST-Q – Postoperative scale (Breast Conserving Therapy module) ............................................. 13 
BREAST-Q – Postoperative scale (Mastectomy module) .................................................................... 15 
Appendix 3: EQ-5D-5L questionnaire ...................................................................................................... 17 
Dutch EQ-5D-5L version: ..................................................................................................................... 17 
French EQ-5D-5L version: .................................................................................................................... 20 
English EQ-5D-5L version: .................................................................................................................... 23 
Appendix 4: Assessment of Cosmetic Outcome ...................................................................................... 26 
Physician-reported cosmetic outcome................................................................................................ 26 

Page 10 of 73 
 
Appendix 5: CTCAE V5 ............................................................................................................................. 27 
Appendix 6: Amendment history ............................................................................................................ 28 
Protocol v2.0, amendment 1 24-NOV-2024 ........................................................................................ 28 
5.1.2 Treatment period ....................................................................................................................... 33 
5.1.3 Follow-up Period ........................................................................................................................ 33 
5.4.3 Clinical Assessment .................................................................................................................... 33 
5.4.4 BREAST-Q questionnaire ............................................................................................................ 33 
5.4.5 European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) questionnaire ................... 34 
5.4.6 Digital Photographs of the Breasts ............................................................................................. 34 
5.4.7 Assessment of Surgical Complications ....................................................................................... 34 
5.4.8 Assessment of Pathological Tumour Response and pathology TNM ......................................... 34 
5.4.9 Collection of Data on Tumour Recurrence Rates ....................................................................... 34 
6.4.2 Stratification ............................................................................................................................... 35 
6.4.3 Randomisation ............................................................................................................................ 35 
8.3.2 Secondary Endpoints .................................................................................................................. 36 
Protocol v3.0, amendment 2 17-JUN-2025 ......................................................................................... 37 
Protocol v4.0, amendment 3 05-DEC-2025 ......................................................................................... 47 
Appendix 7: Study overview (detailed) ................................................................................................... 54 
 
 

Page 11 of 73 
 
List of In-text Tables and Figures 
Table 1 Schedule of Events 
Table 2 Objectives and Endpoints 
Table 3 National consensus on dosimetric parameters and target volume names to be used in the 
evaluation of a breast cancer RT-plan (Hurkmans et al., 2021) 
Table 4 Adverse Event Causal Relationship with Study Intervention 
Figure 1 Study design 
Figure 2 Example of digital photographs 
Figure 3 Power vs. Sample Size 
List of Attachments 
Appendix 1 Eastern Cooperative Oncology Group Performance Status Assessment 
Appendix 2 BREAST-Q questionnaire (Mastectomy, BCT, and Reconstruction versions)  
Appendix 3 EQ-5D-5L questionnaire  
Appendix 4 Assessment of cosmetic outcome 
Appendix 5 CTCAE v5  
Appendix 6 Amendment history 
Appendix 7 Study overview (detailed) 
 
 

Page 12 of 73 
 
List of Abbreviations 
Abbreviation Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALND 
Axillary Lymph Node Dissection 
AR 
Adverse Reaction 
BCS 
Breast Conserving Surgery  
BCT 
Breast Conserving Therapy  
BMI 
Body Mass Index 
BP 
Bisphosphonates 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBR 
Delayed Breast Reconstruction 
DCIS 
Ductal Carcinoma In Situ 
DFS 
Disease-free survival 
DIEP 
Deep Inferior Epigastric Perforator  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EHR 
Electronic Health Record(s) 
EMA 
European Medicine Agency 
EQ-5D-5L 
European Quality of Life 5 Dimensions 5 Level 
EU 
European Union 
EVF 
Eligibility Verification Form 
FU 
Follow-up 
GEE 
Generalised Estimating Equation  
GCP 
Good Clinical Practice 
GDPR 
General 
Data 
Protection 
Regulation; 
in 
Dutch: 
Algemene 
Verordening 
Gegevensbescherming (AVG) 
IBR 
Immediate Breast Reconstruction 
ICE 
Inter-Current Event(s) 
ICF 
Informed consent form 
ICH 
International Counsil for Harmonisation 
IEC 
Independent Ethics Committee 
IQR 
Inter-Quartile Range (statistics) 
ITT 
Intention-to-treat population/analysis 
KM 
Kaplan-Meier 
LMM 
Linear Mixed Model(s) 
LPLV 
Last Patient Last Visit 
LST 
Last study visit (last treatment instance of RT of Onco/Recon surgery, finalising 
treatment; systemic therapies are not taken in consideration in this respect) 
ME 
Mastectomy, broad term which covers all forms. 
NACT 
Neoadjuvant chemotherapy 
MCAR 
Missing Completely At Random 
MRM 
Modified Radical Mastectomy 
MWU 
Mann Whitney U (statistical test) 

Page 13 of 73 
 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSM 
Nipple Sparing Mastectomy 
OAR 
Organs At Risk (Radiotherapy related term) 
OS 
Overall Survival 
pCR 
Pathological Complete Response 
PMRT 
Postmastectomy radiotherapy 
Postop-RT 
Postoperative radiation therapy 
Preop-RT 
Preoperative radiation therapy 
PROM 
Patient Reported Outcome Measure 
RT 
Radiation therapy 
SAE 
Serious Adverse Event  
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation (statistics) 
SNP 
Sentinel Node Procedure 
SoC 
Standard of Care (therapy) 
SoE 
Schedule of Events 
SSM 
Skin Sparing Mastectomy 
SUSAR 
Suspected Unexpected Adverse Reaction 
TE 
Tissue Expander 
TT 
Targeted Therapy 
TTE 
Time-To-Event (statistics) 
UAR 
Unexpected Adverse Reaction 
VAS 
Visual Analogue Scale 
 
 
 

Page 14 of 73 
 
Amendments  
History of the protocol and its amendments 
Protocol version 
Date of IEC application 
Protocol v1.0, original protocol 
22-APR-2024 
Protocol v2.0, amendment  
25-OCT-2024 
Protocol v3.0, amendment  
17-JUN-2025 
Protocol v4.0, amendment 
24-DEC-2025 
 
Protocol v4.0, amendment  
Purpose of this amendment: 
1. A new BREAST-Q scale was added, the “satisfaction with breasts” scale from the “Mastectomy” 
module was added to the IMFU visit, in order to capture the BREAST-Q score at the moment 
after mastectomy, and before reconstructive surgery.  
2. After developing and discussing the statistical analysis plan some minor discrepancies existed 
between the statistical methods described in the previous protocol version, and the SAP. This 
amendment will correct these discrepancies. These changes do not reflect major changes in the 
hypotheses posed in this trial, nor their conclusions. 
3. More in-depth discussion of the recruitment process 
4. The randomisation process was moved from section 6, to section 5 where it is more 
appropriately placed as it is an integral part of the study procedures. 
5. The eligibility criterium concerning a history of breast cancer/radiation therapy is more 
specifically defined as ipsilateral, as the previous wording could be interpreted as excluding 
contralateral disease/radiation therapy history as well.  
6. A transformation of the EQ-5D-5L index score to the 0 to 1 scale was added, due to the fact that 
this scale is proposed by the EQ-5D-5L documentation, and improves interpretability.  
7. The BREAST-Q outcome variable was removed from the secondary variables. Initially the 
BREAST-Q was included as both the primary and a secondary variable due to the fact that the 
initially planned statistical assessment would be different. After reforming the SAP this is no 
longer necessary as all outcomes will be assessed using both a LMM and MWU-test.  
8. The analysis of the pathological response outcome variable was changed to account for the fact 
that Preop-RT can be regarded as a preoperative therapy, eliciting response assessment, even 
when there was no preoperative-systemic therapy administration. Since the time between 
Preop-RT and oncological surgery is 2-6 weeks, we don’t expect this to impact the pathological 
response at this short interval. Which would lead to an inflation of the ‘No signs of response 
(Pinder 3)’ category in the experimental arm.  
This will be handled by defining that this outcome will only be assessed in the group of patients 
receiving preoperative systemic therapy.  
However, all reported pathological response categories will be recorded and these will be 
presented in the safety data, next to the previously defined outcome.  
A summarised list of key changes is provided in appendix 6: amendment history 
 

Page 15 of 73 
 
Synopsis 
Title 
Preoperative Radiation Therapy and Immediate Breast Reconstruction, a 
phase 3 randomised controlled trial in the Belgian population. (PRADAIIBE) 
Protocol number 
CTO23023GZA 
Study sites 
The study will be conducted at multiple centres across Belgium.  
Please refer to the study sites list for an up to date listing of participating 
study sites. This is available upon motivated inquiry.  
Disease under study 
Breast cancer 
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
Satisfaction 
with breasts, 
PROM 
(BREAST-Q) 
 
Operationalisation (measurement variable): 
The satisfaction with breasts outcome variable is operationalised through the 
“satisfaction with breasts” scale from the BREAST-Q (v2) ‘Reconstruction’, ‘Breast 
Conserving Treatment’, or ‘Mastectomy’ modules (as applicable).  
The answers from the questionnaire are then transformed into a ‘BREAST-Q Score’, 
using the provided conversion scales.(3) The BREAST-Q score can range from 0 to 
100. The BREAST-Q v2 questionnaires are discussed in section 5.4.4, and added in 
appendix 2. 
Analysis metric: 
The transformed value of the BREAST-Q score will be used for analysis.  
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
A baseline assessment is performed during the screening visit, followed by repeated 
measurements during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up 
visits. The primary endpoint is assessed at 1 year of follow-up after the last study 
treatment (LST).  
Rationale: 
The BREAST-Q is a validated and widely accepted tool for assessing different PROMs 
in women after (oncological) breast surgery. The ‘Satisfaction with breasts’ scale 
offers a relatively short (max 15 items) yet complete (assessing feel, comfort, 
cosmesis, etc.) assessment of the patient’s satisfaction with their breasts after 
reconstructive surgery (or BCS/ME).   
Secondary 
Quality of Life, 
PROM (QoL, 
EQ-5D-5L VAS 
and Index 
score) 
Operationalisation (measurement variable): 
‘Quality of Life’ will be assessed using the EQ-5D-5L questionnaire. From this 
questionnaire the VAS-score and Index-score will be derived. The VAS-score can be 
used as recorded. The index score is derived from the answers to each of the 5 Liker-
scale items, using a formula validated in the Belgian population. The EQ-5D-5L VAS-
score can range from 0 to 100, while the Index-score can range from -0.533 to 
0.962.(4,5) 
The EQ-5D-5L questionnaire is discussed in section 5.4.5, and added in appendix 3. 
 
 
 

Page 16 of 73 
 
Analysis metric: 
The VAS-score will be used as recorded. The Index-score will be transformed to a 
scale between 0 and 1, proportional to its original distribution. This transformation 
will be achieved using the following formula, where f(IS) represents the transformed 
score, IS the index score, 0.533 is the correction of the lowest value to zero, and 
1.495 is the range difference: 
𝑓(𝐼𝑆) = (𝐼𝑆+ 0.533)/1.495 
The rationale for this transformation, is to adhere to the scale proposed by the EQ-
5D-5L documentation, and improve interpretability of the index score. 
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
A baseline assessment is performed during the screening visit, followed by repeated 
measurements during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up 
visits. 
Rationale: 
The EQ-5D-5L questionnaire offers a very short (6 items) validated questionnaire 
assessing QoL, offering an index score based on 5 domains using 5 level Likert-scales, 
as well as a general QoL assessment using a VAS item.  
Breast 
cosmesis, 
objective 
assessment 
(AIS – TAS) 
 
Operationalisation (measurement variable): 
Breast cosmesis will be assessed through a blinded panel of experts, using the 
‘Aesthetic Items Scale’ to score a set of photographs taken during study visits. This 
set will consist of 4 2D digital photographs. The AIS has 5 items, each are scored 
from 1 to 5. These items are then summed to derive the ‘Total Aesthetic Score’ 
(TAS). The TAS can range from 5 to 25. (6,7) 
These are discussed in section 5.4.6, and appendix 4. 
Analysis metric: 
The derived value of the Total Aesthetic Score (TAS) from each assessor will be 
averaged to derive the TAS of each set of photos.   
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
Photographs are taken during the screening visit, followed by repeated photographs 
during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up visits. Expert panel 
assessment will take place at a later moment. A more detailed description is 
included in Appendix 4. 
Rationale: 
The use of photographs was included to be able to assess cosmesis in a more 
objective way. In order to achieve this objectiveness an expert panel will be used. 
The AIS-tool was selected due to its simplicity and good inter-rater validity in 
professionals. 
 
 
 
 

Page 17 of 73 
 
Frequency and 
severity of 
adverse events 
(AEs) 
Operationalisation (measurement variable): 
During the study all adverse events (AEs) codes and grades will be recorded in the 
eCRF, based on the ‘National Cancer Institute Common Terminology Criteria for 
Adverse Events’ (NCI-CTCAE) v5.0 reporting system.(8)  
The NCI-CTCAE v5.0 and (S)AE registration is discussed in section 5.4.8 and section 7, 
and added in appendix 5. 
CAVEAT: Not all postoperative complications are explicitly listed in the CTCAE v5.0 
framework, for example: capsular contraction, implant malposition, reconstructive 
failure, etc. are not listed but need to be recorded. These will be registered under 
“Injury, poisoning and procedural complications - Other, specify” CTCAE term  
Analysis metric: 
Tabulation of AE frequency, type and severity. As well as the highest grade AE for 
each participant.  
Method of aggregation: 
AEs will be aggregated based on their grades. Two composite measures will be 
reported, consisting of 1) any AE vs. no AE, and 2) grade > 3 AEs vs. no or grade <3 
AEs. Tables presenting both frequency and proportions of each grade and the 
composite measures will be presented. Proportions will be reported as AEs 
compared to ‘highest grade per patient’, and to ‘total set of AEs’. For comparisons 
and estimands, please refer to the SAP. 
Time point(s):  
AEs will be assessed and recorded continuously, with explicit querying during all 
follow-up visits.  
Rationale: 
In order to assess safety and to ensure that the experimental treatment does not 
differ significantly from the Standard of Care (SoC)/control treatment regarding AEs, 
the AEs were adopted as a secondary outcome variable. The NCI-CTCAEv5 was 
selected due to its uniformity in reporting and wide adoption in oncological 
research.   
Frequency and 
severity of 
adverse events 
(AEs), related 
to surgery 
Operationalisation (measurement variable): 
Cfr. ‘Frequency and severity of adverse events (AEs)’ (supra). For this outcome 
variable only the AEs related to surgical study interventions will be taken into 
consideration. This relationship is registered when the AE is recorded in the eCRF.  
Analysis metric: 
Tabulation of surgical AE frequency, type and severity. As well as the highest grade 
surgical AE for each participant.  
Method of aggregation: 
Surgical AEs will be aggregated based on their grades. Two composite measures will 
be reported, consisting of 1) any AE vs. no AE, and 2) grade > 3 AEs vs. no or grade 
<3 AEs, relating to surgical AEs. Tables presenting both frequency and proportions of 
each grade and composite measures will be presented. Proportions will be reported 
as surgical AEs compared to ‘highest grade per patient’, and to ‘total set of surgical 
AEs’. For comparisons and estimands, please refer to the SAP.  
Time point(s):  
Cfr. ‘Frequency and severity of adverse events (AEs)’ (supra). 
 
 
 

Page 18 of 73 
 
Rationale: 
In addition to the rationale mentioned for AEs in general, we wanted to look at the 
surgical AEs specifically as we believe that this subgroup is the most important one 
to monitor in this study.  
Treatment 
duration   
Operationalisation (measurement variable): 
The dates of diagnostic, study, and treatment milestones will be recorded in the 
eCRF. Time intervals expressed in days, will be assessed for: 
- 
Randomisation to last study treatment (LST) 
- 
Randomisation to oncological breast surgery 
- 
Oncological breast surgery to last study treatment (LST) 
As discussed in section 5.4.11. 
Analysis metric: 
The ‘randomisation to last study treatment (LST)’ time interval, expressed in days. 
Method of aggregation: 
KM-estimates and derived estimates for central tendency and spread will be 
provided. For comparisons and estimands, please refer to the SAP. 
Time point(s):  
These outcome variables will be continuously recorded as the participant progresses 
through the study and the data is entered in the eCRF.  
Rationale: 
The experimental treatment theoretically leads to a shorter treatment duration. In 
order to prove this theoretical assumption in practice, the treatment duration was 
adopted as a secondary outcome.  
Pathological 
(complete) 
response rate 
(pCR) 
Operationalisation (measurement variable): 
Patients receiving preoperative therapy undergo pathological response assessment 
of the removed breast tissues (SoC assessment). The reported response Pinder-
classification or ‘No preoperative therapy’ will be recorded in the eCRF.(9) 
The assessment of pathological tumour response is discussed in section 5.4.10. 
Analysis metric: 
The response category as described in the pathology report will be recorded for all 
participants, but this outcome will only be assessed in participants receiving 
preoperative-systemic therapy (with, or without Preop-RT).  
Therefore, the response category value of participants receiving Preop-RT without 
preoperative-systemic therapy will not be included in this outcome due to the fact 
that no response is expected at 2-6 weeks after radiation therapy monotherapy, 
which would result in an unfair comparison.  
Both this subset of the ITT set, and the complete safety set will be used in the safety 
assessment, as described in the SAP.  
Method of aggregation: 
The frequency and proportion of the response categories will be presented in a 
table. For comparisons and estimands, please refer to the SAP.  
Time point(s):  
This outcome variable will be assessed after the pathology report of the removed 
breast tissues is available. This is checked intermittently during the treatment phase, 
or at least during the 3 months follow-up visit.  
 
 
 

Page 19 of 73 
 
Rationale: 
The pathological response rate was added as a secondary outcome in order to assess 
the effects of preoperative radiotherapy on this parameter. On the one hand as a 
method of assessing the experimental treatment does not negatively impact 
oncological safety. While on the other hand assessing the potential synergistic 
effects on preoperative systemic therapy.  
Tertiary 
Oncological 
survival and 
time-to-event 
data:  
Operationalisation (measurement variable): 
The oncological survival and TTE data are operationalised as time-to-event intervals 
for the events of interest listed below. These events are recorded according to the 
2015 DATECAN consensus: (10) 
- 
Death  
o All-cause mortality  
o Death from breast cancer 
- 
Any recurrence vs. none. 
If any recurrence has occurred it will be recorded using the subtypes:  
o Invasive ipsilateral breast tumour recurrence/progression 
o Local invasive recurrence/progression 
o Regional invasive recurrence/progression 
o Appearance/occurrence of metastasis/distant recurrence 
o Ipsilateral DCIS  
The following TTE/survival metrics will be reported according to the 2015 DATECAN 
consensus: Overall Survival (OS), Breast Cancer-Specific Survival (BCSS), Relapse-Free 
Survival (RFS), Locoregional Relapse-Free Survival (L-RFS), and Distant-Relapse Free 
Survival (D-RFS).(10) 
As discussed in section 5.4.10. 
Analysis metric: 
The TTE data is registered in days from randomisation (Rz). Censoring will be used 
for participants without events at the end of their follow up.  
Method of aggregation: 
KM-estimates with derived estimates for central tendency and spread, as well as 
proportions free from events at follow-up visit timepoints will be reported. The non-
aggregated data will be used for survival analysis. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
Oncological TTE data will be registered at 1, 2, 5, and 10 years of follow-up after the 
last study treatment (LST). However, the exact dates of diagnosis/death will be used.  
Rationale: 
These oncological survival parameters were added as a tertiary outcome variable in 
order to assess oncological safety of the experimental treatment. These variables will 
be pooled with other international parallel studies, as it is likely that results from this 
study will be underpowered. 
 
 
 

Page 20 of 73 
 
Study Design 
Study design 
synopsis 
The PRADAIIBE trial is a multicentric, prospective, open-label, phase-III 
interventional, randomised controlled trial in patients with breast cancer for whom 
a skin/nipple-sparing mastectomy (SSM/NSM) and postoperative radiation therapy 
(Postop-RT) are indicated and who have a wish for a breast reconstruction. After 
providing informed consent, patients will be randomised in one of the following 
treatment arms: 
- 
Standard treatment arm: Standard of Care (SoC) treatment: Mastectomy (ME) 
combined with an immediate or delayed breast reconstruction (IBR/DBR) 
followed by radiation therapy (Postop-RT). 
- 
Experimental treatment arm: Preoperative radiotherapy (Preop-RT) followed by 
ME combined with immediate breast reconstruction (IBR), or BCS (in the unlikely 
event of downstaging). 
The primary objective of the PRADAIIBE trial is to investigate whether Preop-RT 
followed by ME combined with an immediate breast reconstruction (implant based 
or autologous) improves the patient’s satisfaction with the breast reconstruction 
when compared to the standard of care therapy, with ME followed by Postop-RT 
and immediate or delayed breast reconstruction. 
Participation in the study will comprise a screening period, where the screening 
assessments must be completed before participants are enrolled and randomised. 
Eligible, consenting participants will then undergo treatment according to their 
assigned treatment group. Following the treatment period, safety (AEs, survival, 
pCR) and efficacy (breast satisfaction,  cosmetic outcome and quality of life) are 
assessed during a follow-up period of 10 years. 
Sample size 
n=180 
Eligibility 
criteria 
Screening assessments, including review of all study eligibility criteria must be 
completed before enrolment and randomisation.  
Inclusion criteria: 
In order to be eligible to participate in this study, a participant must meet all of the 
following criteria: 
1. Women ≥18 years with histopathologically confirmed breast cancer who: 
a. require SSM/NSM for any reason (e.g. extensive disease) 
b. require postoperative radiation therapy of at least the chest wall 
c. have a wish for a breast reconstruction 
2. An Eastern Cooperative Oncology Group (ECOG) performance status grade ≤ 2 
3. Participant is able and willing to provide written informed consent, which 
includes compliance with and ability to undergo all study procedures, and attend 
the scheduled follow-up visit(s) per protocol. 
Exclusion criteria: 
A potential participant who meets any of the following criteria will be excluded from 
participation in this study: 
1. A previous history of breast cancer or irradiation of the chest wall for any other 
indication, on the other side (ipsilateral). A bilateral SSM/NSM + reconstruction 
(e.g. in case of a contralateral prophylactic SSM/NSM), or previous contralateral 
breast cancer disease/treatment, do not fall under this criterium and are thus 
allowed. 
2. Collagen synthesis disease 

Page 21 of 73 
 
3. Ongoing pregnancy  
4. Actively breastfeeding 
5. Smoking  at time of inclusion (a history of smoking is allowed but needs to be 
registered in the eCRF). No interval between smoking cessation and study 
inclusion is defined, but the reconstructive surgeon needs to be willing to 
operate the patient using autologous tissue transfer. This generally translates to 
a smoking cessation of >3months preoperatively.  
6. BMI > 35 kg/m2 
7. cT4d tumour, metastatic disease or any reason making SSM/NSM not indicated 
 
NOTE: If neoadjuvant chemotherapy is given, and if the indication for adjuvant 
systemic treatment is dependent on the presence or absence of a pathological 
complete tumour response pCR (such as in patients with a triple negative or Her2 
positive tumour), centres can choose  
- to exclude these patients,  
- only to include these patients when a non-pCR is proven via a biopsy prior to the 
start of the RT.  
- to include these patients after the end of neoadjuvant chemotherapy, since earlier 
studies in partial breast RT showed that pCR rate of Preop-RT only, followed by 
surgery <6-8 weeks is very low in the general breast cancer population (17 of the 
110), whilst it seems to be higher in patients with triple negative (6/8) and Her2 
positive (1/1) (11). 
However, the decision to include or exclude the patients which fall into this 
category, should be made before the participant is randomised. 
Length of 
Participation 
and study visits 
Follow-up visits to assess safety and efficacy will occur as delineated in the Schedule 
of Events (SoE). Participants in the standard arm, who underwent DBR, will be 
invited for an additional intermediate follow-up (IMFU) visit at 3 months after 
PMRT. The first follow-up visit occurs at 3 months of follow-up (after LST). The 
primary endpoint will be analysed at 1 year of follow-up after last study treatment 
(LST), defined as the last radiotherapy session or definitive (reconstructive) surgery. 
After reaching the primary endpoint, participant follow-up will continue at 2 years, 5 
years and 10 years after LST. 
Study 
Interventions 
/treatments 
Radiation therapy 
Preop-RT must be planned to commence as quickly as reasonably possible after 
randomisation, at the discretion of the Investigator, treating physician,  or no longer 
than 6 weeks after the last dose of neoadjuvant chemotherapy (if applicable) or 
randomisation. Postop-RT will be initiated 6-12 weeks after oncological breast 
surgery. 
Patients will be treated according to departmental protocol, these protocols should 
follow current guidelines and deliver a radiation dose of 40Gy in 15 fraction, over 3 
weeks, or a biologically equivalent dose (i.e. 26Gy/5 fx). Radiation techniques and 
quality assurance procedures are identical to the SoC radiation therapy techniques 
applied in Post-Mastectomy RT (PMRT) or Whole Breast RT (WBRT), and should fulfil 
the criteria as defined by this protocol. 
Oncological breast Surgery 
In accordance with SoC, a skin-sparing (SSM), nipple-sparing mastectomy (NSM), or 
modified radical mastectomy (MRM) will be performed within 6 weeks after 
randomisation or last dose of neoadjuvant chemotherapy (if applicable) for patients 

Page 22 of 73 
 
in the standard treatment arm. Patients in the experimental treatment arm proceed 
to SSM/NSM/MRM or a breast-conserving surgery (in case of downstaging after 
Preop-RT), at 2-6 weeks after the last radiation fraction. This timing can be delayed if 
necessary, e.g. in case of severe acute toxicity after RT or logistical reasons, but this 
needs to be documented as a protocol deviation. 
Breast reconstruction surgery 
The type/technique of breast reconstruction performed is at the discretion of the 
patient and the treating plastic/reconstructive surgeon, within the bounds of the 
assigned randomisation/treatment group. The options include implant-based (+/- in 
two steps with a temporary tissue expander), autologous tissue -based (e.g.: Deep 
Inferior Epigastric Perforator (DIEP) flap), or a combined technique using both 
autologous tissue and an implant/TE. Adjuvant reconstruction techniques such as fat 
grafting, or an acellular dermal matrix can also be used in addition to the primary 
technique.  
In the standard treatment arm, both immediate (IBR) and delayed breast 
reconstruction (DBR) techniques can be used according to SoC and patient/surgeon 
preferences.  
In the experimental treatment arm, only immediate breast reconstruction (IBR) 
techniques are allowed. An exception is made for two-stage implant-based 
reconstruction, in which case a tissue expander is placed at the time of the oncological 
surgery, followed by a later definitive breast reconstruction, within the study this will 
be considered as IBR. If there are unforeseen conditions, in which immediate 
reconstruction is not in the best (medical/safety) interests of the patient, the treating 
physician and medical team should act in the best interest of the patient, if this leads 
to a protocol deviation, it should be recorded as such.  
Statistical 
Methods 
The sample size has been calculated to detect a difference in ‘satisfaction with 
breasts’ as operationalised by the BREAST-Q score (‘Satisfaction with Breasts’ scale 
from the Breast Q v2 ‘Reconstruction’, ‘Breast Conserving Therapy’, or ‘Mastectomy’ 
modules; appendix 2), measured at 1 year follow-up, between patients in the 
control group, receiving the standard treatment (Postop-RT) and the experimental 
group/treatment (Preop-RT+IBR). Based on previous studies assessing general 
BREAST-Q score means after breast reconstructions, we expect a mean score of 58 
(SD 18) in the standard arm. Based on minimally important differences from 
previous BREAST-Q literature, we consider a difference of 8 points between groups 
to be realistic and clinically relevant.(12) To detect a difference of at least 8 points 
with 80% power and a two-sided alpha of 0.05 using the Students’ t-test, we need to 
include n=81 women in each treatment arm. To account for dropout of at least 10%, 
we aim to randomise n=90 women per treatment arm, resulting in n=180 patients in 
total. 
Statistical methods will be further outlined in a Statistical Analysis Plan (SAP). All 
analyses will be performed on the entire population as per the intention-to-treat 
(ITT) principle. The methodology and standards of ‘The Estimands Framework’ will 
be used to ensure correct reporting of hypothesis tests, and to correct for 
intercurrent events (ICE).(13) 
 
 

Page 23 of 73 
 
Schedule of Events 
The Schedule of events (SOE) is presented in Table 1. 
Table 1A. Schedule of events for patients in the control treatment arm 
Period 
Ref. 
Screening  
Treatment period 
Follow-up Period 
Closeout 
Visits 
  
Screening 
visit 
Oncological 
breast surgery 
+/- IBRe 
Postop-RTf 
Definitive 
breast 
reconstruction 
IMFU visit 
3 Months 
FU visit 
1 Year 
FU visit 
2, 5, 10 Year 
FU visits 
Closeout 
visitg 
Study Visit number 
1 
- 
- 
- 
[2x] 
2 
3 
4, 5, 6 
  
Scheduling 
≤10 bd of 
ICF 
Rz or NACT 
+≤6w 
Onco surg + 6-
12w 
As planned 
If DBR; 
RT+3M 
LST + 3M 
LST+1Y 
LST+2/5/10Y 
  
Window 
  
  
  
  
±1M 
±1M 
±1M 
±6M 
  
ICFa 
9.2 
Before visit 
  
  
  
  
  
  
  
  
Enrolment 
Eligibility screening 
4.2,4.3 
x 
  
  
  
  
  
  
  
  
Demographics 
5.4.1 
x 
  
  
  
  
  
  
  
  
Health data 
5.4.2, 
5.4.7 
x  
  
  
  
  
  
  
  
  
Concomitant 
medications 
5.4.2 
x 
  
  
  
  
  
  
  
  
Clinical 
assessments 
5.4.3 
  
  
  
  
  
  
  
  
  
Height 
  
x 
  
  
  
  
  
  
  
  
Body weight 
  
x 
  
  
  
  
  
  
  
  
ECOG score 
  
x 
  
  
  
  
  
  
  
  
Randomisation(Rz)b 
6.4.3 
x 
  
  
  
  
  
  
  
  
 
 
 

Page 24 of 73 
 
Assessments (baseline, treatment and follow-up) 
BREAST-Q (pre-op) 
5.4.4 
x  
  
  
  
  
  
  
  
  
BREAST-Q (post-op) 
5.4.4 
  
  
  
  
x 
x 
x 
x 
(x) 
EQ-5D-5L 
5.4.5 
x 
  
  
  
X 
x 
x 
x 
(x) 
Photographs 
5.4.6 
x 
  
  
  
x 
x   
x 
x 
(x) 
AE assessmentc 
5.4.8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Data on systemic 
therapy, RT and 
surgery 
6.5 
  
x 
x 
x 
  
x 
  
  
(x) 
Data on pathology 
and pathological 
tumour response  
5.4.9 
x 
x 
  
  
  
x 
  
  
(x) 
Data on oncological 
survivald 
5.4.10 
  
  
  
  
  
  
x 
x 
(x) 
Study related interventions/treatments 
Oncological surgery 
6.2 
  
x 
  
  
  
  
  
  
  
Radiotherapy 
6.1 
  
  
x 
  
  
  
  
  
  
Breast 
reconstruction 
6.3 
  
(x) 
  
(x) 
  
  
  
  
  
Abbreviations: Ref. = reference within this document; IBR = Immediate Breast Reconstruction; RT = Radiation Therapy; IMFU = InterMediate Follow-Up; FU = Follow-Up; bd = business days; ICF = Informed 
Consent Form; Rz = Randomisation; NACT = NeoAdjuvant ChemoTherapy; Onco Surg = Oncological surgery; DBR = Delayed Breast Reconstruction; LST = Last study treatment; w= week; M = month (30 
days); Y = Year (365 days); ECOG = Eastern Cooperative Oncology Group; pre-op = Preoperative; post-op = postoperative; AE = Adverse Event. 
a. 
Informed consent from the patient must be documented before any study specific procedure, including procedures for screening, are undertaken. 
b. 
Patients can be randomised as soon as eligibility has been confirmed by the Coordinating Investigator. 
c. 
Elicitation of all AEs will occur at each interaction with the patient from the time of informed consent onwards. Patients will be questioned regarding AEs at each visit, and will 
be instructed to inform the Investigator or staff of any AEs or intercurrent events/illnesses experienced at any time during the trial. Adverse events will be coded and graded 
according to the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). 
d. 
Oncological follow-up of patients will be planned according to local institutional guidelines.  
e. 
Oncological breast surgery  should be performed within 6 weeks of patient randomisation (Rz) or within 6 weeks of the last dose of neoadjuvant chemotherapy (NACT). 
f. 
Post-mastectomy/Postoperative radiation therapy will be initiated 6-12 weeks after oncological breast surgery. 
g. 
In the case of premature discontinuation from study participation, the participant should be asked to return to the clinic/study site and complete an early termination visit. 
The indicated assessments can be considered depending on the status of the participant, timing of discontinuation and the consent of the participant.  
Note: additional unscheduled visits may occur at the discretion of the Investigator, i.e. if considered necessary for clinical safety reasons.  
 

Page 25 of 73 
 
Table 1B. Schedule of events for patients in the experimental treatment arm 
Period 
Ref. 
Screening  
Treatment period 
Follow-up Period 
Closeout 
Visits 
  
Screening 
visit 
Preop-RTe 
Oncological 
breast surgery 
+IBRf 
(Definitive 
breast 
implant) 
IMFU 
visit 
3 
Months 
FU visit 
1 Year 
FU visit 
2, 5, 10 Year 
FU visits 
Closeout 
visitg 
Study Visit number 
1 
- 
- 
- 
NA 
2 
3 
4, 5, 6 
  
Scheduling 
≤10 bd of 
ICF 
Rz or NACT 
+≤6w 
Preop RT + 2-
6w 
As planned  
NA 
LST + 
3M 
LST+1Y 
LST+2/5/10Y 
  
Window 
  
  
  
  
NA 
±1M 
±1M 
±6M 
  
ICFa 
9.2 
Before 
visit 
  
  
  
  
  
  
  
  
Enrolment 
Eligibility screening 
4.2,4.3 
x 
  
  
  
  
  
  
  
  
Demographics 
5.4.1 
x 
  
  
  
  
  
  
  
  
Health data 
5.4.2, 
5.4.7 
x  
  
  
  
  
  
  
  
  
Concomitant 
medications 
5.4.2 
x 
  
  
  
  
  
  
  
  
Clinical assessments 
5.4.3 
  
  
  
  
  
  
  
  
  
Height 
  
x 
  
  
  
  
  
  
  
  
Body weight 
  
x 
  
  
  
  
  
  
  
  
ECOG score 
  
x 
  
  
  
  
  
  
  
  
Randomisation(Rz)b 
6.4.3 
x 
  
  
  
  
  
  
  
  
 
 
 

Page 26 of 73 
 
Assessments (baseline, treatment and follow-up) 
BREAST-Q (pre-op) 
5.4.4 
x  
  
  
  
  
  
  
  
  
BREAST-Q (post-op) 
5.4.4 
  
  
  
  
  
x 
x 
x 
(x) 
EQ-5D-5L 
5.4.5 
x 
  
  
  
  
x 
x 
x 
(x) 
Photographs 
5.4.6 
x 
  
  
  
  
x   
x 
x 
(x) 
AE assessmentc 
5.4.8 
x 
x 
x 
x 
  
x 
x 
x 
x 
Data on systemic 
therapy, RT and 
surgery 
6.5 
  
x 
x 
x 
  
x 
  
  
(x) 
Data on pathology 
and pathological 
tumour response  
5.4.9 
x 
x 
  
  
  
x 
  
  
(x) 
Data on oncological 
survivald 
5.4.10 
  
  
  
  
  
  
x 
x 
(x) 
Study related interventions/treatments 
Oncological surgery 
6.2 
  
  
x 
  
  
  
  
  
  
Radiotherapy 
6.1 
  
x 
  
  
  
  
  
  
  
Breast 
reconstruction 
6.3 
  
  
x 
(x) 
  
  
  
  
  
Abbreviations: Ref. = reference within this document; IBR = Immediate Breast Reconstruction; RT = Radiation Therapy; IMFU = InterMediate Follow-Up; FU = Follow-Up; bd = business days; ICF = Informed 
Consent Form; Rz = Randomisation; NACT = NeoAdjuvant ChemoTherapy; Onco Surg = Oncological surgery; DBR = Delayed Breast Reconstruction; LST = Last study treatment; w= week; M = month (30 
days); Y = Year (365 days); ECOG = Eastern Cooperative Oncology Group; pre-op = Preoperative; post-op = postoperative; AE = Adverse Event. 
a) 
Informed consent from the patient must be documented before any study specific procedure, including procedures for screening, are undertaken. 
b) 
Patients can be randomised as soon as eligibility has been confirmed by the Coordinating Investigator. 
c) 
Elicitation of all AEs will occur at each interaction with the patient from the time of informed consent onwards. Patients will be questioned regarding AEs at each visit, 
and will be instructed to inform the Investigator or clinic staff of any AEs or intercurrent events/illnesses experienced at any time during the trial. Adverse events will be 
coded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). 
d) 
Oncological follow-up of patients will be planned according to local institutional guidelines.  
e) 
Preoperative Radiation Therapy should be initiated within 6 weeks of Randomisation (Rz) or within 6 weeks of the last dose of neoadjuvant chemotherapy (NACT).  
f) 
Oncological breast surgery should be performed within 2-6 weeks after preoperative radiotherapy. 
g) 
In the case of premature discontinuation from study participation, the participant should be asked to return to the clinic/study site and complete an early termination 
visit. The indicated assessments can be considered depending on the status of the participant, timing of discontinuation and the consent of the participant.  
Note: additional unscheduled visits may occur at the discretion of the Investigator, i.e. if considered necessary for clinical safety reasons. 
 

Page 27 of 73 
 
1. Introduction 
1.1 Background 
In the past decades, there has been a two- to threefold increase in patients with breast cancer receiving 
immediate breast reconstruction (IBR) combined with postmastectomy radiotherapy (PMRT). This is best 
explained by the increasing number of patients opting for IBR due to concerns with cosmesis and its wider 
availability, as well as the broader application of PMRT due to changing guidelines and insights (14–19). 
One of the reasons for an increase in PMRT, is that regional RT is preferred over axillary lymph node 
dissection when 1-3 lymph nodes are found to be positive.(20,21)  
This shifting paradigm poses challenges, since regardless of breast reconstruction technique, PMRT leads 
to an increase in complications, with the frequency of  any complication at 23% in non-irradiated vs. 28.9% 
in irradiated patients.(22) These complications are also known to result in diminished patient 
satisfaction.(23,24) Furthermore, postoperative complications following IBR leads to an average RT delay 
of 19.7 days (61.62 days if no complications vs. 81.32 days if any complication), which is a statistically 
significant difference (p=0.021).(25) PMRT induced increases in the complication rates is further 
compounded when combined with IBR, and is highest for implant-based IBR, with complication rates of 
up to 38.9%, compared to 21.8% without PMRT, at 2 years of follow-up.(22) This increase is observed on 
both the short and long term, complications include loss of reconstruction, pain, infection, postoperative 
bleeding, hematoma, capsular contracture, fibrosis, implant malpositioning, seroma, impaired cosmetic 
results, and lower patient satisfaction.(26–31) The prevalence of Baker grade 3 or 4 capsular contracture 
when PMRT is administered to either a tissue expander or permanent implant was reported to be 37.5% 
in an n=1286 meta-analysis of 9 studies.(32) In the case of autologous IBR on the other hand, no statistically 
significant difference was seen in the rate of complications between those who did and did not receive 
PMRT. For example, a prospective observational study with n=199 (Autologous +RT) and n=332 
(Autologous, no RT) patients reported a complication rate of 25.6% and 28.3% respectively.(26)  
1.2 Rationale for Use of Preop-RT to improve IBR outcomes 
The high complication rate and impaired cosmetic results, following from IBR and PMRT, have led to 
practice variations and controversy in breast reconstruction practices when PMRT is indicated.(33,34) As 
a result, in some centres, only autologous reconstructions are being offered when PMRT is indicated. In 
other centres IBR is withheld when PMRT is indicated, and only delayed breast reconstructions (DBR) are 
offered. However, IBR does have several distinct advantages over DBR: 1) Improved skin and sometimes 
even nipple sparing options, resulting in a superior cosmetic outcome (35,36); 2) No period without a 
(reconstructed) breast, waiting for DBR (usually about 6-12 months after PMRT); 3) Overall treatment 
duration is significantly (at least 6-12 months) shorter; 4) A single major surgery, in contrast to two 
surgeries with accompanying revalidation periods (without additional aesthetic corrections). 
A promising alternative approach, with the hope of improving IBR outcomes in patients requiring PMRT, 
is to change the RT sequence from postoperative (Postop-RT) to preoperative (Preop-RT). This approach 
would allow for irradiated breast tissues to be removed during surgery and avoids irradiation of the 
reconstructed tissues and/or prothesis. Preop-RT is routinely used for several other types of cancer, such 
as e.g. rectal cancer (37), oesophageal cancer (38), and sarcomas (39,40), with improved options for tissue-
preserving surgeries and higher rates of complete pathologic response. Several studies showed no 
oncologic disadvantages for Preop-RT versus Postop-RT in breast cancer, with some studies suggesting 

Page 28 of 73 
 
lower recurrence rates, but no difference in overall survival (OS).(41–46) These studies include two 
prospective studies demonstrating that preoperative RT is safe and technically feasible in node-positive 
and locally advanced breast cancer.(44,45) 
1.3 Benefit-risk assessment 
1.3.1 Complication rates 
When consulting the currently available literature, the Preop-RT followed by ME and IBR approach does 
not seem to significantly increase the rate of complications, when compared to the ME, PMRT and DBR 
sequence.(47–52) A retrospective observational study by the American College of Surgeons, with a study 
population of n=77902 (ME-only 61039 vs. ME+IBR 16863), assessed the impact of Preop-RT on 30-day 
postoperative morbidity after ME with or without IBR. From the study population n=266 ME-only, and 
n=75 ME+IBR patients were identified as having received preoperative RT. In the ME-only group, the 
subgroup with Preop-RT experienced ‘any type of morbidity’ in 9.4% of cases, vs. 11.1% without Preop-RT 
(p=0.48). While in the ME+IBR group this was 14.7% vs. 11.2% (p=0.22). In both the ME-only and ME+IBR 
groups, preoperative RT was not associated with a significantly increased risk of complications upon 
multivariate regression analysis.(47) Another study compared preoperative chemo-radiation therapy 
followed by ME and IBR (Latissimus dorsi flap + breast implant) n=26 to ME followed by postoperative 
chemo-radiation therapy and DBR (Latissimus dorsi flap + breast implant) n=78. They reported no 
significant difference in both early (p=0.645) and late (p=0.362) complications.(45) Similarly, two 
observational studies of n=83 and n=111 patients, observed low rates of skin necrosis (6% and 5.4%, 
respectively) in patients receiving preoperative chemo-radiation therapy followed by ME and implant-
assisted latissimus dorsi flap IBR.(53,54) Although, when looking at patients who underwent Preop-RT and 
NACT followed by ME and IBR, a retrospective study observed higher rates of skin necrosis (within 30 days) 
in a transverse rectus abdominis musculocutaneous (TRAM)-flap subgroup (33.9%), compared to other 
reconstruction options (17.5%) consisting of a latissimus dorsi flap with or without breast implant, or 
breast implant alone. The authors of this study reported a relative risk (RR) of 1.9 for early complications 
and a RR of 6.4 for the occurrence of flap necrosis (of any degree) in a TRAM-flap based IBR compared to 
other IBR options.(55) These results seem to advise against the use of TRAM-flaps in the setting of Preop-
RT and IBR. However, there was no direct comparison of the Preop-RT to Postop-RT or no RT groups, 
making it harder to put these findings into perspective.  
The PRADA pilot study demonstrated that Preop-RT followed by skin-sparing mastectomy (SSM) and 
immediate microvascular DIEP-flap reconstruction is technically feasible and safe. This multicentric, phase-
II, prospective feasibility study showed that  in the study sample of n=33, 4 (12%) open wounds (>1cm) 
occurred, of which 3 were minor wounds treated conservatively and 1 needed debridement and skin 
grafting. As well as 6 (18%) events of limited fat necrosis occurred, all with minimal cosmetic impact. It can 
be concluded that the rate of open wounds, mastectomy skin necrosis, fat necrosis, and unplanned returns 
to the operating theatre were low, with no DIEP flap failures. Twelve months after surgery, the patients in 
the PRADA-trial reported high levels satisfaction with the breast reconstruction, and very good aesthetic 
outcomes were observed on panel assessment.(56) 
A similar pilot study came to an equivalent conclusion, that Preop-RT followed by ME and IBR was deemed 
to be both feasible and safe. Out of n=48 patients receiving ME with IBR, 41 had microvascular autologous 
tissue IBR, 5 received a pedicled latissimus dorsi flap, and 2 patients had tissue expanders implanted at 

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the moment of ME. There were no reconstructive failures, 8 patients (18.2%) had some degree of partial 
autologous flap necrosis of which only 1 (2.27%) needed re-intervention.(42) 
1.3.2 Oncological outcomes 
Concerning oncological outcomes, the literature seems to show no significant differences between Preop-
RT and Postop-RT concerning local/locoregional recurrence, overall survival, and disease-free survival, 
with a general trend in favour of Preop-RT. (48,57–61)  
A large retrospective observational study based on the Surveillance, Epidemiology, and End Results (SEER) 
database, included n=250195 female patients with early-stage breast cancer, of which n=2554 received 
Preop-RT, and n=247641 Postop-RT. This study concluded that the disease-free survival and mortality were 
not significantly different in both groups, only the oestrogen receptor positive subgroup showed a 
significant Hazard Ratio (HR) of 0.64 (p<0.0001) which was in favour of Preop-RT for second primary 
tumours.(59) Another retrospective observational study in n=315 Preop-RT and n=329 Postop-RT patients 
found that the 10-year relapse-free survival was not significantly different between the Preop-RT (67.96%), 
and Postop-RT (66.31%) groups. For the 10-year overall survival the Preop-RT (68.59%) and Postop-RT 
(64.96%) groups were again not significantly different, while the Preop-RT group did have a non-significant 
trend for better outcomes (HR=0.813; p=0.1037).(61) The PRADA I pilot-study also showed no local or 
locoregional recurrences during a 23.6 month median follow-up period, with 4 (12%) cases of distant 
metastatic disease, and 2 (6%) cancer related deaths, resulting in an overall survival of 93.9%, and disease-
free survival of 84.8%.(48) In a retrospective study with a cohort of n=30 patients treated with Pre-
operative radiotherapy for locally advanced breast cancer, propensity-score matched to a cohort of n =81 
control patients treated with Postop-RT, the pathological complete response (pCR) rate was 22.6% vs. 
14.9% (p<0.001), disease-free survival at 3 years of follow-up was 81% vs. 69% (p=0.186), overall survival 
at 3 years of follow-up was 89% vs. 74% (p=0.162), in Preop-RT vs. Postop-RT groups, respectively.(62)  
Another observational study of n=111 patients receiving Preop-RT for locally advanced breast cancer, 
found that after a median follow-up time of 31.6 months, there was a recurrence rate of 9%. This 9% 
consisted of 0.9% local recurrence and 8.1% distant metastatic disease, as a % of the study sample. At 5 
years of follow-up the disease-free survival was 93.2%, and overall survival was 98.3%. While this study 
lacks a comparison group, it shows very low local recurrence rates and high levels of 5 year disease-free, 
and overall survival compared to known rates for Postop-RT in the general literature.(54)  
1.4 Concluding the introduction 
The current study (PRADAIIBE) will now compare efficacy and safety outcomes of Preop-RT followed by 
ME and IBR, to these outcomes in the conventional SoC treatment consisting of ME followed by PMRT 
and either IBR or DBR (according to local practices), in a randomised controlled trial (RCT). It is our 
hypothesis that Preop-RT will improve patient reported satisfaction with breasts, quality of life (QoL), 
and cosmesis, while not leading to more complications, worse pCR rates, nor worse oncological 
outcomes. Preop-RT is also projected to streamline the treatment timeline by minimising delays 
associated with Postop-RT and shortening treatment duration. In addition, Preop-RT might theoretically 
achieve an antitumour immune response directed at subclinical disease, potentially decreasing the odds 
of recurrence, through the abscopal effect, which in turn may open avenues to other adjunct treatment 
modalities.(63,64) Which should be investigated through additional fundamental and translational 
research projects.  
 

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2. Objectives and Endpoints  
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
Satisfaction 
with breasts, 
PROM 
(BREAST-Q) 
 
Operationalisation (measurement variable): 
The satisfaction with breasts outcome variable is operationalised through the 
“satisfaction with breasts” scale from the BREAST-Q (v2) ‘Reconstruction’, ‘Breast 
Conserving Treatment’, or ‘Mastectomy’ modules (as applicable).  
The answers from the questionnaire are then transformed into a ‘BREAST-Q Score’, 
using the provided conversion scales.(3) The BREAST-Q score can range from 0 to 
100. The BREAST-Q v2 questionnaires are discussed in section 5.4.4, and added in 
appendix 2. 
Analysis metric: 
The transformed value of the BREAST-Q score will be used for analysis.  
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
A baseline assessment is performed during the screening visit, followed by repeated 
measurements during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up 
visits. The primary endpoint is assessed at 1 year of follow-up after the last study 
treatment (LST).  
Rationale: 
The BREAST-Q is a validated and widely accepted tool for assessing different PROMs 
in women after (oncological) breast surgery. The ‘Satisfaction with breasts’ scale 
offers a relatively short (max 15 items) yet complete (assessing feel, comfort, 
cosmesis, etc.) assessment of the patient’s satisfaction with their breasts after 
reconstructive surgery (or BCS/ME).   
Secondary 
Quality of Life, 
PROM (QoL, 
EQ-5D-5L VAS 
and Index 
score) 
Operationalisation (measurement variable): 
‘Quality of Life’ will be assessed using the EQ-5D-5L questionnaire. From this 
questionnaire the VAS-score and Index-score will be derived. The VAS-score can be 
used as recorded. The index score is derived from the answers to each of the 5 Liker-
scale items, using a formula validated in the Belgian population. The EQ-5D-5L VAS-
score can range from 0 to 100, while the Index-score can range from -0.533 to 
0.962.(4,5) 
The EQ-5D-5L questionnaire is discussed in section 5.4.5, and added in appendix 3. 
Analysis metric: 
The VAS-score will be used as recorded. The Index-score will be transformed to a 
scale between 0 and 1, proportional to its original distribution. This transformation 
will be achieved using the following formula, where f(IS) represents the transformed 
score, IS the index score, 0.533 is the correction of the lowest value to zero, and 
1.495 is the range difference: 
𝑓(𝐼𝑆) = (𝐼𝑆+ 0.533)/1.495 
The rationale for this transformation, is to adhere to the scale proposed by the EQ-
5D-5L documentation, and improve interpretability of the index score. 
 

Page 31 of 73 
 
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
A baseline assessment is performed during the screening visit, followed by repeated 
measurements during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up 
visits. 
Rationale: 
The EQ-5D-5L questionnaire offers a very short (6 items) validated questionnaire 
assessing QoL, offering an index score based on 5 domains using 5 level Likert-scales, 
as well as a general QoL assessment using a VAS item.  
Breast 
cosmesis, 
objective 
assessment 
(AIS – TAS) 
 
Operationalisation (measurement variable): 
Breast cosmesis will be assessed through a blinded panel of experts, using the 
‘Aesthetic Items Scale’ to score a set of photographs taken during study visits. This 
set will consist of 4 2D digital photographs. The AIS has 5 items, each are scored 
from 1 to 5. These items are then summed to derive the ‘Total Aesthetic Score’ 
(TAS). The TAS can range from 5 to 25. (6,7) 
These are discussed in section 5.4.6, and appendix 4. 
Analysis metric: 
The derived value of the Total Aesthetic Score (TAS) from each assessor will be 
averaged to derive the TAS of each set of photos.   
Method of aggregation: 
Mean, SD, median, IQR, and range will be reported. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
Photographs are taken during the screening visit, followed by repeated photographs 
during the IMFU (if applicable), 3M, 1Y, 2Y, 5Y, and 10Y follow-up visits. Expert panel 
assessment will take place at a later moment. A more detailed description is 
included in Appendix 4. 
Rationale: 
The use of photographs was included to be able to assess cosmesis in a more 
objective way. In order to achieve this objectiveness an expert panel will be used. 
The AIS-tool was selected due to its simplicity and good inter-rater validity in 
professionals. 
Frequency and 
severity of 
adverse events 
(AEs) 
Operationalisation (measurement variable): 
During the study all adverse events (AEs) codes and grades will be recorded in the 
eCRF, based on the ‘National Cancer Institute Common Terminology Criteria for 
Adverse Events’ (NCI-CTCAE) v5.0 reporting system.(8)  
The NCI-CTCAE v5.0 and (S)AE registration is discussed in section 5.4.8 and section 7, 
and added in appendix 5. 
CAVEAT: Not all postoperative complications are explicitly listed in the CTCAE v5.0 
framework, for example: capsular contraction, implant malposition, reconstructive 
failure, etc. are not listed but need to be recorded. These will be registered under 
“Injury, poisoning and procedural complications - Other, specify” CTCAE term  
Analysis metric: 
Tabulation of AE frequency, type and severity. As well as the highest grade AE for 
each participant.  
 

Page 32 of 73 
 
Method of aggregation: 
AEs will be aggregated based on their grades. Two composite measures will be 
reported, consisting of 1) any AE vs. no AE, and 2) grade > 3 AEs vs. no or grade <3 
AEs. Tables presenting both frequency and proportions of each grade and the 
composite measures will be presented. Proportions will be reported as AEs 
compared to ‘highest grade per patient’, and to ‘total set of AEs’. For comparisons 
and estimands, please refer to the SAP. 
Time point(s):  
AEs will be assessed and recorded continuously, with explicit querying during all 
follow-up visits.  
Rationale: 
In order to assess safety and to ensure that the experimental treatment does not 
differ significantly from the Standard of Care (SoC)/control treatment regarding AEs, 
the AEs were adopted as a secondary outcome variable. The NCI-CTCAEv5 was 
selected due to its uniformity in reporting and wide adoption in oncological 
research.   
Frequency and 
severity of 
adverse events 
(AEs), related 
to surgery 
Operationalisation (measurement variable): 
Cfr. ‘Frequency and severity of adverse events (AEs)’ (supra). For this outcome 
variable only the AEs related to surgical study interventions will be taken into 
consideration. This relationship is registered when the AE is recorded in the eCRF.  
Analysis metric: 
Tabulation of surgical AE frequency, type and severity. As well as the highest grade 
surgical AE for each participant.  
Method of aggregation: 
Surgical AEs will be aggregated based on their grades. Two composite measures will 
be reported, consisting of 1) any AE vs. no AE, and 2) grade > 3 AEs vs. no or grade 
<3 AEs, relating to surgical AEs. Tables presenting both frequency and proportions of 
each grade and composite measures will be presented. Proportions will be reported 
as surgical AEs compared to ‘highest grade per patient’, and to ‘total set of surgical 
AEs’. For comparisons and estimands, please refer to the SAP.  
Time point(s):  
Cfr. ‘Frequency and severity of adverse events (AEs)’ (supra). 
Rationale: 
In addition to the rationale mentioned for AEs in general, we wanted to look at the 
surgical AEs specifically as we believe that this subgroup is the most important one 
to monitor in this study.  
Treatment 
duration   
Operationalisation (measurement variable): 
The dates of diagnostic, study, and treatment milestones will be recorded in the 
eCRF. Time intervals expressed in days, will be assessed for: 
- 
Randomisation to last study treatment (LST) 
- 
Randomisation to oncological breast surgery 
- 
Oncological breast surgery to last study treatment (LST) 
As discussed in section 5.4.11. 
Analysis metric: 
The ‘randomisation to last study treatment (LST)’ time interval, expressed in days. 
Method of aggregation: 
KM-estimates and derived estimates for central tendency and spread will be 
provided. For comparisons and estimands, please refer to the SAP. 

Page 33 of 73 
 
Time point(s):  
These outcome variables will be continuously recorded as the participant progresses 
through the study and the data is entered in the eCRF.  
Rationale: 
The experimental treatment theoretically leads to a shorter treatment duration. In 
order to prove this theoretical assumption in practice, the treatment duration was 
adopted as a secondary outcome.  
Pathological 
(complete) 
response rate 
(pCR) 
Operationalisation (measurement variable): 
Patients receiving preoperative therapy undergo pathological response assessment 
of the removed breast tissues (SoC assessment). The reported response Pinder-
classification or ‘No preoperative therapy’ will be recorded in the eCRF.(9) 
The assessment of pathological tumour response is discussed in section 5.4.10. 
Analysis metric: 
The response category as described in the pathology report will be recorded for all 
participants, but this outcome will only be assessed in participants receiving 
preoperative-systemic therapy (with, or without Preop-RT).  
Therefore, the response category value of participants receiving Preop-RT without 
preoperative-systemic therapy will not be included in this outcome due to the fact 
that no response is expected at 2-6 weeks after radiation therapy monotherapy, 
which would result in an unfair comparison.  
Both this subset of the ITT set, and the complete safety set will be used in the safety 
assessment, as described in the SAP.  
Method of aggregation: 
The frequency and proportion of the response categories will be presented in a 
table. For comparisons and estimands, please refer to the SAP.  
Time point(s):  
This outcome variable will be assessed after the pathology report of the removed 
breast tissues is available. This is checked intermittently during the treatment phase, 
or at least during the 3 months follow-up visit.  
Rationale: 
The pathological response rate was added as a secondary outcome in order to assess 
the effects of preoperative radiotherapy on this parameter. On the one hand as a 
method of assessing the experimental treatment does not negatively impact 
oncological safety. While on the other hand assessing the potential synergistic 
effects on preoperative systemic therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tertiary 
Oncological 
survival and 
time-to-event 
data:  
Operationalisation (measurement variable): 
The oncological survival and TTE data are operationalised as time-to-event intervals 
for the events of interest listed below. These events are recorded according to the 
2015 DATECAN consensus: (10) 
- 
Death  
o All-cause mortality  
o Death from breast cancer 
- 
Any recurrence vs. none. 
If any recurrence has occurred it will be recorded using the subtypes:  
o Invasive ipsilateral breast tumour recurrence/progression 
o Local invasive recurrence/progression 
o Regional invasive recurrence/progression 
o Appearance/occurrence of metastasis/distant recurrence 
o Ipsilateral DCIS  
The following TTE/survival metrics will be reported according to the 2015 DATECAN 
consensus: Overall Survival (OS), Breast Cancer-Specific Survival (BCSS), Relapse-Free 
Survival (RFS), Locoregional Relapse-Free Survival (L-RFS), and Distant-Relapse Free 
Survival (D-RFS).(10) 
As discussed in section 5.4.10. 
Analysis metric: 
The TTE data is registered in days from randomisation (Rz). Censoring will be used 
for participants without events at the end of their follow up.  
Method of aggregation: 
KM-estimates with derived estimates for central tendency and spread, as well as 
proportions free from events at follow-up visit timepoints will be reported. The non-
aggregated data will be used for survival analysis. For comparisons and estimands, 
please refer to the SAP. 
Time point(s):  
Oncological TTE data will be registered at 1, 2, 5, and 10 years of follow-up after the 
last study treatment (LST). However, the exact dates of diagnosis/death will be used.  
Rationale: 
These oncological survival parameters were added as a tertiary outcome variable in 
order to assess oncological safety of the experimental treatment. These variables will 
be pooled with other international parallel studies, as it is likely that results from this 
study will be underpowered. 
Table 2 Objectives and Endpoints 
 
 

Page 35 of 73 
 
3. Overall Study Design 
3.1 General Scheme of Study Design 
The PRADAIIBE study is a multicentric, prospective, randomised controlled, open-label, phase-III 
interventional clinical trial in patients with breast cancer for whom a skin/nipple-sparing mastectomy 
(SSM/NSM) and Postop-RT are indicated and who have a wish for a breast reconstruction. After providing 
informed consent and verifying eligibility, data collection starts and patients will be randomised in one of 
the following treatment arms: 
- 
Standard treatment arm: Standard of Care (SoC) treatment: ME combined with an immediate or 
delayed breast reconstruction (IBR/DBR) followed by radiation therapy (Postop-RT). 
- 
Experimental treatment arm: Preoperative radiotherapy (Preop-RT) followed by ME combined with 
immediate breast reconstruction (IBR), or BCS (in the unlikely event of downstaging). 
The primary objective of the PRADAIIBE study is to investigate whether Preop-RT followed by ME 
combined with an IBR (implant based or autologous) improves the patient’s satisfaction with the breast 
reconstruction when compared to the SoC therapy, with Postop-RT, and IBR or DBR. 
Participation in the study will comprise a screening period, where the screening assessments must be 
completed before participants are enrolled and randomised. Eligible, consenting participants will then 
undergo treatment according to their assigned treatment group.  
The intervention consists of a change in the therapy sequence, where radiation therapy is provided in 
the preoperative setting as compared to the usual postoperative setting.  Due to this changed sequence 
the breast reconstruction surgery can be performed concurrently with the ME (immediate breast 
reconstruction; IBR), avoiding irradiation of the reconstructed breast, and the fear of complications or 
inferior aesthetic results associated with it. In the unlikely event of downstaging due to Preop-RT, BCS 
could be performed, but this is not expected to occur. This treatment sequence consists of the SoC 
therapy for both the surgical and radiotherapeutic treatments, as appropriate for their specific situation, 
with only a change in the sequence in which these therapies are administered.  
In the standard treatment group there will be no manipulation of the treatment (sequence), the 
participants will receive their breast cancer treatment in the same manner and sequence as they would 
when they wouldn’t have enrolled in this clinical trial.  
Chemotherapeutic or other systemic treatments, either in the neo-adjuvant/preoperative or 
adjuvant/postoperative setting will be left to the discretion of the treating medical team, there will be no 
manipulation of this treatment in this clinical trial. Therefore systemic therapies will not be considered 
study related treatments. However, the treatment details will be recorded in the eCRF for statistical 
analysis.  
In the intervention group there is a slight chance of downstaging due to Preop-RT, in this case breast 
conserving surgery (BCS) can be performed. However, we expect that this will be a minority of cases as 
the timing of surgery at 2-6 weeks after Preop-RT is deemed to be too short to expect significant 
downstaging. We debated excluding these patients as they will not undergo breast reconstruction 
surgery and are therefore not a fair comparison for our research question, we came to the conclusion 
that due to the intention-to-treat (ITT) principle we need to include these patients, but in the handling of 
intercurrent events (ICE), these patients will be excluded from the analysis.  

Page 36 of 73 
 
With regards to the standard treatment (control) group, the choice of immediate vs. delayed breast 
reconstruction surgery is left at the discretion of the treating plastic/reconstructive surgeon and the 
patient. However, we expect that the choice for IBR will be a smaller group and will mainly entail the 
placement of a tissue expander during oncological surgery. We expect that a substantial amount of these 
control-group patients will undergo DBR, in which case they will typically have to wait 6-12 months until 
receiving their DBR. In order to provide proper study participant follow-up, and to assess safety and 
efficacy outcomes in the intermediate period (after oncological treatment, before breast reconstruction), 
an additional study visit (InterMediate Follow-Up; IMFU) is provided at 3 months after conclusion of 
Postop-RT. This visits (IMFU) is specific to control group participants undergoing DBR, and includes a 
BREAST-Q ‘satisfaction with breasts’ from the ‘Mastectomy’ module assessment (Section 5.4.4; Appendix 
2); QoL assessment using the EQ-5D-5L questionnaire (Section 5.4.5; Appendix 3); Photographs of the 
chest anatomy, which will be evaluated by an expert panel (Section 5.4.6; Appendix 4); and AE/SAE 
registration according to the CTCAE V5 (Section 7; Appendix 5). 
After the treatment period is finalised, safety and efficacy are assessed during a follow-up period of 10 
years. Follow-up visits will occur at 3 months, 1 year, 2 years, 5 years and 10 years after treatment 
finalisation, also known as ‘last study treatment’ (LST). During this follow-up period, the AEs/SAEs will be 
registered using the CTCAE V5 (Section 7; Appendix 5). Oncological outcomes will be reported from the +1 
year follow-up visit onwards and registered based on patient interview and Electronic Health Record (EHR) 
review (Section 5.4.10). The cosmesis and satisfaction with breasts will be evaluated using the self-
reported ‘Satisfaction with breasts’ scale of the BREAST-Q v2 ‘Reconstruction’, ‘Breast Conserving 
Therapy’, or ‘Mastectomy’ modules (as applicable for the current situation), as well as through 
photographs evaluated by a panel of blinded experts (Section 5.4.6; Appendix 4). The QoL will be assessed 
using the self-reported EQ-5D-5L questionnaire (Section 5.4.5; Appendix 3).  
The screening, treatment and follow-up schedule is shown in the Schedule of Events (SoE; Table 1). 
A schematic presentation of the study design is shown in Figure 1 (Concise overview) and Appendix 7 
(Detailed overview). 

Page 37 of 73 
 
 
 
Figure 1: Study design 
 
 

Page 38 of 73 
 
3.2 Study Duration, Enrolment and Number of Sites 
3.2.1 Duration of Study Participation 
Following study enrolment and randomised allocation to a study treatment group, participants will receive 
their assigned treatment. After the study related treatments have been concluded (variable length), there 
will be a follow-up period of 10 years.  
3.2.2 Total Number of Study Sites/Total Number of Participants Projected 
The study will be conducted at multiple study sites in Belgium. In total, n=180 patients will be enrolled in 
the study. The study will be closed when the last patient completes their last visit. We project a total of 10 
study sites. An up to date list of participating study sites is kept in a separate document, which will be 
submitted to the central EC whenever a site is added or removed. This document is available upon request. 
We expect a patient accrual period of 3 years. Total study duration is therefore projected to be 13 years. 
 
 

Page 39 of 73 
 
4. Population 
4.1 Definitions 
Participants officially enter the screening period following provision of informed consent. Screening 
assessments must be completed before enrolment and randomisation. 
The inclusion and exclusion criteria for enrolling participants in this study are described in the following 
sections. Enrolment will occur only if the participant meets all study eligibility criteria, or if an eligibility 
criteria deviation permission is provided by the central PI, and has been assessed by the Investigator as 
being an appropriate candidate for study participation. If there is a question about any of these criteria, 
the Investigator must consult with the appropriate Sponsor representative and resolve any issues before 
enrolling a participant in the study. If a participant’s clinical status changes (including any available 
test/diagnostic/etc. results or receipt of additional medical records) after screening but before 
randomisation such that they no longer meet all eligibility criteria, then the participant should be excluded 
from participation in the study. 
An enrolled participant is one who has provided informed consent, has been screened and deemed 
eligible, but who has not yet been assigned to a treatment group through randomisation. 
Before randomisation, the local Investigator should submit a signed and dated Eligibility Verification  Form 
(EVF) to cancertrials@zas.be. The central Investigator will reply by email to confirm eligibility within 1 
business day. After eligibility has been centrally confirmed, patients can be randomised (see Section 6.4.3). 
After treatment allocation through the randomisation procedure in the eCRF, the patient is defined as 
(enrolled and) randomised.  
4.2 Participant Inclusion Criteria 
In order to be eligible to participate in this study, a participant must meet all of the following criteria: 
1. Women ≥18 years with histopathologically confirmed breast cancer who: 
a. require SSM/NSM for any reason (e.g. extensive disease) 
b. require postoperative radiotherapy of at least the chest wall 
c. have a wish for a breast reconstruction 
2. An Eastern Cooperative Oncology Group (ECOG) performance status grade ≤2 
3. Participant is able and willing to provide written informed consent, which includes compliance 
with and ability to undergo all study procedures, and attend the scheduled follow-up visit(s) per 
protocol. 
 
 

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4.3 Participant Exclusion Criteria 
A potential participant who meets any of the following criteria will be excluded from participation in this 
study: 
1. A previous history of breast cancer or irradiation of the chest wall for any other indication, on the 
ipsilateral side. A bilateral SSM/NSM + reconstruction (e.g. in case of a contralateral prophylactic 
SSM/NSM), or previous contralateral breast cancer disease/treatment, do not fall under this 
criterium and are thus allowed. 
2. Collagen synthesis disease 
3. Ongoing pregnancy  
4. Actively breastfeeding 
5. Smoking  at time of inclusion (a history smoking is allowed but needs to be registered in the eCRF). 
No interval between smoking cessation and study inclusion is defined, but the reconstructive 
surgeon needs to be willing to operate the patient using autologous tissue transfer. This generally 
translates to a smoking cessation of >3months preoperatively.  
6. BMI > 35 kg/m2 
7. cT4d tumour, metastatic disease or any reason making SSM/NSM not indicated 
 
NOTE: If neoadjuvant chemotherapy is given, and if the indication for adjuvant systemic treatment is 
dependent on the presence or absence of a pathological complete tumour response pCR (such as in 
patients with a triple negative or Her2 positive tumour), centres can choose  
- to exclude these patients,  
- only to include these patients when a non-pCR is proven via a biopsy prior to the start of the RT.  
- to include these patients after the end of neoadjuvant chemotherapy, since earlier studies in partial 
breast RT showed that pCR rate of Preop-RT only, followed by surgery <6-8 weeks is very low in the general 
breast cancer population (17 of the 110), whilst it seems to be higher in patients with triple negative (6/8) 
and Her2 positive (1/1) (11). 
However, the decision to include or exclude the patients which fall into this category, should be made 
before the participant is randomised. 
4.4 Study Restrictions 
Participants will be informed and reminded of all study restrictions during recruitment, the informed 
consent process, and during screening and other scheduled assessments. Compliance with all restrictions 
will be required for the duration of the study. 
4.4.1 Contraceptive Requirements 
Local recommendations related to contraception and pregnancy testing must be followed, to avoid 
potential problems associated with radiation exposure to the unborn child, as per standard of care. The 
study is not responsible for contraceptive measures or pregnancy testing.  
 
 

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4.4.2 Other Lifestyle Considerations and Study Restrictions 
The patient is not allowed to be an active smoker for the duration of the study, defined as from the 
moment of inclusion until at least the assessment of the primary outcome (follow-up visit at 1 year after 
LST). The smoking cessation eligibility criterium does not define a minimal cessation period, but the 
plastic/reconstructive surgeon must be (at least theoretically) willing to perform microsurgical breast 
reconstruction on the participant, based on their smoking cessation status. Active smoking is defined as 
the active use/consumption of any tobacco products or nicotine replacement products.  
No other lifestyle restrictions apply. 
4.4.3 Prior and Concomitant Therapies 
There are no restrictions on the use of medication during the study. 
4.5 Screen Failures 
A screen failure is a consenting participant who has been deemed ineligible during screening, on the basis 
of the eligibility criteria, or who has withdrawn consent prior to randomisation. Rescreening must be 
discussed with and approved by the Sponsor on a case-by-case basis.  
The Investigator agrees to complete a participant identification and enrolment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by the 
Sponsor study-site contact for completeness. The participant identification log will be treated as 
confidential and will be filed by the investigator in the investigator study file (ISF). To ensure participant 
confidentiality, no copies will be made. All reports and communications relating to the study will identify 
all participants by participant identification, redacting all other direct identifiers (e.g. participant first/last 
name, email address, or their exact date of birth). 
 
 

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5. Study Conduct 
5.1 Study Procedures 
As noted in Section 3.1, participation in the PRADAIIBE study will comprise a screening period, where 
screening assessments must be completed before participants are enrolled and randomised. Eligible, 
consenting participants will then be randomised and undergo treatment according to their assigned 
treatment group, with a post-treatment follow-up period to assess safety and efficacy. The visit schedule 
and all study procedures and assessments are presented in the SoE (table 1).  
The results of all assessments and procedures will be documented in the participant’s medical record and 
in the study documentation, including the electronic case report form (eCRF), as applicable. 
5.1.1 Recruitment 
Recruitment will mainly rely on local investigators (or their assigned deputies) being present in 
multidisciplinary meetings where all patients with breast cancer being diagnosed/treated at that study site 
are being discussed, in order to raise the question of study participation. When a potential study 
participant is identified, the treating physician and local trial team (investigators and clinical trial office) 
will be notified. If all parties agree upon apparent study eligibility, the best method and moment of 
approaching the patient will be discussed and enacted. If the patient is willing, they will be invited to 
discuss the Informed Consent Form (ICF) with a study investigator trained in the ICF-procedure. The 
potential participant will be given adequate opportunity and time to reflect and ask questions concerning 
the ICF and study participation. If the potential candidate agrees to participate in the study, and signs the 
ICF, they will be invited to the screening visit. During the ICF-procedure, the patient will be adequately 
informed of the study related risks and benefits, their rights and the expected commitments, as well as 
the fact that they are able to retract their informed consent and discontinue the study at any point, without 
prejudice or a negative impact on their further treatment options. In providing the ICF and planning the 
screening visit, careful consideration will be taken as not to apply undue pressure to the patient in making 
their decision on study participation.  
Additionally, there will be dissemination of public information concerning the PRADAIIBE trial, through 
channels of patient support groups, flyers, and websites.  
5.1.2 Assignment of the Participant Identification Number 
At screening, each consenting study participant will be assigned a participant identification number that 
will be retained as the primary identifier for the participant throughout the study. The participant-id 
consists of a sequential 6-digit number (comprised of a 3-digit study site number: 110, 120, etc.- and a 3-
digit number incremental per centre representing the sequential order in which participants are screened: 
110-0001, 110-0002, etc.), so that each participant is numbered uniquely across the entire study and eCRF 
database. Upon signing the ICF, the participant is assigned to the next sequential participant-id available 
to the Investigator through the electronic data capture system. Each site keeps an updated participant 
identification log, in which the name of the participant is linked to their assigned study-id. This log is kept 
in a designated secured location with restricted access, managed by the local study personnel. The link 
between the participant name and study-id will never be shared outside of the local study team, except 
for monitoring or auditing purposes, as indicated. If a participant is a screen failure, their study-id will not 
be re-used and it will remain unique to them. 

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5.1.3 Screening Period 
Screening of consenting patients, confirmation of eligibility by the central investigator, and randomisation 
will be performed within 10 business days after a patient has provided informed consent to participate in 
this clinical trial. This deadline serves the purpose of avoiding treatment delays, which could compromise 
oncological outcomes. If this time interval is not respected, a protocol deviation must be logged.  
Written informed consent by the patient must be documented before any study specific procedure, 
including procedures or data collection for screening purposes, are undertaken. The patient will be 
adequately informed that screening visit cancellation and withdrawal of informed consent is possible at 
any point, without the necessity of providing a reason for withdrawal, in order to withdraw. A reason will 
be asked for registration purposes, but answering this question is not mandatory.   
Screening evaluations for this study will include the following: 
- 
Review of the study inclusion/ exclusion criteria (see Section 4.2 and Section 4.3) 
- 
Collecting demographic information (see Section 5.4.1) 
- 
Review of medical history and concomitant medications (see Section 5.4.2 and Section 4.4.3) 
- 
Clinical assessment includes the evaluation of performance status (ECOG), and measurement of body 
weight and height (see Section 5.4.3). 
- 
Assessment of baseline breast cancer disease characteristics (see Section 5.4.7) 
- 
Assessment of baseline ‘satisfaction with breasts’ using the preoperative ‘Satisfaction with Breasts’ 
scale of the BREAST-Q v2 questionnaires, which is uniform among modules (see Section 5.4.4).  
- 
Assessment of baseline QoL using the EQ-5D-5L questionnaire (see Section 5.4.5). 
- 
Four digital photographs of the breasts (see Section 5.4.6). 
- 
Elicitation of all  Adverse Events (AEs) will be recorded from the moment of inclusion until study 
conclusion, and recorded according to the NCI-CTCAE v5.0 (see Section 7).  
All results must be available for review and verification prior to participant enrolment to the study. 
The Investigator should submit a signed and dated Eligibility Verification Form (EVF) to 
cancertrials@zas.be. The central investigator will reply by email to confirm eligibility within 1 business day. 
After eligibility has been confirmed, patients can be randomised using the eCRF in Castor EDC (see Section 
6.4.3). 
5.1.4 Study participant randomisation 
5.1.4.1 Stratification 
The randomisation will be balanced according to clinical trial site. More factors were considered, however 
the decision was made not to add more stratification parameters due to the risk of treatment group 
imbalances. Post-hoc subgroup analysis will be used to compensate for this decision.  
5.1.4.2 Randomisation 
Participants will be randomised using a computer generated permuted block randomisation. The 
randomisation scheme is further discussed in a separate file, to avoid bias due to predictability following 
from randomisation scheme knowledge. This separate file is included in the ethical commission application 
of this study protocol.  
 

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Randomisation of a participant can be performed by the site staff using the electronic randomisation tool 
built into the eCRF (Castor EDC), as soon as patient eligibility has been confirmed by the central 
investigator. The randomisation tool consists of an automatic calculation which checks if all eligibility and 
baseline assessment data are entered into the eCRF and if the patient is eligible for participation. When 
all pre-requisites are met, the eCRF will unlock the randomisation option. The study personnel performing 
the randomisation will press a button after which a dialogue box opens, displaying the randomisation arm, 
which is from then on also displayed in the participant’s eCRF overview page. The study personnel are not 
able to change any settings of this randomisation process, nor are they able to see the sizes of the 
permutated blocks.  
Participants will be randomised in a 1:1 ratio to one of the two treatment groups (SoC treatment, the 
control group, or experimental treatment, the intervention group).  
5.4.1.3 Blinding 
There is no blinding of the participants, nor research personnel in this study. This decision is made due to 
the consideration that blinding of the administration of Preop-RT and breast reconstruction timing are 
both impractical and may raise ethical concerns regarding oncological safety and informed consent.  
There is blinding of the expert panels scoring the photographs using the aesthetic items scale (AIS). Due 
to the nature of this assessment there is no need for an unblinding protocol.  
5.1.5 Treatment period 
Following randomised allocation to a study treatment group, the participant will start their assigned 
treatment. See Section 6 for the timing and a detailed description of the study interventions. 
During the treatment period no study related visits are planned, except for the participants in the standard 
treatment group, receiving DBR. In this group of participants an additional intermediary follow-up (IMFU) 
study visit is planned at 3 months after the last Postop-RT treatment session. During this visit the following 
investigations will be performed: 
- 
Assessment of ‘satisfaction with breasts’ using the ‘Satisfaction with Breasts’ scale from the 
‘Mastectomy’ module of the BREAST-Q v2 questionnaire (see Section 5.4.4). 
- 
Assessment of QoL using the EQ-5D-5L questionnaire (see Section 5.4.4). 
- 
Four digital photographs of the breast-area (see Section 5.4.6). 
- 
Elicitation of all (S)AEs and their potential links to study treatments. Adverse events will be graded 
according to the NCI-CTCAE v5.0 (see Section 5.4.8, and Section 7).  
For all participants, the following data should be recorded in the eCRF during, or after conclusion of the 
treatment period: 
- 
Treatment characteristics of radiation therapy (Section 6.1; 6.5.1).  
- 
Treatment characteristics for oncological and reconstructive breast surgery (Section 6.2; 6.5.2). 
- 
Treatment characteristics of (pre-/postoperative) systemic therapy (if applicable) (Section 6.5.3) 
- 
Pathological tumour response as evaluated on the resection specimen (Section 5.4.9) 
- 
Pathological staging (p/ypTNM) as evaluated on the resection specimen (Section 5.4.9).   
 
 

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5.1.6 Follow-up Period 
Participants will return to the site during the follow-up period to complete the following assessments.  
The follow-up period starts after ‘last study treatment’ (LST), which is defined as the last radiotherapy 
session or definitive (reconstructive) surgery. Follow-up visits will be defined in relation to this point in 
time.  
At 3 Months after last study treatment (LST) 
The first follow-up visit occurs at 3 (+/-1) months after the last study treatment (LST). The following 
investigations should be performed: 
- 
Assessment of satisfaction with breasts using the ‘Satisfaction with Breasts’ scale from the 
postoperative ‘Reconstruction’, ‘Breast Conserving Therapy’, or ‘Mastectomy’ modules of the BREAST-
Q v2 questionnaire, as appropriate for the clinical situation (see Section 5.4.4). 
- 
Assessment of QoL using the EQ-5D-5L questionnaire (see Section 5.4.5). 
- 
Four digital photographs of the breasts (see Section 5.4.6). 
- 
Elicitation of all (S)AEs and their potential links to study treatments. Adverse events will be graded 
according to the NCI-CTCAE v5.0 (see Section 5.4.8, and Section 7).  
- 
Checking of treatment characteristics registration, as defined in section 5.1.5.  
At 1, 2, 5 and 10 years of follow-up (after LST) 
Visits during the follow-up period are to be conducted within ± 1 month of the nominal time point for the 
visit at 1 year after LST and ± 6 months for the visits at 2, 5 and 10 years after LST. The following 
investigations should be performed: 
- 
Assessment of satisfaction with breasts using the ‘Satisfaction with Breasts’ Scale from the 
postoperative ‘Reconstruction’, ‘Breast Conserving Therapy’, or ‘Mastectomy’ modules of the BREAST-
Q v2 questionnaire, as appropriate for the clinical situation (see Section 5.4.4). 
- 
Assessment of QoL using the EQ-5D-5L questionnaire (see Section 5.4.5). 
- 
Four digital photographs of the breasts (see Section 5.4.6). 
- 
Elicitation of all (S)AEs and their potential links to study treatments. Adverse events will be graded 
according to the NCI-CTCAE v5.0 (see Section 5.4.8, and Section 7).  
- 
Data on the regional, locoregional or metastatic tumour recurrence, or death must be collected. Used 
for TTE/survival assessment (see Section 5.4.11). 
5.1.7 End of Study 
End of study is defined as the last visit of the last patient (LPLV). 
5.1.8 Unscheduled Visits 
The Investigator or participant may request additional, unscheduled visits. Assessments at unscheduled 
visits will be undertaken as clinically indicated and registered in the eCRF. 
5.1.9 Early Termination 
In the case of premature discontinuation from study participation, the date and reason for termination (if 
willingly provided) should be documented in the eCRF, as discussed in section 5.2. The participant should 
return to the clinical site and complete an early termination visit (if they agree to this visit) as delineated 
in the SoE (Table 1). 

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5.2 Discontinuation or Withdrawal 
5.2.1 Individual participants 
5.2.1.1 Withdrawal from Study 
In accordance with applicable regulations, a participant has the right to withdraw from the study, at any 
time and for any reason, without prejudice to their future medical care, nor having to provide a reason. 
If a participant withdraws consent, the date and reason for consent withdrawal should be documented. 
This is documented by registering an ‘Unscheduled visit’ in the eCRF. If a participant does not wish to 
provide a reason for withdrawal, this will not have any consequence for the participant, their medical 
treatment, or their withdrawal from the study. Participant data will be included in the analysis up to the 
date of the withdrawal of consent.  
Apart from withdrawal of consent, reasons for early termination of individual participants may include: 
- 
Protocol deviations or participant non-compliance (must be specified in the eCRF/deviation log) 
- 
Adverse events 
- 
The Investigator considers that it is in the participant’s best interest to discontinue their participation 
in the study 
- 
The participant is lost to follow-up 
- 
The participant is deceased 
- 
Other (must be specified and motivated) 
If a participant is withdrawn because of an (S)AE, the Investigator should follow each (S)AE until the event 
has resolved to baseline grade or better, the event is assessed as stable by the Investigator, the participant 
is lost to follow-up, or the participant withdraws consent. Every effort should be made to follow all SAEs 
considered to be related to the study, until a final outcome can be reported. 
Wherever possible, the specified assessments should be performed for all participants who discontinue 
prior to the completion of the study. 
5.2.1.2 Replacement of Participants 
Participants who are enrolled and randomised but do not receive study treatment will not be replaced. 
5.2.1.3 Participants Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for scheduled visits and are unable 
to be contacted by the study centre. 
The following actions must be taken if a participant fails to return to the study centre for a required study 
visit: 
- 
The study centre must attempt to contact the participant and reschedule the missed visit as soon as 
possible. The study centre must counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether the participant wishes to and/or should continue in the study. 
- 
Before a participant is deemed lost to follow-up, the Investigator or designee must make every effort 
to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address or equivalent methods). These contact attempts 
should be documented in the participant’s (e)CRF. 
- 
Should the participant continue to be unreachable, they will be considered to have withdrawn from 
the study, and will be classified as ‘lost to follow-up’. 

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5.3 Study Termination 
The study will be completed as planned unless: 
- 
New information or other evaluations regarding the safety of the study treatment indicates a change 
in the known risk/benefit profile for the treatment, such that the risk/benefit is no longer acceptable 
for study participants. This may be determined by the Sponsor, the Investigator, the Trial Steering 
Committee (TSC), the Independent Ethics Committees (IEC) or regulatory authorities. 
- 
The study is terminated by the Sponsor for administrative reasons. 
If the Sponsor, the IEC, the TSC, or regulatory authority elects to terminate or suspend the study or the 
participation of the investigational site, a study specific procedure for early termination or suspension will 
be provided by the Sponsor. The procedure will be followed by the investigational site during the course 
of termination or study suspension. 
5.4 Study Assessments 
5.4.1 Demographics 
The following demographics will be recorded as part of the screening procedures.  
- 
Date of screening visit 
- 
Year of birth and age 
- 
Biological sex 
- 
Preferred language (Dutch, French or English) 
- 
Height 
- 
Weight 
- 
BMI (calculated) 
- 
Ethnicity 
5.4.2 Medical History 
The following details of the Medical history will be recorded during the screening visit: 
- 
Confirmation of breast cancer diagnosis. 
- 
Check if there is a history of breast cancer or radiotherapy of the chest wall or axilla.  
- 
Check if the patient had any form of previous breast surgery, if so including a description. 
- 
Check if the patient has a confirmed collagen synthesis disease/disorder. 
- 
Smoking status and history. 
- 
Check if the patient is currently pregnant or breastfeeding. 
- 
Alcohol consumption habits. 
- 
Use of illicit drugs 
- 
Comorbidities 
- 
Registration of concomitant medications (farmaca, route of administration, dosage, start/stop date) 
5.4.3 Clinical Assessment 
Clinical assessment includes the evaluation of the ECOG performance status, the measurement of body 
weight and height, and recording currently used (chronic) medications. 
 
 

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5.4.3.1 Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status and the date of its assessment should be documented in the participant’s 
medical record or study source documentation at the screening visit. A copy of the document is included 
in Appendix 1 (Eastern Cooperative Oncology Group Performance Status Assessment) for reference. 
5.4.3.2 Height and Body Weight 
Height (cm) and body weight (kg) will only be measured during the screening visit. The (calculated) BMI 
will also be recorded as part of the screening procedures. 
5.4.3.3 Currently used (chronic) medication use 
Patients will be questioned regarding concomitant medication use, only during the screening visit. The 
patient will be asked to report all the medication they currently use, especially those medications which 
are taken on a regular basis (chronic use). The substance, route of administration, dose, and start/stop 
date (if known) will be recorded.  
All prior and concomitant systemic therapy (including neoadjuvant systemic chemotherapy, adjuvant 
systemic therapy, endocrine therapy, immune therapy, or any other forms of systemic therapy) for breast 
cancer are not recorded as concomitant medication, they must be recorded in the eCRF as discussed in 
Section 6.5.3. 
5.4.4 BREAST-Q questionnaire 
Satisfaction with breasts will be reported by patients using the Satisfaction with Breasts scale from the 
BREAST-Q v2 questionnaires.  
Preoperative and postoperative versions of the ‘Satisfaction with Breasts’ scale from the ‘Reconstruction’, 
‘Breast Conserving Therapy’, and ‘Mastectomy’ modules of the BREAST-Q Version 2.0 questionnaires will 
be used, as detailed above and supplied in appendix 2. These scales measure body image through patients’ 
satisfaction with their breasts, based on questions about the comfort of the operated or reconstructed 
breasts, both clothed and unclothed. It also evaluates self-image, the comfort of wearing clothes, breast 
symmetry, smoothness, sensation, and size. 
Participants will be asked to self-complete these BREAST-Q v2 questionnaires, they will be administered 
to patients on paper or via the Castor EDC platform (eCRF). 
Since this study lets the patient and medical team decide on the preferred method of breast reconstruction 
(within the bounds of the randomisation group), there are a number of potential situations to take into 
account. All participants are set to receive a breast reconstruction, as this is an inclusion criterium, 
therefore the pre- and postoperative ‘Satisfaction with Breasts’ scale from the ‘Reconstruction’ module of 
the BREAST-Q v2 will be considered the standard module during this study. The preoperative 
questionnaire will be assessed during the screening visit and the postoperative questionnaire at each 
follow-up visit after treatment finalisation.   
 
 

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Considering the slight chance that Preop-RT may result in downstaging, we must consider the possibility 
that patients in the treatment group may become eligible for breast conservative surgery. The 
preoperative ‘Satisfaction with Breasts’ scale from the BREAST-Q v2 ‘Breast Conserving Therapy’ Module 
is identical to that of the ‘Reconstruction’ module, and as such no extra questionnaire needs to be provided 
at the screening visit. During follow-up these patients will be evaluated with the postoperative 
‘Satisfaction with Breasts’ scale from the BREAST-Q v2 ‘Breast Conserving Therapy’ module.  
Likewise, there is the possibility of patients not having received a breast reconstruction yet (in DBR 
patients, during the IMFU visit), the occurrence of flap failure, or the patient deciding not to go forward 
with breast reconstructive surgery. In these cases the ‘Satisfaction with Breasts’ scale from the BREAST-Q 
v2 ‘Mastectomy’ module will be used. The preoperative questionnaire is again identical to those in the 
other modules.   
Using the BREAST-Q documentation, the (raw) score for each scale is transformed into the corresponding 
BREAST-Q score, using the provided module-specific conversion scales. This BREAST-Q score can range 
from 0 (signifying the least possible level of satisfaction) to 100 (signifying the highest possible level of 
satisfaction). 
5.4.5 European Quality of Life 5 Dimensions, 5 Levels (EQ-5D-5L) questionnaire 
EQ-5D-5L is a widely used generic measure of QoL status consisting of two parts (see Appendix 3).  
The first part assesses QoL in five dimensions (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression), each of which has five levels of response (no problems, slight problems, moderate 
problems, severe problems, extreme problems/unable to). The patient is asked to indicate their 
QoL/health state by ticking the box next to the most appropriate statement in each of the five dimensions. 
This part of the EQ-5D-5L questionnaire provides a descriptive profile that can be used to generate a health 
state profile. For example, a patient in health state 12345 would have no problems with mobility, slight 
problems with self-care (washing or dressing), moderate problems with doing usual activities, severe pain 
or discomfort and extreme anxiety or depression. Each health state can potentially be assigned a summary 
index score based on societal preference weights for the health state. Health state index scores generally 
range from 0 to 1, with 0 representing a health state equivalent to dead, and 1 is a perfect health state. 
Each population has an individually validated method of calculating the EQ-5D-5L index score. In this study 
the method validated in the Belgian population will be used, as recommended by the EuroQoL website 
and materials, and as published by Bouckaert et al., 2022.(65) This formula results in an index score ranging 
from -0.533 to 0.962. Since this validated formula to derive the index score in the Belgian population does 
not result in a score ranging from 0 to 1, the score will be transformed using the provided formula. This 
will increase interpretability of the score, and comparison to other populations.  
Rescaling formula, where the rescaled score value is a function of the initially calculated index score (IS): 
𝑓(𝐼𝑆) = (𝐼𝑆+ 0.533)/1.495 
The second part of the questionnaire consists of a visual analogue (VAS) scale on which the patient rates 
their perceived health, on that specific day, from 0 (the worst imaginable health) to 100 (the best 
imaginable health).  
 
 

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Participants will be asked to self-complete the EQ-5D-5L questionnaire during study visits, at the screening 
visit (baseline), IMFU visit (for DBR patients), and during the follow-up visits at 3months, 1 year, 2 years, 5 
years and 10 years after LST. The EQ-5D-5L questionnaire  requires a low level of cognitive strain, consisting 
of 5 dimensions with 5 possible levels on a Likert answering scale and a single VAS-scale based question. 
It takes only a few minutes to complete. The self-complete version of the EQ-5D-5L questionnaires will be 
administered to subjects on paper or via the Castor EDC platform (eCRF). 
5.4.6 Digital Photographs of the Breasts 
Digital, two-dimensional, colour photographs of both breasts, will be taken during study visits, at the 
screening visit (baseline), IMFU visit (for DBR patients), and during the follow-up visits at 3months, 1 year, 
2 years, 5 years and 10 years after LST. Each set of photographs will be assessed by a blinded panel of 
experts using the Aesthetic Items Scale (AIS; see Appendix 4). 
It is of great importance that they are taken according to a standardised protocol to ensure comparability 
between visits and between participants. For this reason the following guidelines must be adhered to: 
- 
Within each study site a certain location should be chosen to take these photographs. Ideally this 
location has:  
o 1) A blank (no frames, drawings, closets etc.) white wall or screen;  
o 2) No windows or the option to block out sunlight, as sunlight varies greatly depending on 
time-of-day and weather conditions;  
o 3) Adequate artificial light, so that a flash is not necessary, and these lighting options 
should always be available (e.g.: if a desk-lamp is used in the initial setup, this desk-lamp 
should always be available when taking photographs). 
- 
Regarding the photography device, either a smartphone, or a dedicated camera device (DSLR, 
mirror-less, etc. camera) can be used. The following requirements apply:  
o 1) At least 10 Megapixels;  
o 2) Always use the same device, or verify that image quality is similar (before using the 
device);  
o 3) Use the automatic settings of the device;  
o 4) Always check the quality of the photographs after taking them, if needed repeat the 
photograph(s);  
o 5) Avoid using the Flash function, but it is allowed when the image quality/clarity is 
insufficient without the Flash.  
Before the first patient, the location and device should be determined. Test photographs should be taken 
at the location, using the selected device (or multiple locations/devices to decide which are the best 
options). Take photographs according to these guidelines, using a stand-in model (clothed, preferably in a 
white/beige/brown top) in order to verify adequate image quality.  
The participant should be positioned +/- 30-50cm from the background. The chest anatomy should be 
clearly visible, clothes and jewellery obstructing the view of the chest anatomy should be removed. 
Ensuring an unobstructed view for photographs which will be framed to include at least the low neck, 
upper border of the shoulders to the umbilicus in the cranio-caudal axis and the entire width and depth of 
the body in the sagittal and antero-posterior axes respectively. 

Page 51 of 73 
 
The camera device should be positioned in such a way that the device is not tilted (no front/back and no 
left/right tilting), at least 50cm from the participant, increasing the distance as needed to correctly frame 
the participant within the view of the camera device.  
Before the visit, please check the availability of the location and device. Check the standardised conditions 
and other prerequisites: lighting of the room, background, battery-life, storage capacity, camera settings.  
Photograph 1: The participant is positioned in front of the camera in a 0°-angle. The arms should be down, 
next to the body with the hands placed on the gluteal region. Ensure correct framing of the photograph, 
including at least the low neck, upper border of the shoulders to the umbilicus in the cranio-caudal axis 
and the entire width of the body in the sagittal axis. 
 
Figure 2.1: Photograph position 1, frontal view and arms down. 
Photograph 2: The participant is positioned in front of the camera in a 0°-angle. The arms should be lifted 
up until the maximal height is achieved. Ensure correct framing of the photograph, including at least the 
low neck, upper border of the shoulders to the umbilicus in the cranio-caudal axis and the entire width of 
the body in the sagittal axis. 
 
Figure 2.2: Photograph position 2, frontal view and arms up. 
 
 

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Photograph 3: The participant is positioned in front of the camera in a Right-facing 90°-angle, exposing 
the left flank. The arms should be lifted up at maximal height. Ensure correct framing of the photograph, 
including at least the low neck, upper border of the shoulders to the umbilicus in the cranio-caudal axis 
and the entire width and depth of the body in the sagittal and antero-posterior axes respectively. 
 
Figure 2.3: Photograph position 3, left lateral view and arms up. 
 
Photograph 4: The participant is positioned in front of the camera in a Left-facing 90°-angle, exposing the 
right flank. The arms should be lifted up at maximal height. Ensure correct framing of the photograph, 
including at least the low neck, upper border of the shoulders to the umbilicus in the cranio-caudal axis 
and the entire width and depth of the body in the sagittal and antero-posterior axes respectively. 
 
Figure 2.4: Photograph position 4, right lateral view and arms up. 
 
Afterwards, please verify the image quality. Correctly name the photograph using the format: 
“Photograph_[VISIT]_[Participant ID]_[#] of 4”. 
5.4.7 Disease baseline characteristics 
The following information regarding aspects of the patient’s breast cancer will be recorded in the eCRF 
- 
Date of diagnosis 
- 
Affected side 
- 
Diagnostic measures performed (+ details such as amount and region of sampled lymph nodes) 
- 
Signs of lymphovascular invasion (Pathology report) 
- 
The c/ycTNM classification, as reported by the MDO 
- 
Immuno-histochemical, molecular and/or genetic tests performed, including results 
- 
Check if there is an indication for SSM/NSM 
- 
Check if there is an indication for PMRT 
- 
Check if there is a wish for breast reconstruction 
 
 

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5.4.8 Assessment of (S)AEs and Surgical AEs 
The definition, registering and follow-up of (S)AEs is discussed in section 7.  
Elicitation of general (S)AEs and surgical (S)AEs will occur at IMFU, 3 months, 1, 2, 5 and 10 years after LST. 
Surgical AEs are defined as any complication (AE or SAE) related to surgical treatment/intervention. In this 
study this pertains to both the oncological and reconstructive surgeries. Surgical (S)AEs/complications are 
reported using the Common Terminology Criteria for Adverse Events (CTCAE, version 5). During the 
reporting of an AE/SAE the relatedness to a study intervention is also registered, here the relatedness to 
surgical treatment/intervention will be registered. If an (S)AE is scored as ‘Possibly related’ or higher, 
relating to a surgical study treatment, then it will be considered as a surgical AE.   
CAVEAT: Not all postoperative complications are listed in the CTCAE v5.0 database, for example: 
capsular contraction, implant malpositioning, reconstructive failure, etc. are not listed but need to be 
recorded. These can be registered under “Injury, poisoning and procedural complications - Other, 
specify” CTCAE term  
5.4.9 Treatment duration 
Throughout the study the dates of important treatment milestones will be recorded. These include the 
dates of diagnosis, screening visit, lymph node biopsy, randomisation, preoperative systemic therapy (start 
and stop), radiotherapy (start and stop), oncological surgery, reconstructive surgery(/-ies), postoperative 
systemic therapy (start and stop). 
These parameters will be used to calculate the following outcome variables, expressed in days: 
- 
Randomisation to last study treatment (LST) 
- 
Randomisation to oncological breast surgery 
- 
Oncological breast surgery to last study treatment (LST) 
Other time intervals will be calculated in the eCRF, based on the aforementioned milestone dates. These 
will not be used in the primary statistical analysis, but could be used in the post hoc analysis.  
5.4.10 Assessment of Pathological Tumour Response and resection specimen pathology TNM 
Pathological tumour response, as assessed on the resection specimen, must be registered in the eCRF.  
This outcome should always be reported when preoperative-systemic therapy was administered. Preop-
RT without preoperative-systemic therapy, may also be seen as a reason to assess the tumour response 
category. However, at an interval of 2-6 weeks after radiation therapy we don’t expect any effect on the 
pathological response. Therefore, if we would compare the response categories between the standard 
and experimental groups, this would result in an unfair comparison. For this reason this outcome will be 
assessed in a subset of the ITT set, which is defined as the population that received preoperative systemic 
therapy. In the safety set this will remain unchanged and in safety analysis of this outcome both sets will 
be analysed.  
 
 

Page 54 of 73 
 
Response categories should be recorded according to the Pinder classification or ‘no preoperative 
therapy’: (9)  
- 
No residual carcinoma nor DCIS (complete response) = Pinder 1i 
- 
No residual carcinoma but DCIS present = Pinder 1ii 
- 
Partial response (>90%) = Pinder 2i 
- 
Partial response (50-90%) = Pinder 2ii 
- 
Partial response (<50%) = Pinder 2iii 
- 
No signs of response = Pinder 3  
- 
No preoperative therapy 
After oncological surgery it is standard of care for the pathologist to assess the resection specimen and 
resected lymph nodes if applicable. Resulting from this assessment a pathology-based TNM classification 
is reported (pTNM or ypTNM). The resulting pathology TNM and additional IHC or genetical testing results 
will be collected from the patient’s EHR and registered in their (e)CRF.  
5.4.11 Collection of Data on oncological survival 
Oncological follow-up of patients will be planned according to local institutional guidelines. 
During follow-up visits (from LST +1 year onwards) the oncological outcome parameters, as described 
below, will be registered in the patient’s (e)CRF. Registration will be based on both patient interview during 
the follow-up visit, as well as EHR reviewing (source documents).  
The following events must be recorded if applicable, as defined in the 2015 DATECAN consensus: (10) 
- 
Death  
o All-cause mortality  
o Death from breast cancer 
- 
Any recurrence vs. none. 
If any recurrence has occurred it will be recorded using the subtypes:  
o Invasive ipsilateral breast tumour recurrence/progression 
o Local invasive recurrence/progression 
o Regional invasive recurrence/progression 
o Appearance/occurrence of metastasis/distant recurrence 
o Ipsilateral DCIS  
 
 

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6. Study Intervention 
6.1 Radiation Therapy 
6.1.1 Timing 
Postop-RT/PMRT will be initiated 6-12 weeks after the oncological breast surgery. 
Preop-RT must be planned to commence as quickly as reasonably possible after randomisation, at the 
discretion of the Investigator, but no later than 6 weeks after randomisation or the last dose of 
preoperative chemotherapy (if applicable). 
6.1.2 Patient Positioning and Imaging 
All patients will undergo a radiation therapy-planning CT in a standard semi-supine position according to 
local protocols. Where indicated, patients will be imaged using a breath-hold technique (again, according 
to local protocols). CT images should be acquired at no greater than 5mm intervals, but ideally at 3mm 
intervals. 
6.1.3 Target Volume Definition 
In general, the breast tissue from 5 mm beneath the skin surface to the pectoral fascia will be the clinical 
target volume in all cases. Whether regional nodes are included in the target volume will be based on the 
clinical situation of the individual patient, local treatment protocols, and multidisciplinary meeting advice.  
6.1.4 Treatment Planning 
Breast cancer RT-plans will be prepared according to local protocols, with the aim of covering the 
dosimetric parameters listed in Table 3 (in accordance with the Dutch national consensus guidelines of 
Hurkmans et al. 2021).(66) 
6.1.5 Dose 
Patients will be treated according to departmental protocol, 40Gy in 15 fraction, over 3 weeks, or a 
biologically equivalent dose (i.e. 26Gy/5 fx). Radiation techniques and quality assurance procedures are 
identical to the standard radiation techniques applied in PMRT or WBRT, and should fulfil the criteria as 
defined by this protocol. 
6.1.6 Use of Bolus 
The use of a bolus will be in accordance with 
ESTRO guidelines.(67) When Preop-RT is given 
for a cT4b/c tumour, bolus should be 
administered only on the part of the skin that 
will also be excised during oncological breast 
surgery. 
  
Table 3 National consensus on dosimetric 
parameters and target volume names to be used 
in the evaluation of a breast cancer RT-plan 
(Hurkmans et al., 2021)(66)  

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6.2 Oncological breast Surgery 
At inclusion there should be an indication for skin-sparing (SSM) or nipple-sparing (NSM) mastectomy. 
However, for the actual oncological surgery, a SSM, NSM, breast-conserving surgery (BCS), or Modified 
Radical Mastectomy (MRM) could be performed, as indicated. The possibility of a BCS is believed to be 
very unlikely, but was added in order to accommodate the unlikely event that Preop-RT would lead to 
sufficient downstaging. For the purpose of this protocol we will refer to SSM, NSM, or MRM, as 
‘mastectomy’ or ‘ME’, and if BCS is also included, as ‘oncological surgery’.   
ME will be performed within 6 weeks of randomisation or the last dose of neoadjuvant chemotherapy (if 
applicable) for patients in the standard treatment arm.  
Patients in the experimental treatment arm proceed to oncological surgery at 2-6 weeks after the last 
fraction of Preop-RT.  
The timing of oncological surgery can be delayed if necessary for patient safety, e.g. in case of severe acute 
toxicity after RT, or unforeseen logistical reasons, but this needs to be documented as a protocol deviation. 
6.3 Breast Reconstruction surgery 
The type/technique of breast reconstruction performed is at the discretion of the patient and the treating 
plastic/reconstructive surgeon, within the bounds of the randomisation groups. These options include 
reconstruction using an implant (+/- in two steps with a temporary tissue expander), using autologous 
tissue (e.g.: Deep Inferior Epigastric Perforator (DIEP) flap), or a combined technique using both 
autologous tissue and an implant/TE. Adjuvant reconstruction techniques such as fat grafting, or an 
acellular dermal matrix, could also be used in addition to the primary technique.  
In the standard treatment arm both immediate and delayed (IBR or DBR) techniques can be used according 
to standard of care and patient/surgeon preferences. The placement of a tissue expander (TE) is 
considered an IBR approach within this study. 
In the experimental treatment arm only immediate reconstruction (IBR) techniques are allowed, this could 
also consist of a TE placed during oncological surgery. If there are unforeseen conditions, in which IBR is 
not in the best (medical/safety) interests of the patient, the treating physician and medical team should 
act in the best interest of the patient, such events should be recorded as a protocol deviation. 
6.5 Treatment Characteristics, Compliance and Adherence  
6.5.1 Radiation therapy characteristics 
The following characteristics regarding RT will be recorded in the eCRF: 
- 
Setting (preoperative vs. postoperative) 
- 
Start and stop dates 
- 
Prescribed dose and fractioning for both breast/thorax and axillary regions 
- 
Modality of RT employed, and if proton-based RT is used, the MeV delivered.  
- 
Homogeneity of delivery 
- 
Target volume parameters (PTV volume, D98%, Dmean, D02%) for both breast and axillary regions  
- 
Organs At Risk (OAR) parameters (Dmean ipsilateral lung, V5Gy ipsilateral lung, Dmean heart, Dmean 
contralateral breast, Thyroid V30Gy) 
- 
Whether DICOM file(s) will be locally stored for at least 10 years.  
 

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6.5.2 Surgery characteristics 
The following characteristics regarding oncological surgery will be recorded in the eCRF: 
- 
Date of surgery 
- 
Type of surgery (SSM, NSM, MRM, BCS, None/other) 
- 
Weight of removed breast tissues (pathology report) 
- 
Type of lymph node procedure, including number removed and positive nodes 
The following characteristics regarding reconstructive surgery will be recorded in the eCRF: 
- 
Immediate vs. delayed breast reconstruction (IBR vs. DBR) 
- 
Date of surgery(/-ies) 
- 
Primary technique of reconstruction (Autologous, implant-based, or combined; +/- Tissue Expander) 
- 
Tissue expander starting volume 
- 
Breast implant details: positioning, shape, profile, volume, and texture 
- 
Autologous flap details: type of flap, pedicled/free-flap, number of anastomoses, and stacked yes/no 
- 
Adjuvant breast reconstruction techniques 
- 
If applicable, reconstructive failure details 
6.5.3 Systemic treatment characteristics 
The following characteristics regarding systemic therapies will be recorded in the eCRF: 
- 
Preoperative and/or postoperative administration of systemic therapy 
- 
Types of systemic therapy used. (This includes, but is not limited to chemotherapy (ChT) regimens, 
endocrine therapy (ET), Immuno-therapy, targeted therapies (TT) and Bisphosphonates (BP))  
- 
Start and stop dates  
- 
Agents used 
 
 

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7. Safety Monitoring 
The Investigator and any designees are responsible for detecting, documenting, and recording events that 
meet the definition of an AE or SAE and remain responsible for following up (S)AEs that are serious, 
considered related to the study treatment or study procedures, or that caused the participant to 
discontinue the study (see Section 5.2). 
7.1 Definition of Adverse Events (AEs) 
An AE is any untoward medical occurrence in a participant, temporally associated with the study 
intervention, whether or not considered related to the study intervention. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the study intervention. 
Events meeting the definition of an AE include: 
- 
Any abnormal laboratory test results (haematology, biochemistry, etc.) or other medical (safety) 
assessments (e.g., ECG, radiological scans, vital signs measurements, etc.), including results that 
worsen from baseline, considered clinically significant in the medical and scientific judgment of the 
Investigator, which are not (clearly) related to progression of any underlying disease. 
- 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/ or intensity of the condition. 
- 
New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
- 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
- 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
7.2 Definition of Adverse Reaction (AR) 
Adverse reactions are all noxious and unintended responses to a study intervention. In determining 
whether an adverse event is an adverse reaction, consideration shall be given to whether there is a 
reasonable possibility of establishing a causal relationship between the event and the study intervention 
based on an analysis of available evidence. 
7.3 Definition of Unexpected Adverse Reaction (UAR) 
An adverse reaction, the nature or severity of which is not consistent with the available safety evidence 
for the study intervention.  
7.4 Definition of Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR) 
An SAE is defined as any untoward medical occurrence that, at any dose: 
- 
Results in death 
Report if you suspect that the death was an outcome of the adverse event, and include the date 
if known.  
 

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- 
Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
- 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
In general, hospitalisation signifies that the patient has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/ or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious. Hospitalisation for elective treatment of a pre-
existing condition that did not worsen from baseline is not considered an AE. 
- 
Results in persistent disability/ incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute 
a substantial disruption. 
- 
Results in a congenital anomaly/ birth defect 
Report if you suspect that exposure to a medical product/treatment prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
- 
Results in other situations (important medical events) 
Report when the event does not fit the other outcomes, but the event may jeopardise the patient 
and may require medical or surgical intervention (treatment) to prevent one of the other 
outcomes. Examples include allergic bronchospasm (a serious problem with breathing) requiring 
treatment in an emergency room, serious blood dyscrasias (blood disorders) or 
seizures/convulsions that do not result in hospitalisation. The development of drug dependence 
or drug abuse would also be examples of important medical events. 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
situations which were not explicitly mentioned, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such medical events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalisation, or development of drug dependency or drug abuse. 
Note: If an event is not an AE per definition presented in Section 7.1, then it cannot be an SAE even if 
serious conditions are met (e.g., hospitalisation for signs/ symptoms of the disease under study, death due 
to progression of disease). 
In determining whether a serious adverse event (SAE) is a serious adverse reaction (SAR), consideration 
shall be given to whether there is a reasonable possibility of establishing a causal relationship between 
the event and the study intervention based on an analysis of available evidence.  

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7.5 Severity or Intensity of an Adverse Event 
AEs are to be recorded in the eCRF. Severity will be graded according to the NCI-CTCAE v 5.0, published 
November 27, 2017 (NCI-CTCAE v5.0 – see Appendix 5).  
CAVEAT: Not all postoperative complications are listed in the CTCAE v5.0 framework, for example: 
capsular contraction, implant malpositioning, reconstructive failure, etc. are not listed but need to be 
recorded. These can be registered under “Injury, poisoning and procedural complications - Other, 
specify” CTCAE term  
 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the grades listed in the NCI-CTCAE v5.0. These grades generally follow this model: 
- 
Grade 1: Mild; an event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
- 
Grade 2: Moderate; an event that causes sufficient discomfort and interferes with normal everyday 
activities. 
- 
Grade 3: Severe; an event that prevents normal everyday activities. 
Note: An AE that is assessed as severe should not be confused with a SAE. Severe is a category utilised 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
- 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
- 
Grade 5: Death related to AE. 
Caveat: An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described 
in the definition of an SAE, NOT when it is graded as severe (grade 3). 
7.6 Causal Relationship or Relatedness of an Adverse Event 
The Investigator is obligated, and will use clinical judgment, to assess the relationship between the study 
interventions and each occurrence of each AE/ SAE. The AE must be characterised as unrelated, unlikely 
to be related, possibly related, probably related, definitely related, or unknown (unable to judge) to the 
study intervention (i.e. oncological breast surgery, radiation therapy and breast reconstruction surgery). 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration will be considered and 
investigated. 
The Investigator will also consult the available evidence on the safety of the study intervention in his/ her 
assessment. 
For each AE/ SAE, the Investigator must document in the medical notes that he/ she has reviewed the AE/ 
SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report. However, it is very important that the Investigator always makes an 
assessment of causality for every event before the initial transmission of the SAE data to the Sponsor 
medical representative. 
The Investigator may change his/her opinion of causality in light of follow-up information and complete 
an SAE follow-up report with the updated causality assessment. 

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The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
The following definitions, and the content of Table 4, are general guidelines to help assign grade of 
attribution: 
Adverse reaction (AR) – An AR is any AE caused by the study interventions 
Serious adverse reaction (SAR) – An SAR is any SAE caused by the study interventions 
Suspected unexpected serious adverse reaction (SUSAR) – An SAR for which there is a reasonable 
possibility that the study interventions caused the SAE. A “reasonable possibility” means there is evidence 
to suggest a causal relationship between the study intervention and the AE. SUSAR implies a lesser degree 
of certainty about causality than AR/SAR. 
Unexpected – An event is considered unexpected if there is no evidence available for its occurrence with 
the particular interventions under investigation. 
Table 4 Adverse Event Causal Relationship with Study Intervention 
Definitely Related  
Clear evidence to suggest a causal relationship with other possible 
contributing factors has been ruled out. The clinical event occurs within an 
acceptable time relationship to study treatment, improves when stopping 
the treatment, and re-appears when exposure resumes if necessary. 
Probably Related 
Facts, evidence, and/or arguments suggest a causal relationship, yet there is 
still room for doubt. 
Possibly Related 
The association of the AE with the study intervention is unknown; however, 
the AE is not reasonably supported by other conditions. 
Unlikely to be 
Related 
Only a remote connection exists between the study intervention and the AE. 
Other conditions, including chronic illness, progression or expression of the 
disease state or reaction to concomitant therapy, appear to explain the 
reported AE. 
Unrelated 
No reasonable possibility that the study intervention caused the AE. 
Unknown  
All efforts should be made to classify the AE according to the above 
categories. The category “unknown” (unable to judge) may be used only if 
the causality is not assessable, e.g., because of insufficient evidence, 
conflicting evidence, conflicting data, or poor documentation. 
 
7.7 Outcome 
Outcome of an AE or SAE will be recorded in the AE report form and eCRF as follows: 
- 
Recovered/ resolved 
- 
Recovering/ resolving 
- 
Recovered/ resolved with sequalae 
- 
Not recovered/ not resolving 
- 
Fatal 
- 
Unknown 

Page 62 of 73 
 
7.8 Method of Detecting Adverse and Serious Adverse Events 
(S)AEs will be reported by the participant. Participants are able to report (S)AEs at any point during the 
duration of the study and follow-up, there will be formal inquiries regarding (S)AEs occurrence during all 
study related visits (cfr. SoE). Care will be taken not to introduce bias when detecting (S)AEs. Open-ended 
and nonleading verbal questioning of the patient is the preferred method to inquire about (S)AE 
occurrences. 
(S)AEs can also be reported by any involved physician if they have a mandate from the patient or if 
reporting the (S)AE is in the best interest of the patient and/or other participants. (S)AEs may also come 
to light when the patient file is being reviewed. 
7.9 Recording of Adverse and Serious Adverse Events 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. The Investigator 
will then record all relevant AE/ SAE information in the eCRF. Each event must be recorded separately. 
There may be instances when copies of medical records of specific cases are requested by the coordinating 
study staff or other authorised organisations. In this case, all direct identifiers of participant identity, with 
the exception of the participant study ID, will be redacted on the copies of the medical records before 
submission. The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/ or other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
7.10 
Follow-up of Adverse and Serious Adverse Events 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor medical representative, to elucidate the 
nature and/or causality of the AE or SAE as thoroughly as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other healthcare 
professionals. If a participant dies during study participation or during a recognised follow-up period, the 
Investigator will provide the Sponsor with a copy of any post-mortem findings including histopathology, if 
relevant and applicable. New or updated information will be recorded in the originally completed eCRF. 
The Investigator will submit any (updated) SAE data to the sponsor representatives (through 
‘cancertrials@zas.be’) within 24 hours of receipt of the information.  
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at subsequent 
visits/contacts. All SAEs will be followed until resolution, stabilisation, the event is otherwise explained, or 
the participant is lost to follow-up. 
7.10.1 Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the final study visit. All SAEs will be 
recorded and reported to the Sponsor within 24 hours. The Investigator will submit any updated SAE data 
to the Sponsor within 24 hours of it being available. Investigators are not obligated to actively seek AE or 
SAE information after conclusion of study participation. However, if the Investigator learns of any SAE, 
including a death, at any time after a participant has discontinued study participation/follow-up, and 
he/she considers the event to be reasonably related to the study treatment or study participation, the 
Investigator must promptly notify the Sponsor. 

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7.11 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal obligations and 
ethical responsibilities toward the safety of study participants and the safety of a study treatment under 
clinical investigation are met. 
The Sponsor will comply with European and country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IEC/IRB, and investigators. 
Investigator safety reports must be prepared for each suspected unexpected serious adverse reactions 
(SUSAR), and serious adverse reactions (SAR), in accordance with European and local regulatory 
requirements and Sponsor policy, and forwarded to investigators as necessary. SUSARs are defined as all 
SAEs which are ‘unexpected’ and are suspected to be related to the study intervention. SARs are defined 
as all SAEs which are deemed to be related to the study intervention 
All SAEs (initial and follow-up information) and pregnancies occurring during this study must be reported 
by emailing the completed initial report section of the SAE form within 24 hours after becoming aware of 
the SAE to: gza.safetycto@zas.be. 
The IEC/IRB will be informed by the Sponsor about SAEs, SUSARs or safety issues according to the European 
Union Clinical Trial Regulation No 536/2014 and/ or local regulations. 
7.11.1 Annual Safety Report 
The Sponsor will provide annual safety reports to the Ethics Committee. This obligation starts with the first 
authorisation of the trial and concludes with the end of the trial.  
7.12 
Clinical Laboratory Findings 
Abnormal laboratory findings (e.g., haematology or biochemistry) or other abnormal assessments (e.g., 
vital signs) are not necessarily reported as AEs. However, those abnormal findings that are deemed 
clinically significant or are associated with signs and/or symptoms must be recorded as AEs if they meet 
the definition of an AE (or recorded as an SAE if they meet the criteria of being serious) as described 
previously. Clinically significant abnormal laboratory or other abnormal findings that are detected after 
consent or that are present at baseline and worsen after consent are included as (S)AEs.   
The Investigator should exercise his/her medical and scientific judgement in deciding whether an 
abnormal laboratory finding, or other abnormal assessment is clinically significant. Usually, the 
abnormality should be associated with a clinically evident sign or symptom, or be likely to result in an 
evident sign or symptom in the near future, to be considered clinically significant. 
 

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8. Statistical Considerations 
8.1 Justification of Sample Size 
This trial will assess the efficacy of Preop-RT and the fact that it enables IBR. Therefore, the level of 
satisfaction of women with their reconstructed breasts was selected as its primary outcome variable. This 
will be assessed at 1 year of follow-up after LST, and compared to the standard of care treatment (Postop-
RT and IBR or DBR).  
The sample size was thus calculated to detect a difference in satisfaction with breasts as operationalised 
by the BREAST-Q score (‘Satisfaction with Breasts’ scale from the Breast Q v2 ‘reconstruction’, ’BCT’, or 
‘Mastectomy’ module; appendix 2), between patients in the experimental and control groups. Based on 
previous studies assessing the mean BREAST-Q score after breast reconstructions, we expect a mean score 
of 58 (SD 18) in the standard treatment/control arm.(12) The minimally important difference in the 
BREAST-Q score for satisfaction with breasts (reconstruction module) was found to be 4, based on earlier 
research.(12) This would however lead to an exceedingly high sample size. Therefore an 8 point difference 
was selected as a balance between a workable sample size and a difference in BREAST-Q scores which is 
achievable, detectable and clinically relevant.    
To detect a difference of at least 8 points (expected x̄ > 66) with 80% power and a two-sided alpha of 0.05, 
using the Students’ t-test for two independent sample means, we need to include n=81 women in each 
treatment arm. To account for a dropout rate of 10%, we aim to randomise n=90 women per treatment 
arm, resulting in n=180 patients in total.  
 
Figure 3: Power (y-axis) vs. Sample size (x-axis), per difference in means (legend) 

Page 65 of 73 
 
8.2 Analysis Populations 
The primary population for all statistical analyses is the Intention-To-Treat Population (ITT). The ITT 
population consists of all enrolled and randomised participants whether or not they received any study 
treatment. ‘The Estimands Framework’ will be used to define an inter-current events (ICE) strategy, which 
is described in the SAP. 
8.3 Statistical Methods for Analysing Primary, Secondary, and Tertiary Outcomes 
Statistical analysis will be performed under the authority of the Sponsor. A brief description of the main 
statistical principals, methods and considerations will be discussed in this study protocol. The full details 
concerning data handling and statistical analyses will be provided in the Statistical Analysis Plan (SAP), 
which is available upon request. 
Continuous outcomes 
All continuous primary and secondary outcomes (BREAST-Q, EQ-5D-5L VAS, EQ-5D-5L Index Score, AIS-TAS) 
will be analysed using Linear Mixed Models (LMM) regression analysis with a Wald-test of the grouping 
variable for formal hypothesis testing. This model will define study centre and participant levels as random 
effect factors, taking multiple measurements per participant into account. Fixed effect factors (regressors) 
are defined in the SAP and will be added to the model, in the primary statistical analysis there will be no 
post hoc adjustments of the predefined model. This is supplemented by a Mann-Whitney U (MWU) test 
which will be hierarchically inferior to the conclusions from the LMM, unless the assumptions of the LMM 
are not met. Data analysis occurring after 1Y of follow-up, will be based on a ‘Generalised Estimating 
Equation’ (GEE). These tests and the reported statistics will be further discussed in the SAP.   
Dichotomous outcomes 
The dichotomous secondary outcomes (General AEs, Surgical AEs, pathological Complete Response rate) 
will be assessed using a two-sided Z-test comparing two independent sample proportions. In the safety 
assessment an Agresti-Caffo corrected 95% Confidence Interval of the difference in proportions will be 
used. These tests and the reported statistics will be further discussed in the SAP.   
Time-To-Event outcomes 
The TTE secondary and tertiary outcomes (Treatment duration , Overall Survival, Breast Cancer Specific 
Survival, Relapse-Free Survival, Locoregional Relapse-Free Survival, and Distant-Disease Free Survival) will 
be assessed using survival analysis methods. These will consist of the construction of a Kaplan-Meier (KM) 
curve and estimates, and the performance of a cox-regression analysis comparing the treatment groups. 
These tests and the reported statistics will be further discussed in the SAP.   
8.3.1 Primary Endpoint 
For the primary endpoint, the ‘Satisfaction with Breasts’ scale from the Breast Q v2 ‘reconstruction’, 
‘Breast conserving therapy’, or ‘Mastectomy’ module (as applicable for the clinical situation) (appendix 2), 
at 1 year of follow-up after the last study treatment (LST), will be used. To score a BREAST-Q scale, the raw 
scores for the set of items in a scale are added together to produce a total raw score. If missing data is less 
than or equal to 50% of the scale’s items, the within person mean for the completed items can be imputed. 
If more than 50% of the scale’s items are missing, the summed score for this participant cannot be 
computed and will be classified as missing data. Once a total raw score for the scale is computed, the 

Page 66 of 73 
 
BREAST-Q conversion table will be used to convert the raw score into a BREAST-Q score, which ranges 
from 0 (worst) to 100 (best).   
8.3.2 Secondary Endpoints 
Health related quality of life 
The EQ-5D-5L questionnaire contains a VAS-scale ranging from 0 (worst) to 100 (best) to reflect the 
participant’s overall QoL/health assessment at that point in time, this score is used without 
transformation. The Index score is calculated from the answers to the 5 items of the questionnaire. The 
raw scores per item are weighted and then entered into a formula which has been validated in the 
Belgian population.(65) The resulting score is the index-score, ranging from -0.533 (worst)  to 0.962 
(best). This score is then transformed to a scale ranging from 0 to 1 using the following formula, where 
f(IS) represents the transformed score, IS the index score, 0.533 is the correction of the lowest value to 
zero, and 1.495 is the range difference: 
𝑓(𝐼𝑆) = (𝐼𝑆+ 0.533)/1.495 
This scoring and transformation is automatically applied in the eCRF, and the transformed index score will 
be used in statistical analysis.  
Cosmetic outcome (AIS – TAS score) 
The average Total Aesthetic Score (TAS) will be derived from a panel of independent observers (consisting 
of at least 2, ideally 5 physicians with a background in either plastic surgery, mammary surgery, or 
mammary radiation therapy) assessing the photographs per participant and study visit, using the 
‘Aesthetic Items Scale’ (AIS). Inter- and intra-observer agreement of the ratings will be calculated and 
expressed as intraclass correlation coefficients (ICCs). An ICC of >0.7 will be considered to indicate a good 
inter-rater reliability.(68)  
Adverse events 
Clinician-reported AEs will be graded using NCI-CTCAE v5. The highest grade per participant will be 
recorded, and then used for the composite outcomes: proportion of participants experiencing no AE vs. 
any grade AE, and grade < 3 AE vs. grade > 3 AE.   
Surgical adverse events. 
From the adverse events data (as described above), those related to the surgical study interventions 
(oncological surgery and breast reconstruction surgery) will be sourced and evaluated separately. The 
methods of outcome reporting and hypothesis testing will be the same as described for the general AEs.  
Treatment pathway duration time 
Each of the treatment duration variables (infra) are compared between treatment groups.  
- 
Randomisation to last study treatment (LST) 
- 
Randomisation to oncological breast surgery 
- 
Oncological breast surgery to last study treatment (LST) 
The time interval of ‘Randomisation to last study treatment (LST)’ will be used in hypothesis testing  
 
 

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Pathological response 
Participants receiving preoperative systemic or radiation therapy treatment(s) undergo pathological 
response assessment of the removed breast tissues (SoC assessment). The reported Pinder-classification 
response or ‘No preoperative therapy’ will be recorded in the eCRF: (9) 
- 
No residual carcinoma nor DCIS (complete response) = Pinder 1i 
- 
No residual carcinoma but DCIS present = Pinder 1ii 
- 
Partial response (>90%) = Pinder 2i 
- 
Partial response (50-90%) = Pinder 2ii 
- 
Partial response (<50%) = Pinder 2iii 
- 
No signs of response = Pinder 3  
- 
No preoperative therapy 
The analysis of this secondary outcome will be performed on a subset of the ITT set, which is defined as 
those participants that received preoperative systemic therapy. 
More details on the rationale can be found in section 5.4.10. 
8.3.3 Tertiary Endpoints 
Oncological survival and time-to-event data 
The following TTE/survival outcomes will be reported: Overall Survival (OS), Breast Cancer Specific Survival 
(BCSS), Relapse-Free Survival (RFS), Locoregional Relapse-free Survival (L-RFS), and Distant-Relapse Free 
Survival (D-RFS). These TTE/survival outcomes and their events of interest are defined according to the 
2015 DATECAN consensus.(10) 
8.4 Interim Analyses 
Interim Analyses will be performed when n=90 participants (50% of the target sample size) fulfil a follow-
up visit assessment, and their data has been adequately monitored (at least remote monitoring of the 
eCRF). This analysis will be performed on the safety set (and ITT subset for the Pathological response 
outcome). During the interim analyses, only the safety outcomes will be assessed, these are: AEs, surgical 
AEs, Pathological response, and Oncological events/survival. Analysis will be performed according to the 
methods described in the primary statistical analysis of the SAP, except for the dichotomous outcomes, 
which will be analysed using an Agresti-Caffo 95% Confidence Interval. This is further discussed in the SAP 
under section ‘7. Safety evaluation’.   
The results of the interim analyses will be discussed by the Trial Steering Committee (TSC), who will then 
advise on the need of adjustments or trial termination, if applicable. Interim analyses will be stopped when 
the treatment of the last participant is concluded, since at this point these analyses will no longer be able 
to influence any study related treatments. Further details on interim analyses will be provided in the SAP. 
8.5 Handling of Missing Data 
Efforts will be made to minimise and manage missing data to show a robust result. Since a LMM is used in 
the primary (and some of the secondary) outcome(s), this means that missing data will be implicitly 
handled as ‘Missing at random’ (MAR), and that implicit imputation is used. Additionally a ‘Missing Not At 
Random’ (MNAR) sensitivity analysis will be performed. 
Further details on missing data handling will be provided in the SAP. 

Page 68 of 73 
 
9. Study Management 
9.1 Regulatory and Ethical Considerations 
9.1.1 Regulations and Guidelines 
The investigator is responsible for ensuring that the study is performed in compliance with this protocol, 
the principles of the Declaration of Helsinki (2024), the current IHC guidelines on Good Clinical Practice 
(ICH-GCP E6 R3) and all of the applicable regulatory requirements(1,69).(1,2) 
9.1.2 Independent Ethics Committees (IEC) 
The protocol, protocol amendments, ICF, participant information materials and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and approved by 
the IRB/IEC before the study is initiated, or  before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to patients. A central IRB/IEC is appointed 
upon the initial request for approval, when setting up study sites, approval from the central, and applicable 
local IRB/IECs will be sought.   
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the study centre and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable regulations. 
After reading the protocol, each Investigator will sign the protocol signature page and send a copy of the 
signed page to the Sponsor or the Sponsor representative. The study will not start at any study centre at 
which the Investigator has not signed the protocol. 
9.1.3 Insurance 
The Sponsor will ensure sufficient insurance is available to enable them to indemnify and hold the 
Investigators and relevant staff as well as any hospital, Institution, ethics committee or the like, harmless 
from any claims for damages for unexpected injuries, including death, that may be caused by the 
investigational therapy but only to the extent that the claim is not caused by the fault or negligence of the 
participants or investigators. An insurance certificate will be supplied to the involved parties, including the 
Investigator(s). 
The Sponsor has taken a no fault insurance for this study, in accordance with the relevant legislation 
(article 29, Belgian Law of May 7, 2004): 
- 
Sponsor: GasthuisZusters Antwerpen vzw - Oosterveldlaan 22 – B-2610 Wilrijk 
- 
Insurance details: MS Amlin Insurance SE - Koning Albert II-laan 37 - B-1030 Brussel 
9.2 Informed Consent 
For each study participant, informed consent will be obtained in writing before any protocol-related 
activities commence. As part of this procedure, the investigator must explain orally and in writing, by 
means of the ICF, the nature, duration, purpose of the study, number of visits, assessments being 
performed, procedures to undergo, and the action of the treatment in such a manner that the participant 

Page 69 of 73 
 
is aware of the potential risks, inconveniences, or adverse effects that may occur. Participants should be 
informed that they may withdraw from the study at any time without any resulting disadvantage or 
prejudice to their standard treatment care. They will receive all information that is required by national 
regulations and current ICH GCP guidelines. The ICF contains additional provisions concerning the use of 
participant e-mail communications, data sharing for research purposes, and sharing unexpected health-
related findings.  
The participant and the investigator will sign the ICF. A copy will be provided to the participant. The 
originally signed ICF will remain at the study centre. The medical record must include a statement that 
written informed consent was obtained before the participant was enrolled in the study and the date and 
hour at which the written consent was obtained.  
All participants will be insured against injury caused by their participation in the study according to the 
legal requirements. They will be informed about the insurance and the resulting obligations on their part. 
A model ICF form is available upon motivated request.  
9.3 Participant Identification, Enrolment and Screening Logs 
The investigator agrees to complete a ‘subject identification and enrolment log’ to permit easy 
identification of each participant during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrolment log will be treated as confidential and will be filed by the 
investigator in the ISF. To ensure participant confidentiality, no copy will be made. All reports and 
communications relating to the study will identify participants by their study-id.  
9.4 Quality Control and Assurance 
The sponsor will implement a system to manage quality throughout the design, conduct, recording, 
evaluation, reporting and archiving of the study with a focus on study activities essential to ensuring 
protection of participants and the reliability of study results. The quality management system will use a 
risk-based approach.  
9.4.1 Data Monitoring 
Study monitors will perform ongoing source data verification to confirm that data entered into the CRF by 
authorised study centre personnel is accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH-GCP, and all applicable 
regulatory requirements.  
The Medical Monitor will act as the main point of contact for PIs and sites to assess participant eligibility 
and ongoing protocol/safety management issues. 
The monitor will record dates of the visits in a study-site visit log that will be kept at the study-site. The 
first post-initiation visit will be made as soon as possible after enrolment has begun. At these visits, the 
monitor will compare the data entered into the eCRF with the source documents (e.g., hospital medical 
records). The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the eCRF are known to the Sponsor and study-site personnel and are 

Page 70 of 73 
 
accessible for verification by the sponsor study-site contact. If electronic records are maintained at the 
study-site, the method of verification must be discussed with the study-site personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of verifying that the 
recorded data are consistent with the original source data. Findings from this review will be discussed with 
the study-site personnel. The Sponsor expects that, during monitoring visits, the relevant study-site 
personnel will be available, the source documents will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these remote 
contacts, study-site personnel will be available to provide an update on the progress of the study at the 
site. 
9.4.2 Audits 
The study may be audited by the Sponsor or by regulatory authorities. If such an audit occurs, the 
Investigator must agree to allow access to required participant records. By signing this protocol, the 
Investigator grants permission to personnel from the Sponsor, its representatives, and appropriate 
regulatory authorities, for on-site monitoring/auditing of all relevant study documentation, as well as on-
site review of the procedures employed in eCRF generation, where clinically relevant.  
The Investigator should contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection. 
9.4.3 Protocol Amendments 
Neither the Investigator nor the Sponsor will modify or alter this protocol without the agreement of the 
other. All agreed protocol amendments will be clearly documented and will be signed and dated by the 
original protocol approving signatories. All protocol amendments will be submitted to the relevant IECs 
for approval before implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to trial participants. In this case, the necessary 
action will be taken first, with the relevant protocol amendment following shortly thereafter. When a 
protocol amendment is approved by both the central and local IECs, the local PIs will be contacted in order 
to adequately inform them of any changes. The local PI oversees dissemination of this information to their 
delegates/study personnel.  
9.4.4  Protocol Deviations 
All protocol deviations will be assessed and documented on a case-by-case basis before database lock. 
Important protocol deviations related to study inclusion or exclusion criteria, conduct of the study, non-
compliance, participant management, or participant assessment should be described. Protocol deviations 
will be listed on a protocol deviation log, and significant protocol deviations will be reported to the IEC.  
9.4.5 Records 
9.4.5.1 Data Capture and Management 
Study data will be recorded in the provided eCRF (electronic case report forms) with regular back up and 
controls for further analyses. Study investigators and authorised study staff will be granted access to the 
eCRF, and will be identifiable by login.  

Page 71 of 73 
 
9.4.5.2 Source Documentation 
Source documentation will include the demographic data, visit dates, signed ICF, and study number 
relating to the eCRF, and will be kept in a secured location of the local study site, as defined during the site 
initiation visit of that site. 
9.4.5.3 (Electronic) Case Report Forms 
The Investigator should maintain adequate and accurate source documents and study records that include 
all pertinent observations on each of the centre’s study participants. Source data should be attributable, 
legible, contemporaneous, original, accurate, and complete.   
All clinical data will be captured via electronic data capture. The Investigator’s study centre staff will enter 
and edit the data via a secure network. Electronic CRFs will be used for all participants. The Investigator’s 
data will be accessible from the Investigator’s site throughout the study. The eCRF must be kept current 
to reflect participant status at each phase of the study. The eCRF will not capture directly identifying data. 
The Investigator must make a separate confidential record of directly identifying data (name and initials) 
on the participant identification and enrolment log. All changes to data are done by the investigator or 
designated site personnel through the electronic data capture system.  
It is the responsibility of the principal investigator of the study centre to ensure that all participant 
discontinuations or changes in treatment entered on the participant’s eCRF are also registered in the 
participant’s medical records. The (e)CRFs for any participant leaving the study should be completed at 
the time of the final visit or shortly thereafter. 
9.4.5.4 Confidentiality and Data Protection 
All study data will be handled in accordance with the law on General Data Protection Regulation (GDPR) 
and institutional rules [Belgian law dated on 30 July 2018 and 22 Aug. 2002]. 
The collection and processing of personal data from participants enrolled in this study will be limited to 
those data that are necessary to fulfil the objectives of the study. These data must be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable data 
privacy protection laws and regulations. Appropriate technical and organisational measures to protect the 
personal data against unauthorised disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration must be put in place. Sponsor and site personnel whose responsibilities require access 
to personal data agree to keep the identity of participants confidential. 
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the Investigator/institution to allow direct access to their original medical records 
(source data/documents) for study-related monitoring, audit, ethics committee review and regulatory 
inspection. This consent also addresses the transfer of the data to other entities, if applicable. 
9.4.5.5 Records Retention 
In compliance with the ICH-GCP guidelines, the Investigator/Institution will maintain all eCRF and all source 
documents that support the data collected from each participant, as well as all study documents as 
specified in ICH-GCP E6 R3, and all study documents as specified by the applicable regulatory 
requirement(s). All essential documents will be retained according to ICH GCP for a minimum of 25 years 
after study termination and in compliance with all applicable legal and regulatory requirements.  

Page 72 of 73 
 
The Investigator/Institution will take measures to prevent accidental or premature destruction of these 
documents. If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new custodian. 
Under no circumstance shall the Investigator relocate or dispose of any study documents before having 
obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator/Institution must permit access to such reports. 
9.5 Data management plan 
All collected data are discussed in this protocol, including any transformations/coding, the use of 
derivative measures (e.g. mean, median, etc.) and ranges where applicable. Access to data is on an as-
needed basis, the study personnel are listed on the delegation of responsibilities log and access to data is 
managed according to their responsibilities. As a general rule, the central trial team (central PI, SIs and 
project managers) will have access to all study related data except for the subject identification logs; 
local trial teams will have access to participant data of their own study site, as well as their subject 
identification log. Monitors and auditors will be permitted access to study data as-needed to fulfil their 
responsibilities. Access to the eCRF is managed by the central trial teams, logging who has which access, 
as well as the start and end dates of this access.    
A more detailed data management plan, discussing data handling, security and storage, is available upon 
request.   
9.6 Study Termination or Study Site Closure 
The Sponsor, Investigator and the IEC reserve the right to terminate or suspend the study at any time; 
however, this should be discussed between the relevant parties beforehand and the reason for such 
decision recorded. Should this occur, all data available will also be recorded in the CRFs. The Investigator 
should notify the relevant IEC in writing of the study’s completion or early discontinuation. 
Study sites will be closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided reasonable cause and sufficient 
notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not limited 
to: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the IEC or local health 
authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate recruitment of participants by the Investigator. 
- 
Discontinuation of further study treatment development. 
 
 

Page 73 of 73 
 
10. Clinical Study Report 
A CSR will be prepared in accordance with ICH Guidance E3.  
Consideration will be given to any comments on a draft report. The report will incorporate the analytical 
and statistical results and methods produced by the Sponsor or their agents. A final report will be prepared 
to contain all those sections in the draft and a statement of compliance covering all the areas of the study 
conducted at the investigational site and the report, with GCP. The report will be issued under the 
Sponsor’s responsibility. 
Where required by the applicable regulatory requirements, an Investigator signatory will be identified for 
the approval of the CSR. The Investigator will be provided reasonable access to statistical tables, figures 
and relevant reports and will have the opportunity to review complete study results. The Sponsor will also 
provide the Investigator with the full summary of study results. 
The full CSR, or where required the CSR synopsis, will be submitted to the IEC within 12 months from the 
end date of the study. 
11. Publication Policy 
The results from the participating institutions will be analysed together and published as soon as possible. 
Individual groups/clinicians must not publish data concerning their patients that are directly relevant to 
questions posed by the study until the Sponsor has published its report. The Sponsor will form the basis 
of the Writing Committee and will advise on the nature of all publications. 
We will aim to publish this protocol both on a trial registry (e.g. ClinicalTrials.gov) before the start of the 
trial, including amendments after IEC approval, as well as in a peer-reviewed scientific journal before the 
first interim analysis is performed in order to avoid bias.   
All local investigators will be co-authors when at least 5 patients are accrued. The 4 centres with the largest 
number of patients accrued will be allowed 2 co-authors. The first and/or senior author will be chosen by 
the Sponsor institution. 

Page 1 of 6 
 
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and Immediate Breast Reconstruction: A Randomized Clinical Trial. JAMA Netw Open. 
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Zinzindohoué C, Bertrand P, Michel A, Monrigal E, Miramand B, Sterckers N, et al. A Prospective 
Study on Skin-Sparing Mastectomy for Immediate Breast Reconstruction with Latissimus Dorsi Flap 
After Neoadjuvant Chemotherapy and Radiotherapy in Invasive Breast Carcinoma. Ann Surg Oncol. 
2016 Jul 1;23(7):2350–6.  
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delayed autologous abdominal microvascular flap breast reconstruction in patients receiving 
adjuvant, neoadjuvant or no radiotherapy: a meta-analysis of clinical and quality-of-life outcomes. 
BJS Open. 2020;4(2):182–96.  
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Study on Skin-Sparing Mastectomy for Immediate Breast Reconstruction with Latissimus Dorsi Flap 
After Neoadjuvant Chemotherapy and Radiotherapy in Invasive Breast Carcinoma. Ann Surg Oncol. 
2016 Jul 1;23(7):2350–6.  
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with immediate autologous latissimus dorsi breast reconstruction following neoadjuvant 
chemotherapy and radiation therapy: A single institution study of 111 cases of invasive breast 
carcinoma. European Journal of Surgical Oncology. 2016 Jul 1;42(7):949–55.  
55. 
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immediate breast reconstruction after neoadjuvant chemotherapy and radiation therapy. A new 
option for patients with operable invasive breast cancer. Results of a 20 years single institution 
study. European Journal of Surgical Oncology. 2011;37(10):864–70.  
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Thiruchelvam PTR, Leff DR, Godden AR, Cleator S, Wood SH, Kirby AM, et al. Primary radiotherapy 
and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): 
a multicentre, prospective, non-randomised, feasibility study. Lancet Oncol. 2022;23(5):682–90.  
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Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer. Int J Radiat Oncol Biol 
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Paillocher N, Florczak AS, Richard M, Classe JM, Oger AS, Raro P, et al. Evaluation of mastectomy 
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carcinoma. European Journal of Surgical Oncology. 2016 Jul 1;42(7):949–55.  
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early-stage breast cancer and long-term disease-free survival. Breast Cancer Research. 
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Dikmans REG, Nene LEH, Bouman MB, De Vet HCW, Mureau MAM, Buncamper ME, et al. The 
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Plast Reconstr Surg Glob Open. 2017;5(3):1–6.  
  
 
 
 

Page 1 of 53 
 
Appendices 
Appendix 1: Eastern Cooperative Oncology Group Performance Status Assessment 
 
 
 
 

Page 20 of 53 
 
Appendix 4: Assessment of Cosmetic Outcome 
The cosmetics results of the study treatment will be evaluated centrally, by independent ratings by at least 
two observers (at least, one plastic surgeon and one radiation oncologist). 
Physician-reported cosmetic outcome 
Regarding physician-reported cosmetic outcomes, average scores from a blinded panel of independent 
observers (consisting of at least 2, ideally 5 physicians with a background in either plastic surgery, 
mammary surgery, or mammary radiation therapy), using the ‘The aesthetic Items Scale’ will be calculated.  
Inter- and intra-observer agreement of the ratings between the observers will be expressed as intraclass 
correlation coefficients (ICCs) with corresponding 95% confidence intervals. An ICC of >0.7 will be 
considered to indicate a good inter-rater reliability.(68) 
Twenty randomly selected photographs (not included in the actual study) will be shown to the panel 
before scoring begins in order to avoid a learning-curve effect. 
In the aesthetic items scale, the breasts are evaluated with respect to volume, shape, symmetry, scars, 
and nipple areola complex. For each of these items a 5-point Likert scale is used for scoring. This scale 
ranges from “very dissatisfied,” “dissatisfied,” “neutral,” “satisfied,” to “very satisfied.” The Total Aesthetic 
Score (TAS), is derived by summing the score of the 5 items.(69) The TAS will be used for outcome 
operationalisation.  
 
 
 
 
 

Page 21 of 53 
 
Appendix 5: CTCAE V5 
The Cancer Therapy Evaluation Program NCI-CTCAE version 5.0 (November 27, 2017) can be viewed online 
at the following NCI website: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
CAVEAT: Not all postoperative complications are listed in the CTCAE v5.0 framework, for example: 
capsular contraction, implant malpositioning, reconstructive failure, etc. are not listed but need to be 
recorded. These can be registered under “Injury, poisoning and procedural complications - Other, 
specify” CTCAE term  
 
 
 

Page 22 of 53 
 
Appendix 6: Amendment history 
All previous versions of amendments will be collected in this appendix, the overview of changes relating 
to the current version of the protocol will be displayed at the beginning of this document. All previous 
amendment overviews will be kept in this appendix.  
History of the protocol and its amendments 
Protocol version 
Date of IEC application 
Protocol v1.0, original protocol 
22-APR-2024 
Protocol v2.0, amendment 1 
25-OCT-2024 
Protocol v3.0, amendment 2 
17-JUN-2024 
Protocol v4.0, amendment 
24-DEC-2025 
 
Protocol v2.0, amendment 1 24-NOV-2024 
Purpose of this amendment: 
1) Clarify that the intervention group will only include patients undergoing immediate breast 
reconstruction, not delayed reconstruction. For this purpose, patients undergoing two-stage implant 
based breast reconstruction, where the tissue expander (phase 1) is placed during oncological surgery, 
followed by a later definitive implant/prosthesis placement surgery (phase 2), is considered as 
immediate reconstruction.  
2) A study visit is added for the patients in the control arm, undergoing delayed reconstruction. This visit 
will take place at 3 months after their last Postop-RT. It was added because we feel that this is important 
to gauge QoL changes at this point, as well as provide adequate follow-up, whereas these patients would  
otherwise be seen at +/- 1-1.5y after randomisation, compared to +/- 0.5y for most other patients.  
3) Some minor changes to wording and methodology, made to improve the clarity of the protocol and 
study quality. All changes were tracked with the ‘track changes’ function in Word, as well as summarized 
in the following table. 
Summarised list of key changes: 
Section Number and Name 
Description of change and Brief Rationale 
Cover page 
Description of change: 
- GZA was changed to ZAS, reflection the changes due 
to GZA-ZNA hospital network fusion.  
- Logo’s: change for the PRADAIIBE study, GZA to ZAS 
and KOTK logo was added.  
Brief rationale: 
Updating to changed reality. 
Statement of compliance 
Description of change: 
Declaration of Helsinki version update 
Brief rationale: 
Most recent version 

Page 23 of 53 
 
Confidentiality Statement 
Description of change: 
GZA was changed to ZAS, reflection the changes due to 
GZA-ZNA hospital network fusion. 
Brief rationale: 
Updating to changed reality. 
Sponsor’s Approval 
Description of change: 
- Changed title 
- Changed protocol version and date  
- Changing GZA to ZAS 
Brief rationale: 
The new title better represents the study type and 
population. Updated version to reflect this 
amendment. Updating to changed reality (ZAS) 
Investigator Agreement 
Description of change: 
- Changed title 
- Changed protocol version and date 
Brief rationale: 
The new title better represents the study type and 
population. Updated version to reflect this 
amendment. 
Table of Contents 
Description of change: 
Updated  
Brief rationale: 
To reflect changes due to amendments 
List of In-text Tables and Figures 
Description of change: 
- Addition of table representing the aesthetic items 
scale 
- Addition of figure, exemplifying the digital 
photographs to be taken 
Brief rationale: 
- New assessment scale 
- Updated version  
List of Attachments 
Description of change: 
- Specification of BREAST-Q versions 
- Added Appendix 6 (amendment history) 
Brief rationale: 
Clarity and follow-up.  
List of Abbreviations 
Description of change: 
Added BCS, BCT and Postop-RT 
Brief rationale: 
Clarity 

Page 24 of 53 
 
Amendments 
Description of change: 
Addition of ‘Amendments’ section 
Brief rationale: 
Provide an overview of changes in current amendment 
Administrative Structure 
Description of change: 
- GZA was changed to ZAS, reflection the changes due 
to GZA-ZNA hospital network fusion. 
Brief rationale: 
Update to reflect changed reality. 
Synopsis - Title 
Description of change: 
- Changed title 
 
Brief rationale: 
The new title better represents the study type and 
population. 
Synopsis - Outcomes 
Description of change: 
- Improved specifications 
- Addition of the BREAST-Q for patients undergoing 
Breast Conservative surgery.  
- Add the option of ‘No preoperative therapy’ to the 
pCR outcome evaluation.  
Brief rationale: 
- Clarity 
- To better represent this specific subgroup and 
operationalize changes in their breast satisfaction 
scores, making them comparable to other subgroups. 
- To reflect the group not receiving preoperative 
therapy 
Synopsis – Study design 
Description of change: 
- Improved specifications 
- Remove ‘immediate reconstruction’ from the 
experimental arm description 
Brief rationale: 
- Clarity 
- Only immediate reconstructions will be performed in 
the experimental arm.  
Synopsis – Eligibility criteria; Length of participation 
Description of change: 
- Improved specifications 
- Addition to the clause regarding adjuvant 
chemotherapy based on pCR, that the decision of a 
centre to include/exclude these patients should be 
made before randomisation. 
Brief rationale: 
- Clarity  

Page 25 of 53 
 
- The decision of this clause should be made before 
randomisation to avoid bias and ITT analysis conflicts. 
Synopsis – Intervention 
Description of change: 
- Improved specifications 
- Remove ‘immediate reconstruction’ from the 
experimental arm description 
Brief rationale: 
- Clarity 
- Only immediate reconstructions will be performed in 
the experimental arm.  
Synopsis – Statistical Methods 
Description of change: 
- Improved specifications (2-sided alpha for sample 
size calculation; ITT and PPA analysis) 
Brief rationale: 
- Clarity  
Schedule of events 
Description of change: 
- Improved specifications 
- Addition of Postop-RT + 3M study visit for the 
delayed reconstruction subgroup 
- Removal of medication history registration during 
follow-up visits (only at screening) 
- Addition of systemic treatment registration 
- Addition of the BREAST-Q ‘breast conserving therapy’ 
module 
Brief rationale: 
- Clarity  
- Improved follow-up 
- Removal of unnecessary data registration (lean) 
- Systemic treatment is important for subgroup and 
regression analysis 
- Adequate assessment of the BCS subgroup  
1.1.2 Rationale for Use of Preoperative 
Radiotherapy 
Description of change: 
-Addition of study conclusion 
Brief rationale: 
- Was accidentally missing 
2. Objectives and Endpoints 
Cfr. Synopsis – Outcomes.  
The text and changes in both sections are identical. 
3.1 General Scheme of Study Design 
Description of change: 
- Improved specifications 
- Remove ‘immediate reconstruction’ from the 
experimental arm description 
- Addition of a longer and more detailed explanation 
detailing the scheme of the study 
- Update of figure 1 

Page 26 of 53 
 
Brief rationale: 
- Clarity 
- Only immediate reconstructions will be performed in 
the experimental arm. 
- A more detailed description was added to avoid 
misunderstandings and improve the reader’s 
understanding of how this trial is set up. For example 
detailing the rationale and pitfalls behind including the 
BCS subcategory, as well as the additional visit in the 
delayed reconstruction subgroup.   
- Update of figure 1, to reflect the changes made in 
this amendment 
4.1 Definitions 
Description of change: 
- Improved specifications 
- Changed email address 
Brief rationale: 
- Clarity 
- Changed email address due to organisational changes 
4.3 Subject Exclusion Criteria 
Description of change: 
- Improved specifications 
- Addition to the clause regarding adjuvant 
chemotherapy based on pCR, that the decision of a 
centre to include/exclude these patients should be 
made before randomisation. 
Brief rationale: 
- Clarity  
- The decision of this clause should be made before 
randomisation to avoid bias and ITT analysis conflicts. 
4.4 Study Restrictions 
Description of change: 
- Improved specifications  
- Lifestyle study restriction ‘smoking’ and its definition 
Brief rationale: 
- Clarity  
- Was missing 
4.5 Screen Failures 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
5.1 Study Procedures 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
5.1.1 Screening Period 
Description of change: 
- Improved specifications 

Page 27 of 53 
 
- More detailed description of ICF procedure 
- Changed email address 
Brief rationale: 
- Clarity 
- Clarity and explicit regulation adherence 
- Changed email address due to organisational changes 
5.1.2 Treatment period 
 
Description of change: 
- Improved specifications 
- Specification of intermediary follow-up in the delayed 
reconstruction subgroup 
- Addition of systemic treatment and p/ypTNM 
registration 
Brief rationale: 
- Clarity 
- Rationale and clarity, as well as detailing the 
assessments during this extra study visit. 
- Important medical information for 
subgroup/regression analysis 
5.1.3 Follow-up Period 
 
Description of change: 
- Improved specifications 
- at 3M FU: addition of EQ5D5L assessment; Checking 
of treatment characteristics registration 
- Addition of BCT module for BCS patients 
- Digital photographs from 3 to 4 photographs 
Brief rationale: 
- Clarity 
- Improved follow-up of QoL and assuring correct and 
final treatment registration 
- To represent changes as discussed earlier 
- To reflect changes as discussed in later chapter 
5.2 Discontinuation or Withdrawal 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
5.4.3 Clinical Assessment 
 
Description of change: 
- Addition of concurrent medication use description 
Brief rationale: 
- Was missing, registered at screening 
5.4.4 BREAST-Q questionnaire 
 
Description of change: 
- Elaboration on the use of the BREAST-Q 
questionnaires and in which setting they will be used. 
Brief rationale: 
- Clarity, addition of the BCT module 

Page 28 of 53 
 
5.4.5 European Quality of Life 5 Dimensions 5 Level 
Version (EQ-5D-5L) questionnaire 
 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
5.4.6 Digital Photographs of the Breasts 
 
Description of change: 
- Improved specifications 
- Changed from 3 to 4 photographs, including detailed 
description of how to take them 
Brief rationale: 
- Clarity 
- Improved assessment and reproducibility  
5.4.7 Assessment of Surgical Complications 
 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
5.4.8 
Assessment 
of 
Pathological 
Tumour 
Response and pathology TNM 
 
Description of change: 
- Addition of ‘No preoperative therapy’ option for pCR 
assessment 
- Addition of p/ypTNM reporting 
Brief rationale: 
- Not all patients will receive preoperative therapy, in 
these patients pCR assessment is not applicable 
- p/ypTNM assessment is SoC and important 
oncological information 
5.4.9 Collection of Data on Tumour Recurrence 
Rates 
 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
6.1 Radiation Therapy 
Description of change: 
- Improved specifications 
Brief rationale: 
- Clarity 
6.2 Oncological breast Surgery 
Description of change: 
- Improved specifications 
- Description and positioning of BCS in this trial 
Brief rationale: 
- Clarity 
- Making clear why BCS is included and how it will be 
handled 
6.3 Breast Reconstruction surgery 
Description of change: 
- Improved specifications 

Page 29 of 53 
 
- Removing the delayed reconstruction from the 
experimental group 
Brief rationale: 
- Clarity 
- Only immediate reconstruction in the experimental 
group 
6.4.2 Stratification 
 
Description of change: 
- Decision to only stratify for treatment centre at 
randomisation 
Brief rationale: 
- 1 stratification parameter implies less danger for 
treatment group allocation imbalances 
6.4.3 Randomisation 
 
Description of change: 
- Improved specifications  
Brief rationale: 
- Clarity 
6.5 Treatment Compliance and Adherence 
Description of change: 
- Improved specifications 
- Addition of 6.5.3 Systemic treatment characteristics 
Brief rationale: 
- Clarity 
- Provide succinct description of how these character 
7.8 Method of Detecting Adverse and Serious Adverse 
Events 
Description of change: 
- Improved specifications  
Brief rationale: 
- Clarity 
7.11 Regulatory Reporting Requirements for Serious 
Adverse Events 
Description of change: 
- Email address of GZA was changed to ZAS, reflection 
the changes due to GZA-ZNA hospital network fusion. 
Brief rationale: 
Update to reflect changed reality. 
8.1 Justification of Sample Size 
Description of change: 
- Improved specifications  
- Removal of statement on exploratory subgroup 
analysis 
Brief rationale: 
- Clarity 
- To be discussed in another section, not sample size 
calculation. 
8.2 Analysis Populations 
Description of change: 
- Addition of per-protocol-analysis 

Page 30 of 53 
 
Brief rationale: 
- This will be used to assess outcomes without subject 
who’ve undergone BCS, as these didn’t undergo breast 
reconstruction, but needed to be included in ITT 
analysis.  
8.3.1 Primary Endpoint 
Description of change: 
- Improved specifications  
- Breast reconstruction as subgroup analysis was 
removed, baseline characteristics was added 
- Linear regression analysis was moved to represent 
the first line of statistical analysis. 
Brief rationale: 
- Clarity 
- As advised by statistician 
- As advised by statistician 
8.3.2 Secondary Endpoints 
 
Description of change: 
- Improved specifications  
- BREAST-Q score as a secondary outcome was added  
Brief rationale: 
- Clarity 
- Was not yet included here, only as primary outcome. 
9.4.5.2 Source Documentation 
 
Description of change: 
- Re-definition of possible source documentation 
storage location 
Brief rationale: 
- The initial definition was too narrow and may not 
reflect the situation at all study sites.  
References 
Description of change: 
- 1 references was added, Nr. 40 
Brief rationale: 
- Used in Appendix 4 
Appendix 2 BREAST-Q questionnaire 
Description of change: 
- Improved specifications  
- Addition of the ‘Satisfaction with Breasts’ scale, from 
the ‘Breast Conserving Therapy’ module. (Not yet 
included) 
- English and French versions were added where 
available, for each BREASTQ questionnaire 
Brief rationale: 
- Clarity 
- To reflect the subjects undergoing BCS. Not yet 
included due to the fact that this questionnaire is not 
readily available in Dutch. The Dutch version does exist 
and is requested through the BREAST-Q organisation, 
yet is not yet available to us.  

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At this moment the English and French version is 
included. The Dutch version will be added and supplied 
to the EC as soon as possible.  
- To be able to provide the questionnaire in the 
language of choosing 
Appendix 4 Assessment of Cosmetic Outcome 
Description of change: 
- Elaboration on the process of digital photograph 
evaluation 
- The aesthetic items scale was added as a tool to 
assess the cosmetic outcome, as an expert panel, 
based on digital photographs.   
Brief rationale: 
- Clarity 
- Added as a tool to assess the cosmetic outcome, as 
an expert panel, based on digital photographs.   
Appendix 6 Amendment history 
Description of change: 
- This appendix was added 
Brief rationale: 
- In order to track the history of changes per 
amendment.  
Appendix 7 Study overview (detailed) 
Description of change: 
- This appendix was added 
Brief rationale: 
- To add figures for more detailed information on the 
clinical pathways of subjects in this study.  
 
Protocol v3.0, amendment 2 17-JUN-2025 
Purpose of this amendment: 
1. Exclusion criterium ‘MRI contra indications’ was removed. Contrary to what was initially 
intended, there will be no use of MRI imaging.  
2. During the IMFU visit photographs will also be taken. 
3. Improved, more detailed description of the data collected, and statistical methods. 
4. Overhaul of texts throughout the protocol to be more precise and less redundant.  
5. Implementation of the SPIRIT statement 2013 
Summarised list of key changes: 
Section Number and Name 
Description of change and Brief Rationale 
Cover page + Sponsor’s Approval + Investigator 
Agreement + Administrative Structure 
Description of change: 
- The abbreviated title was changed from PRADA II to 
PRADA IIBE 
- The ClinicalTrials.Gov ID was added   

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- Protocol version and date were updated (to V3.0) 
- Update cancertrials email.  
Brief rationale: 
- Updating to changed reality. 
Statement of compliance 
Description of change: 
- Changed the WMA Declaration of Helsinki from 
2013 to 2024  
Brief rationale: 
- Since the previous amendment, this has become 
the most recent version. 
New headings: ‘Roles and responsibilities’ & 
‘Funding’ 
Description of change: 
- These headings were added, reporting all actors 
and their roles within this trial  
Brief rationale: 
- In compliance with the SPIRIT statement 2013 
items 4 and 5, Increasing transaprancy 
Table of contents 
Description of change: 
- Updated 
Brief rationale: 
- cfr. Other changes 
Removed heading: ‘Administrative structure’ 
Description of change: 
- Merging of contents in new headings ‘Roles and 
responsibilities’ & ‘Funding’ 
Brief rationale: 
- This improves SPIRIT statement compliance and 
clarity 
Amendments 
Description of change: 
- The ‘History of the protocol and its amendments’ 
table was updated. 
- The list of amendments in V2 was moved to - 
Appendix 6 ‘Amendment history’, and a new list for 
V3 was formed.  
Brief rationale: 
- Updates in accordance with the current 
amendment history 
List of Abbreviations 
Description of change: 
- ‘MRI’ was removed 
- ‘IBR’; ‘DBR’; ‘TE’; ‘SoC’; Were added 
Brief rationale: 
- No longer included in the text 
- Adopted in the text 

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Synopsis – General 
Description of change: 
- Changed from PRADA II BE to PRADAIIBE 
- Minor layout changes 
- Addition of “Disease under study” 
Brief rationale: 
- Improved readability 
- In compliance with the WHO trial registration data 
set and SPIRIT statement 2013. 
Synopsis – Objectives/Endpoints 
Description of change: 
- Each outcome variable was rewritten to improve 
clarity. No major changes were made to which 
data/variables will be recorded/used. The new text is 
in compliance with the SPIRIT 2013 statement.  
- Included the BREAST-Q ‘BCT’ module by name. 
Brief rationale: 
- Improved understanding 
- The ‘BCT’ module is used for the rare (is not 
expected) case that BCS is performed.  
- Improved clarity and uniform reporting/naming 
Synopsis – Study Design 
Description of change: 
- Skin-sparing mastectomy (SSM) → Skin/nipple 
sparing mastectomy (SSM/NSM) 
- ‘Number of patients’ → ‘Sample size’ 
Brief rationale: 
- More correct naming 
Synopsis - Eligibility criteria 
Description of change: 
- Inclusion criterium 1: added ‘/NSM’; changed 
‘adjuvant radiation therapy’ to ‘postoperative 
radiotherapy’. 
- Exclusion criterium 1 changed to: “A previous 
history of breast cancer or irradiation of the chest 
wall for any other indication.” 
- Exclusion criterium 3 “Subject is not pregnant or 
breastfeeding” is moved from inclusion criteria to 
exclusion criteria 
- Exclusion criterium concerning MRI 
contraindications was removed 
- Exclusion criterium 7 → Added ‘Metastatic 
disease’, changed wording of ‘SSM not possible’ to 
‘’SSM/NSM not indicated’ 
Brief rationale: 
- Exclusion criteria better reflects the eligibility 
implications 
- MRI contraindications is no longer relevant 
- Metastatic disease as an exclusion criterium was 
already implied by ‘SSM not possible/indicated’, this 
is now explicitly stated 

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Synopsis  - Length of participation 
Description of change: 
- Added mentioning of 3M FU 
Brief rationale: 
- Improved accuracy 
Synopsis - Intervention 
Description of change: 
- Preoperative radiotherapy must be planned to 
commence as quickly as reasonably possible after 
randomization, at the discretion of the Investigator, 
or no longer than 6 weeks after the last dose of 
neoadjuvant chemotherapy (if applicable) or 
randomization. → Added “or randomization” 
Brief rationale: 
- In the initial text there was no hard deadline for 
planning preoperative radiotherapy. This is now 
defined as =<6 weeks.  
Schedule of events 
Description of change: 
- Table 1B SoE for patients in the experimental 
treatment arm. Timing of pre-op RT scheduling was 
changed from “At the discretion of the physician of 
≤6w after last dose of NACT (if applicable)”, to within 
6 weeks of Rz or NACT 
- Indicated that treatment characteristics will also be 
collected/checked at the 3 months after final 
treatment follow-up visit.  
- footnote ‘g’ → Addition that the participant wil be 
asked to return for a termination visit. 
- During IMFU visit photos will also be taken.  
- Complete overhaul of both tables 
Brief rationale: 
- Changed to reflect the change described under 
‘Synopsis – Intervention’ 
- To assure complete and correct registration of all 
treatment characteristics.  
- Participants cannot be forced to return for a 
termination visit. 
- Photos during the IMFU visit will help assess the 
effect on cosmesis between mastectomy and 
reconstruction. Which might be a confounder for the 
primary outcome.  
- The overhaul of SoE tables are intended to make 
the tables more readable and shorter. No further 
content changes were made, the changed content is 
listed above.  
1. Introduction 
Description of change: 
- The text was rewritten and the scientific literature 
references were updated.  

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Brief rationale: 
- Improved readability, improved scientific accuracy 
2. Objectives and Endpoints 
Table 2 was copy-pasted from the same section in 
the ‘Synopsis’ section.  
Cfr. This section for adaptations.  
3. Overall Study Design – 3.1 General Scheme of 
Study Design 
Description of change: 
- PRADA II trial → PRADAIIBE study 
- Skin sparing; SSM→ Skin/Nipple sparing; SSM/NSM 
- Adjuvant → Preoperative 
- Clarification that systemic therapies are not study 
related treatments but ill be recorded.  
- Explicit mentioning of the AIS evaluation during 
IMFU visit.  
- Correction of IMFU taking place 3 months after 
oncological surgery → To 3M after last RT treatment 
- Changed Figure 1, same content/info, less text 
- Other minor changes in word choice and 
grammatic 
 
Brief rationale: 
- Improved clarity 
3. Overall Study Design – 3.2 Study Duration, 
Enrolment and Number of Sites 
Description of change: 
- Improved description of the duration of study 
participation, explicitly stating that treatment 
duration is variable and that the 10 years of follow-
up start from the moment of treatment conclusion.  
- Projection of 10 study sites.  
- Other minor changes in word choice and 
grammatic 
 
Brief rationale: 
- Improved clarity 
4.1 Definitions 
Description of change: 
-  
Brief rationale: 
-  
4. Population – 4.2 + 4.3 (In- and exclusion criteria) 
This section was copy-pasted from the same section 
in the ‘Synopsis’ section.  
Cfr. This section for adaptations. 
4.4 Study restrictions 
Description of change: 
- “…, as per standard of care. The study is not 
responsible for contraceptive measures or 
pregnancy testing” Was added on the end of the 
sentence describing contraceptive requirements. 

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- The main text regarding concomitant medication 
registration is moved tot 5.4.3.3 
Brief rationale: 
- Improved clarity, the study is not responsible for 
the follow-up of potential/accidental pregnancies 
during the study as this is part of the SoC. The study 
merely emphasizes this aspect of the SoC therapy.   
- This section is better suited for registering this 
information. 
5. Study conduct – 5.1  
Description of change: 
- Changed from PRADA II BE to PRADAIIBE 
- Added “Assessment of baseline breast cancer 
disease characteristics” to the list of screening 
evaluations 
- Changed email address: "cancertrials@zas.be"  
- Minor layout/word choice changes 
- Added the taking of photographs to the IMFU visit, 
as an assessment. 
- Addition that an unscheduled visit can also be 
initiated by the participant. 
- Addition of section “5.1.1 Recruitment” 
Brief rationale: 
- Improved clarity 
- This was not explicitly mentioned before but is an 
important factor in post hoc analyses.  
- New email address (old will be kept operational) 
- These photographs at IMFU visit may offer 
important insight in the experience of patients at 
this stage.  
- Included a section on recruitment, in accordance 
with the SPIRIT statement. 
5. Study conduct – 5.2 
Description of change: 
- Added: “This is documented by registering an 
‘Unscheduled visit’ in the eCRF.” 
Brief rationale: 
- Improved clarity on how withdrawal of consent 
needs to be handled.  
5. Study conduct – 5.4 
Description of change: 
- Added: “Patients will be questioned regarding 
concomitant medication use only at the screening 
visit. The patient will be asked to report all the 
medication they currently use, especially those 
medications which are taken on a regular basis 
(chronic use). The substance, route of 
administration, dose and start/stop date (if known) 
will be recorded.  
All prior and concomitant systemic therapy 
(including neoadjuvant systemic chemotherapy, 

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adjuvant systemic therapy, endocrine therapy, 
immune therapy, or any other forms of systemic 
therapy) for breast cancer must be recorded in the 
eCRF, as discussed in Section 6.5.3.” 
- Changed the wording of what the BREAST-Q is 
measuring/asking 
- Changed wording of how the results from the 
BREAST-Q are handled from raw score to the 
BREAST-Q score.  
- Added that photographs will also be taken during 
the IMFU visit. 
- Clarification of how surgical complications will be 
collected/registered. 
- Added section 5.4.7 (and change of subsequent 
sections and their references) – Disease baseline 
characteristics 
- Redefining of surgical (S)AEs in section 5.4.8. 
- 5.4.10 – addition of data concerning overall survival 
- 5.4.11 Treatment pathway times was added 
- Minor layout/word choice changes 
Brief rationale: 
- The indication of the medication will not be 
recorded as this information will be too unstructured 
to be used for analysis, while offering minimal added 
value. The recording of ‘substance’ is added for 
improved clarity. 
- This summation is more precise and correct than 
the previous summation. 
- This description of BREAST-Q results handling is 
more correct.  
- Photographs will also be taken during the IMFU 
visit.  
- All (S)AEs will be collected, surgical complications 
will be extracted from this registry.  
- The data regarding disease characteristics was not 
clearly defined as a separate topic, this is now 
rectified. 
- This description better reflects what constitutes 
surgical (S)AEs.  
- Overall survival is important in assessing 
oncological safety. 
- A description of how the treatment pathway times 
will be recorded and operationalized was added as 
this was not yet explicitly described.  
- Improved clarity 
6. Study Intervention – 6.1 
Description of change: 
- NACT was changed to preoperative radiotherapy 
- Preop-RT planning within 6w of randomization 
Brief rationale: 
- To improve uniformity 
- No max time interval was yet defined for Rz to 

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Preop-RT 
- Improved clarity 
6. Study Intervention – 6.2 
Description of change: 
- Minor changes in wording and grammatic.  
Brief rationale: 
- Improved clarity  
6. Study Intervention – 6.3 
Description of change: 
- Minor changes in wording and grammatic.  
Brief rationale: 
- Improved clarity  
6. Study Intervention – 6.4 
Description of change: 
- Change 5 to 6-digit ID 
- Expand the description of how randomization is 
performed and handled.  
- Addition of “6.4.4 blinding” 
- Minor changes in wording and grammatic.  
Brief rationale: 
- This was changed in Castor software 
- Improved clarity  
6. Study Intervention – 6.5 
Description of change: 
- Re-phrasing of data collected for all treatment 
modalities  
Brief rationale: 
- More detailed overview of the recorded data.   
7. Safety monitoring – 7.5 
Description of change: 
- An update changed the ID size 
- The description of the randomization process 
indicates that there is no way of 1) manipulating Rz 
outcomes, 2) no way of gaining insight into block 
sizes. 
- This subtopic describes the decision of NOT using 
blinding in this trial. Adding that the expert panel will 
be blinded.  
- Minor changes in wording and grammatic.  
Brief rationale: 
- Improved clarity  
7. Safety monitoring – 7.6 
Description of change: 
- Minor changes in wording and grammatic.  
Brief rationale: 
- Improved clarity 
7. Safety monitoring – 7.7 
Description of change: 
- Minor changes in wording and grammatic.  

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Brief rationale: 
- Improved clarity 
7. Safety monitoring – 7.8 
Description of change: 
- Minor changes in wording and grammatic.  
- Added phrase on (S)-AEs reported by physicians 
Brief rationale: 
- Improved clarity 
- This was previously not described but is also a 
possible route of reporting.   
7. Safety monitoring – 7.9 
Description of change: 
- Minor changes in wording and grammatic.  
Brief rationale: 
- Improved clarity 
7. Safety monitoring – 7.10 
Description of change: 
- Changed ”pharmacovigilance” to “sponsor 
representatives”  
Brief rationale: 
- This is not a pharmacological study. 
7. Safety monitoring – 7.11 
Description of change: 
- Removed paragraph on reporting to the EMA  
- Changed EMA to IER/IRB 
Brief rationale: 
- This is not a pharmacological study, therefore the 
EMA is not involved. 
8. Statistical concerns – 8.1 
Description of change: 
- Minor changes in wording and grammatic.  
- Further elaboration on how the detection of a 
minimally important difference was selected.  
Brief rationale: 
- Improved clarity 
- More accurate representation of the decisions 
made in sample size calculation. 
8. Statistical concerns – 8.3 
Description of change: 
- Addition of the ‘Breast conserving therapy’ module 
concerning the BREAST-Q questionnaire and 
improved definition of the primary endpoint 
- Additional explanation concerning the AIS and the 
operationalization of the cosmetic outcome 
secondary endpoint.  
- Added the secondary endpoints ‘surgical AEs’, 
‘pathological response’, ‘Treatment pathway 
duration time’, and ‘Oncological events/survival’ 
- For each endpoint the statistical analyses are 

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summarized and the SAP is referenced for more 
detailed information.  
Brief rationale: 
- Improved clarity and more precise description of 
the primary endpoint 
- Improved clarity and more precise description of 
the cosmetic outcome secondary endpoint 
- These secondary endpoints were not yet explicitly 
defined under section 8.3 
- The SAP contains a more complete description of 
the statistical methods, avoiding redundancy in the 
protocol.  
8. Statistical concerns – 8.4 
Description of change: 
- Redefining of the interim analyses  
Brief rationale: 
- These newly defined timepoints offer improved 
safety monitoring, balanced against feasibility of the 
efforts involved of an interim analysis.  
9. Study management 
Description of change: 
- Minor changes in wording and grammatic. 
- Addition of section “9.5 Data management plan” 
and renaming of “Study termination or study 
closure” to 9.6  
- 9.4.3 protocol amendments: addition of how the 
changes will be communicated to study personnel 
- 9.2 Informed consent: expansion on additional 
provisions.  
Brief rationale: 
- Improved clarity 
- Discussion of the DMP was not yet included, this is 
in accordance with the SPIRIT statement.  
- Change communication plan is in accordance with 
the SPIRIT statement. 
- ICF additional provisions statements is in 
accordance with the SPIRIT statement.   
Appendix 2 
Description of change: 
- Added the BCT Dutch postoperative version.  
- Added a note on the BCT French postoperative 
version 
Brief rationale: 
- This was not yet available to us at the previous 
protocol amendment, now it is.  
- This translation doesn’t yet exist, we will translate 
it and provide it to the EC once available. 
Appendix 4 
Description of change: 
- Improve description of how the expert panel 
evaluation will be organized and performed.    

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Brief rationale: 
- Improved clarity 
Appendix 6 Amendment history 
Description of change: 
- The overview table was updated and the 
amendment history of V2 was moved here.  
Brief rationale: 
- Keeping track of the amendment history. 
 
Protocol v4.0, amendment 3 24-DEC-2025 
Purpose of this amendment: Please refer to section ‘Amendments’ 
Summarised list of key changes: 
Section Number and Name 
Description of change and Brief Rationale 
Cover page + Sponsor’s Approval + Investigator 
Agreement + Administrative Structure 
Description of change: 
- Update of version and date 
- Change date of first registration CTG 
- Update of the trial steering committee members 
- Minor changes in wording 
Brief rationale: 
- Update according to amendment 
- The previously mentioned date was the date of 
final approval. The new date is the date of first 
registration as found on the public CTG page.  
- Update of TSC members 
- Improve clarity and correctness 
Statement of compliance 
Description of change: 
- GCP E6 R3 instead of R2 
Brief rationale: 
-  New current GCP guidelines 
New headings: ‘Roles and responsibilities’ & 
‘Funding’ 
Description of change: 
- Minor changes in wording 
Brief rationale: 
-  Improve clarity and correctness 
“Sponsor’s Approval” & “Investigator Agreement” 
Description of change: 
- Update of version and date 
Brief rationale: 
- Update according to amendment 
Table of contents 
Description of change: 
- Updating of contents according to changes 

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Brief rationale: 
-  Update 
“List of tables and figures” & “List of attachments” & 
“List of abbreviations” 
Description of change: 
- Update according to other changes in this protocol 
Brief rationale: 
-  Update 
Amendments 
Description of change: 
- Addition of this new amendment 
Brief rationale: 
-  Tracking of amendments 
Synopsis – Objectives/Endpoints 
Description of change: 
- BREAT-Q: Addition of the Mastectomy module 
questionnaire, improved details on how the 
outcome will be reported. 
- EQ-5D-5L: Index score transformation to the 0-1 
scale 
- AEs (general and surgical): Improved description of 
tabulation and dichotomous/proportion outcomes 
- pCR: Re-defining this outcome to only include 
patients that received preoperative systemic 
therapy, instead of also including patients that only 
received preop-RT 
+ Improved description of tabulation and 
dichotomous/proportion outcomes 
- Improved definition and overhaul of the tertiary 
outcomes section regarding oncological survival and 
TTE data, according to the DATECAN 2015 
consensus. 
- Minor changes in wording 
Brief rationale: 
- Updating of outcome reporting according to what 
was discussed during the development of the SAP  
- By re-defining the pathological response outcome 
we avoid a large level of bias against the 
experimental arm, as it is improbable that the 
pathological response based on preop-RT alone is 
comparable to preop-chemotherapy. We don’t 
expect that RT by itself (monotherapy in preop 
setting) will have any significant influence on the 
pathological response category at the study interval 
of 2-6 weeks.  
- Improve clarity and correctness 
Synopsis – Study Design 
Description of change: 
- Minor changes in wording 
Brief rationale: 
-  Improve clarity and correctness 

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Synopsis – Eligibility criteria 
Description of change: 
- The first exclusion criterium was specified to only 
concern ipsilateral previous treatment 
Brief rationale: 
-  Improve clarity and avoid confusion concerning 
eligibility. 
Synopsis – Length of participation 
Description of change: 
- Changed the title to “Length of study participation 
and study visits” 
- Added the IMFU visit 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
Synopsis - Intervention 
Description of change: 
- Minor changes in wording 
Brief rationale: 
-  Improve clarity and correctness 
Synopsis - Statistical methods 
Description of change: 
- Addition of the mastectomy module 
- Addition of the estimands framework instead of PP-
analysis 
- Rectification of SZ number (no impact on actual SZ) 
- Minor changes in wording 
Brief rationale: 
-  New questionnaire module 
- Improved statistical methods (estimands 
framework) 
- Small error in the reported results from the SZ-
calculation, which doesn’t change the eventual SZ of 
n=180 due to the same conclusion after correcting 
for dropout.  
- Improve clarity and correctness 
Schedule of events 
Description of change: 
- Addition of the mastectomy module in the IMFU 
visit 
- Minor changes in wording 
Brief rationale: 
-  New questionnaire module 
- Improve clarity and correctness 
1. Introduction 
Description of change: 
- Rewriting of the introduction section, focused on 
presenting the results in a more concise manner and 
avoiding repetition 

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Brief rationale: 
-  This rewriting has led to both a shorter 
introduction section, as well as the addition of some 
important/relevant studies. 
2. Objectives and Endpoints 
Description of change: 
- Copy-paste from the equivalent section in the 
synopsis 
Brief rationale: 
-  Update according to the changes mentioned in the 
synopsis section 
3. Overall Study Design – 3.1 General Scheme of 
Study Design 
Description of change: 
-  
Brief rationale: 
-   
3. Overall Study Design – 3.2 Study Duration, 
Enrolment and Number of Sites 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
4.1 Definitions 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
4.4 Study restrictions 
Description of change: 
- Clarification of the smoking cessation 
limitations/eligibility 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
5. Study conduct – 5.1  
Description of change: 
- Improved and more detailed description of the 
recruitment process  
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
5. Study conduct – 5.2 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
5. Study conduct – 5.3 
Description of change: 
- Minor changes in wording 

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Brief rationale: 
- Improve clarity and correctness 
5. Study conduct – 5.4 
Description of change: 
- Addition of the BREAST-Q ‘Mastectomy’ module 
- Addition of the EQ-5D-5L index score 
transformation 
- The pathological response options were changed to 
fit the Pinder classification, and outcome 
redefenition for patients with Preop-RT without 
Preop Systemic therapy was added.  
- Minor changes in wording 
Brief rationale: 
- New questionnaire 
- Improved interpretability of the Index score 
- Improve clarity and correctness 
6. Study Intervention – 6.1 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
6. Study Intervention – 6.2 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
6. Study Intervention – 6.3 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
6. Study Intervention – 6.4 
Description of change: 
- This subsection was moved to section 5 
Brief rationale: 
- More appropriate location within the document 
6. Study Intervention – 6.5 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.1 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.4 
Description of change: 
- Minor changes in wording 

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Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.6 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.9 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.10 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
7. Safety monitoring – 7.11 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
8. Statistical concerns – 8.1 
Description of change: 
- Minor changes in wording 
- Correction of calculated sample size (cfr. Synopsis, 
no impact on eventual sample size) 
- Addition of SZ-PWR graph 
Brief rationale: 
- Improve clarity and correctness 
- Rectification 
- This graph improves the interpretability of the 
impact of changes in sample size or effect size, on 
the power 
8. Statistical concerns – 8.2 
Description of change: 
- Addition of the estimands framework approach 
instead of PP-analysis 
Brief rationale: 
- Improved handling of intercurrent events 
8. Statistical concerns – 8.3 
Description of change: 
- Addition of the BREAST-Q Mastectomy module 
- The pathological response options were changed to 
fit the Pinder classification 
- Update of the analyses according to what was 
discussed in the development of the SAP 
- Minor changes in wording 

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Brief rationale: 
- New questionnaire 
- Update according to SAP 
- Improve clarity and correctness 
8. Statistical concerns – 8.4 
Description of change: 
- Removal of the 100% mark 
Brief rationale: 
-  This is superfluous, as it would almost coincide 
with completion of accrual 
9. Study management 
Description of change: 
- Minor changes in wording 
Brief rationale: 
- Improve clarity and correctness 
Appendix 2 
Description of change: 
- Addition of the BREAST-Q Mastectomy module 
- Addition of subheadings 
Brief rationale: 
- New questionnaire 
- Improving navigation 
Appendix 3 
Description of change: 
- Addition of the NL and FR translations 
- Addition of subheadings 
Brief rationale: 
- Improved reporting 
- Improving navigation 
Appendix 4 
Description of change: 
- Removal of mentioning the software tool 
Brief rationale: 
- There are currently no active plans to include a 
software-based evaluation  
Appendix 6 Amendment history 
Description of change: 
- Update concerning this amendment 
Brief rationale: 
-  Update 
Appendix 7 
Description of change: 
- Addition of the mastectomy module in the IMFU 
visit 
Brief rationale: 
-  New questionnaire module 
 

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Appendix 7: Study overview (detailed) 
Detailed SOE 
 

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Timelines per treatment arm and subgroups – Experimental arm 
 
 

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Timelines per treatment arm and subgroups – Treatment arm 
 
 

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