Effectiveness of Fluoroscopy-guided Manual Lymph Drainage (MLD) Versus Traditional MLD or Placebo MLD, as Part of Decongestive Lymphatic Therapy, for the Treatment of Breast Cancer-related Lymphoedema (BCRL): a Randomised Controlled Trial
Phase: NA
Conditions: Breast Neoplasm, Lymphedema
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
Page 1 of 33 
 
 
 
 
Protocol study about ‘effectiveness of fluoroscopy-guided manual 
lymph drainage (MLD) for the treatment of breast cancer-related 
lymphoedema (BCRL)’ 
 
Protocol EFForT BCRL trial  
 
Version and date of final protocol: V13 03.09.2018 
 
 
Trial identifiers 
EudraCT Number: 2015-004822-33 
NCT (clinicaltrials.gov): NCT02609724 
 
 
Sponsor: 
 
Name: UZ Leuven (or UH Leuven) 
Address: Herestraat 49, 3000 Leuven 
 
 
Principal Investigator: 
 
Name: Prof. Dr. Nele Devoogdt 
Address: UZ Leuven, Lymphovenous Center, dpt of Physical Medicine and Rehabilitation and dpt 
of Vascular Surgery, Herestraat 49, 3000 Leuven 
Telephone: +32 16 3 42515; Mobile: +32 486 804595 
Fax: / 
Email: nele.devoogdt@uzleuven.be  
 
 
Sub-investigators: 
 
Name: Dr. Sarah Thomis 
Address: UZ Leuven, dpt of Vascular Surgery, Herestraat 49, 3000 Leuven  
Telephone: +32 16 3 46948; M +32  
Fax: +32 16 3 46852; Mobile: +32 498 296629 

 
 
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Email: sarah.thomis@uzleuven.be  
Name: Prof. Dr. Nick Gebruers 
Address: University of Antwerp, Universiteitsplein 1- 2160 Wilrijk - België 
Telephone: +32 3 2652876; Mobile: +32 496184346 
Fax: n/a 
Email: nick.gebruers@uantwerpen.be  
 
Name: Prof. Dr. Wiebren Tjalma 
Address: Antwerp University Hospital, Multidisciplinary Breast Center, Wilrijkstraat 10; 2650 
Edegem 
Telephone: +32 3 821 59 04 
Fax: n/a 
Email: Wiebren.tjalma@uza.be  
 
Name: Dr. Liesbeth Vandermeeren 
Address: Centre Hospitalier Universitaire (CHU) Sint-Pieter, Lymphoedema Clinic 
Telephone: +32 2 5353762; Mobile: +32 495 600004 
Fax: n/a 
Email: liesbethvandermeeren@hotmail.com  
 
Name: Dhr. Jean-Paul Belgrado 
Address: Université Libre de Bruxelles, Unit de Lymphologie 
Mobile: +32 475 633434 
Fax: n/a 
Email: belgrado@ulb.ac.be  
 
Name: Dr. Hanssens Marianne 
Address: AZ Groeninge Kortrijk, Centre of Oncology 
Telephone: +32 56 63 39 00  
Fax: n/a 
Email: marianne.hanssens@azgroeninge.be  
 
Name: Mrs. Ellen Callens 
Address: AZ Groeninge Kortrijk, Centre of Oncology 
Telephone: +32 56 63 39 41 
Fax: n/a 
Email: ellen.callens@azgroeninge.be  
 
Name: Prof. dr. Van Landuyt Koenraad 
Address: UZ Gent, Department of Plastic Surgery 
Telephone: +32 (0)9 332 32 78. 
Fax: n/a 
Email: koenraad.vanlanduyt@ugent.be  
 
 

 
 
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Name: dr. Chris Monten 
Address: UZ Gent, Department of Radiotherapy 
 
          Private cabinet: Amand Casier de Terbekenlaan 43, 9030 Gent 
Telephone: +32 (0)9 332 07 49. 
Fax: n/a 
Email: chris.monten@uzgent.be  
 
Name: dr. Göker Menekse 
Address: UZ Gent, Department of Gynaecology 
Telephone: +32 (0)9 332 37 83. 
Fax: n/a 
Email: menekse.göker@uzgent.be  
 
 
 
 
 
 
 

 
 
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Signatures 
 
Prof. dr. Nele Devoogdt 
 
 
 
 
_________________________ 
 
 
 
____________________ 
Principal Investigator 
 
 
 
 
Date 
 
 
 
Dr. Sarah Thomis 
 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
Prof. Dr. Nick Gebruers 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
 
 
Prof. Dr. Wiebren Tjalma 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
Dr. Liesbeth Vandermeeren 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
 
 
Dhr. Jean-Paul Belgrado 
 

 
 
Page 5 of 33 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
 
Dr. Marianne Hanssens 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
Mrs. Ellen Callens 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
 
Prof. dr. Koenraad Van Landuyt 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
 
 
Dr. Chris Monten 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 
Dr. Menekse Göker 
 
 
 
_________________________ 
 
 
 
____________________ 
 
 
 
 
 
 
 
 
Date 
 

 
 
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Table of Contents 
1. 
Study Synopsis ................................................................................................................................. 8 
2. 
Background and rationale ............................................................................................................. 10 
3. 
Trial objectives and Design ............................................................................................................ 11 
3.1 
Trial objectives................................................................................................................... 11 
3.2 
Primary endpoints ............................................................................................................. 11 
3.3 
Secondary endpoints ......................................................................................................... 11 
3.4 Trial Design .............................................................................................................................. 12 
3.5 Study diagram .......................................................................................................................... 12 
3.6 Trial Flowchart ......................................................................................................................... 13 
4. 
Trial Medication ............................................................................................................................ 14 
4.1 Investigational Medicinal product and dosing regimen .......................................................... 14 
4.2 Drug accountability ................................................................................................................. 14 
4.3 Subject compliance ................................................................................................................. 15 
4.4 Concomitant medication (non-IMP) ........................................................................................ 15 
5. 
Selection and withdrawal of subjects ........................................................................................... 15 
5.1 Inclusion criteria ...................................................................................................................... 15 
5.2 Exclusion criteria ..................................................................................................................... 15 
5.3 Selection of participants .......................................................................................................... 16 
5.4 Randomisation procedure/Code Break ................................................................................... 16 
5.5 Withdrawal of subjects ............................................................................................................ 17 
5.6 Expected duration of trial ........................................................................................................ 17 
6. 
Trial Procedures ............................................................................................................................. 18 
6.1 By visit...................................................................................................................................... 18 
Intensive treatment ....................................................................................................................... 19 
Maintenance treatment ................................................................................................................ 20 
6.2 Laboratory tests....................................................................................................................... 21 
6.3 Other investigations ................................................................................................................ 21 
7. 
Assessment of efficacy .................................................................................................................. 21 
8. 
Assessment of Safety ..................................................................................................................... 24 

 
 
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8.1 Specification, timing and recording of safety parameters ...................................................... 24 
8.2 Procedures for recording and reporting adverse events (AE) ................................................. 24 
8.2.1 Definitions in Law of May 7, 2004 concerning experiments on the human person ............. 24 
8.2.2 Notification of adverse events .............................................................................................. 25 
8.2.3 Notification of serious adverse reactions ............................................................................. 25 
8.2.4 Adverse events that do not require reporting ...................................................................... 26 
8.3 Treatment stopping rules ........................................................................................................ 26 
8.4 Data monitoring committee (DMC) ........................................................................................ 26 
9. 
Statistics ........................................................................................................................................ 27 
9.1 
Sample size ........................................................................................................................ 27 
9.2 
Randomisation................................................................................................................... 27 
9.3 Analysis .................................................................................................................................... 28 
10. 
Quality assurance ...................................................................................................................... 29 
11. 
Direct access to source data and documents ............................................................................ 29 
12. 
Ethics and regulatory approvals ................................................................................................ 29 
13. 
Data Handling ............................................................................................................................ 30 
14. 
Data Management ..................................................................................................................... 30 
15. 
Translational research ............................................................................................................... 30 
16. 
Publication Policy ...................................................................................................................... 30 
17. 
Insurance/Indemnity ................................................................................................................. 31 
18. 
Financial Aspects ....................................................................................................................... 31 
19. 
References ................................................................................................................................. 32 
 
 
 

 
 
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1. Study Synopsis  
Title of clinical trial 
 
 
The effectiveness of fluoroscopy-guided manual lymph 
drainage (MLD) for the treatment of breast cancer-related 
lymphoedema (BCRL) 
Protocol Short Title/Acronym 
 
EFForT BCRL trial 
Study Phase if not mentioned in title 
 
Phase III trial 
Sponsor name 
 
UZ Leuven 
Principal Investigator 
 
Prof. Dr. Nele Devoogdt 
Eudract number 
 
2015-004822-33 
Medical 
condition 
or 
disease 
under 
investigation 
 
Lymphoedema 
Purpose of clinical trial 
 
To investigate the effectiveness of fluoroscopy-guided 
MLD for the treatment of BCRL  
Primary objective 
 
The main scientific objective entails examining the 
effectiveness 
of 
fluoroscopy-guided 
MLD 
versus 
traditional MLD or versus placebo MLD, applied as part of 
the intensive and maintenance phase of Decongestive 
Lymphatic Therapy, for the treatment of BCRL 
Secondary objective (s) 
 
Secondary scientific objectives entail: 
- examining the relationship between different variables 
of lymphoedema at baseline 
- examining reliability and validity of Lymph-ICF (Dutch 
version and French version) with NRS scale  
Trial Design 
 
Multi-centre double-blind randomised controlled trial 
Endpoints 
 
Primary end points: 
- 
Change of lymphoedema volume of arm/ hand 
- 
Change of stagnation of fluid (measured with tissue 
dielectric constant and bio-impedance analyses) at the 
level of shoulder/ trunk 

 
 
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Secondary end points: 
- 
Number of responders after intensive treatment 
(>30% decrease of lymphoedema volume) and after 
maintenance 
treatment 
(<10% 
increase 
of 
lymphoedema volume) 
- 
Change of extracellular fluid in the arm 
- 
Change of tissue dielectric constant in cutis of arm 
- 
Change of thickness and reflectivity of cutis and 
subcutis of arm/ shoulder/ trunk 
- 
Change of lymphatic architecture and function 
- 
Change of problems in functioning related to the 
development of BCRL. 
- 
Change of quality of life 
- 
Number of episodes of erysipelas 
- 
Number of adverse events to MLD 
- 
Cost associated with the disease and its treatment 
Sample Size 
 
201 pts (67 pts/group) 
Summary of eligibility criteria 
 
Patient 
with 
unilateral 
breast 
cancer-related 
lymphoedema 
Chronic lymphoedema, stage I, IIa, IIb 
At least 5% difference between both arms and/ or hands, 
adjusted for dominance 
No active metastases 
IMP, dosage and route of administration 
 
Indocyanine Green 25mg/25 ml aqua, 2x intradermal 
injection of 0.2 ml ICG/ aqua (first webspace and fourth 
webspace) 
Active comparator product(s) 
 
NA 
Maximum duration of treatment of a subject 
 
6 months (+6 months follow-up) 
Version and date of final protocol 
 
V13 03-09-2018 
Version and date of protocol amendments 
 
Approval original protocol V4: 10-2-2016 
V5 Amendement 20.4.2016 (Extra site UMC Sint-Pieter) 
V6 Amendement 22.12.2016 (Follow-up) 
V7 Amendement 28.4.2017 (Extra patients) 

 
 
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V8 Amendement 19.05.2017 (Advertisements) 
V9 Amendement 14.08.2017 (Advertisements) with 
changes 
V10 Amendement 23.08.2017 (Extra site AZ Groeninge + 
treatments for participants in UMC St-Pierre can be 
provided in private practise in Luik) 
V11 Amendement 28.09.2017 (Extra site AZ Groeninge 
treatments for participants in UMC St-Pierre can be 
provided in private practise in Luik) with changes  
V12 Amendement 20.12.2017 (Extra site UZ Gent) with 
changes 
V13 Amendement 03.09.2018 (Extra patients in CHU UCL 
Namur site Mont-Godinne for realizing subtrial secondary 
objective) 
2. Background and rationale 
For many women, lymphoedema is an embarrassing and dreaded morbidity after the treatment of 
breast cancer. It induces not only functional impairments (problems with performing household 
chores, with mobility during activities), but also psychosocial problems such as depression, sexual 
dysfunction, social avoidance and a decrease in self-confidence (1). 
According to the International Society of Lymphology, lymphoedema needs to be treated with 
Decongestive Lymphatic Therapy (2). This is a two-stage treatment programme. During the first or 
intensive phase, lymphoedema has to be maximally reduced. This phase consists of skin care, manual 
lymph drainage (MLD), multi-layer bandaging and exercise therapy. The second or maintenance 
phase aims to conserve and optimise the results obtained in the first phase. It consists of skin care, 
compression by a low-stretch elastic sleeve, exercises and lymph drainage. Skin care, multi-layer 
bandaging, elastic sleeve and exercises are treatment modalities that (after instructing the patient) 
can be performed by the patient herself. MLD has to be applied by a physical therapist and hence 
entails a big financial cost for the patient and the Health Care (3). The effectiveness of MLD applied 
during the intensive phase has been investigated by 5 randomised controlled trials, but there is 
conflicting evidence. So, further investigation is warranted to determine the relative benefit of MLD. 
The effectiveness of MLD applied during the maintenance phase has never been investigated (3-6). 
A possible explanation why MLD is not obviously proven to be effective, is that MLD is applied in an 
inefficient way: during MLD, hand manoeuvres are applied on all lymph nodes and lymphatics that 
may be anatomically present. After axillary dissection and/ or radiotherapy (for the treatment of 
breast cancer), the lymphatic system is damaged: lymph nodes are removed and often fibrosis of 
the superficial lymphatic system occurs. As a result, rerouting of the lymphatic drainage occurs. 
Rerouting is patient-specific, consequently, it is possible that the traditional MLD needs be abandoned 
and a tailored approach needs to be established. Lymphofluoroscopy can aid to apply a more efficient 
MLD. During lymphofluoroscopy, a fluorescent substance is injected subcutaneously in the hand and 

 
 
Page 11 of 33 
 
 
it visualizes the transport of lymph from the hand up to the axilla and it demonstrates alternative 
pathways towards other lymph nodes. 
A second explanation why the traditional method of MLD is not proven to be effective, is that research 
has shown that MLD with high pressure (vs low pressure) is more effective to improve lymph 
transport, as well as gliding (vs no gliding). During the new method of MLD (or fluoroscopy-guided 
MLD), the therapist only performs hand movements on functional lymphatics and lymph nodes. In 
addition, the hand movements are applied with higher pressure and lymph transport through the 
lymph collaterals is stimulated by applying strikes across the skin.  
Belgrado(7) demonstrated by lymphofluoroscopy a temporary physiological effect of MLD on 
lymphatic transport. All patients with BCRL (N=30) had after application of one session (during 20 
minutes) of lymph drainage an increase of lymph transport from the hand to the axilla. Also Tan et 
al(8) showed in patients with BCRL (N=10) after one session of MLD an improvement of lymph 
transport. Whether the application of different sessions of fluoroscopy-guided MLD has in fact a 
clinical and long-lasting effect on the lymphoedema, is yet to be established. 
3. Trial objectives and Design 
3.1 Trial objectives 
The main scientific objective entails examining the effectiveness of fluoroscopy-guided MLD versus 
traditional MLD or versus placebo MLD, applied as part of the intensive and maintenance phase of 
Decongestive Lymphatic Therapy, for the treatment of BCRL 
Secondary scientific objectives entail examining the relationship between different variables of 
lymphoedema at baseline and examining reliability and validity of Lymph-ICF (Dutch and French 
version) with NRS scale. 
3.2 Primary endpoints 
- 
Change of lymphoedema volume of arm/ hand 
- 
Change of stagnation of fluid at the level of shoulder/ trunk 
3.3 Secondary endpoints 
- 
Number of responders after intensive treatment (>30% decrease of lymphoedema volume) 
and after maintenance treatment (<10% increase of lymphoedema volume) 
- 
Change of extracellular fluid in the arm 
- 
Change of water content in the arm 
- 
Change of thickness and reflectivity of cutis and subcutis of arm/ shoulder/ trunk 
- 
Change of lymphatic architecture and function 
- 
Change of venous circulation in arm and thorax 
- 
Change of problems in functioning related to the development of BCRL. 
- 
Change of quality of life 
- 
Number of episodes of erysipelas. 

 
 
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3.4 Trial Design 
Multi-center double-blind placebo-controlled randomised controlled trial 
- 
Multi-center: cooperation between KU Leuven/ UZ Leuven, UAntwerp, UZ Antwerp. UMC Sint-
Pieter, ULB, AZ Groeninge Kortrijk, UZ Gent 
- 
Double-blind: patients and assessor are blinded for the intervention 
- 
Placebo-controlled: the effect of the intervention fluoroscopy-guided MLD is controlled with 
traditional MLD and with placebo MLD 
3.5 Study diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n=201: breast cancer patient with chronic lymphoedema 
Intensive treatment 
Intervention group (n=67) 
Skin care, bandage, exercises + 
Fluoroscopy-guided MLD 
5x/week for 3 weeks 
Maintenance treatment 
Intervention group (n=67) 
Skin care, sleeve, exercises 
Fluoroscopy-guided MLD 
6 months 
Intensive treatment 
Control group 1 (n=67) 
Skin care, bandage, exercises + 
Traditional MLD 
5x/week for 3 weeks 
Maintenance treatment 
Control group 1 (n=67) 
Skin care, sleeve, exercises 
Traditional MLD 
6 months 
Maintenance treatment 
Control group 2 (n=67) 
Skin care, sleeve, exercises 
Placebo MLD 
6 months 
Intensive treatment 
Control group 2 (n=67) 
Skin care, bandage, exercises + 
Placebo MLD 
5x/week for 3 weeks 
Assessment before and 3 weeks after intensive treatment 
- 
Lymphatic architecture and function 
- 
Arm and hand volume and arm circumferences 
- 
Hardness tissue 
- 
Extracellular fluid and tissue dielectric constant in arm/ trunk 
- 
Skin thickness and reflectivity arm, shoulder and trunk 
- 
Venous circulation arm/ trunk 
- 
Problems in functioning 
- 
Quality of life 
- 
Treatment compliance (only after) 
- 
Cost associated with the disease and its treatment 
Assessment after 1(*), 3 and 6 months of maintenance treatment and after 6 months of follow-up 
- 
Arm and hand volume and arm circumferences 
- 
Hardness tissue 
- 
Extracellular fluid and tissue dielectric constant in arm/ trunk 
- 
Venous circulation arm/ trunk 
- 
Problems in functioning 
- 
Quality of life 
- 
Treatment compliance 
- 
Cost associated with the disease and its treatment 
(*)Additional assessment after 1 month of maintenance treatment in first 30 patients: Problems in 
functioning with Lymph-ICF second time 24-48 hours later; Quality of life with SF-36; Assessment of face 
and content validity with questionnaire 
After 6 months of maintenance treatment 
- 
Lymphatic architecture and function 
- 
Skin thickness and reflectivity arm, shoulder and trunk 
- 
Erysipelas 
- 
Adverse events to MLD 

 
 
Page 13 of 33 
 
 
3.6 Trial Flowchart 
 
 
Intensive 
treatment 
Maintenance treatment 
Follow-up 
 
Baseline 
After 
3 
weeks 
After 
1 
month  
After 
3 
months 
After 
6 
months 
After 
6  
months 
Informed consent 
X 
 
 
 
 
 
Clinical evaluation 
- 
Arm 
and 
hand 
volume 
- 
Extracellular fluid at 
level of shoulder/ 
trunk 
- 
Tissue 
dielectric 
constant at level of 
shoulder/ trunk 
- 
Tissue elasticity at 
level 
of 
arm/ 
shoulder/ trunk 
- 
Extracellular 
fluid 
arm 
- 
Tissue 
dielectric 
constant arm 
- 
Quality of life 
- 
Problems 
in 
functioning 
- 
Erysipelas 
X 
X 
X 
X 
X 
x 
Lymphofluoroscopy 
(lymph 
architecture 
and 
lymph 
transport) 
X 
X 
 
 
X 
 
Echography (thickness and 
echogenicity of skin and 
subcutis) 
X 
X 
 
 
X 
x 
Treatment compliance 
 
X 
X 
X 
X 
x 
Costs associated with the 
treatment 
 
X 
X 
X 
X 
 

 
 
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4. Trial Medication 
 
4.1 Investigational Medicinal product and dosing regimen 
At baseline, each included patient receives a lymphofluoroscopy of the arm and shoulder/ trunk to 
visualise the patient-specific lymphatic architecture and transport. The lymphofluoroscopy is repeated 
after 3 weeks of intensive treatment and after 6 months of maintenance treatment. 
Indocyanine Green (ICG), a fluorescent molecule, is injected subcutaneously in the hand/ arm/ 
shoulder on the affected side. ICG emits fluorescence in the near-infrared spectrum (760 nm) and the 
signal is acquired using a camera with a Photo Dynamic Eye (PDE) system. The lymphatic architecture 
of the patient is designed on the body of the patient. Afterwards, a photo is taken from the design. 
We will use the packaging and labeling provided by the manufacturer of the products, i.e. Pulsion. 25 
mg ICG powder is diluted with 25 ml water. 0.2ml of this mixture is injected intradermally in the first 
and fourth webspace of the hand of the patient. ICG, aqua, syringe and plasters are bought by the KU 
Leuven. For description of the product, see appendix. 
Before the injection, landmarks (that are visible on the PDE camera) are drawn on the dorsal side of 
the forearm and biceps side of the upper arm. These landmarks are necessary to measure lymph 
propagation velocity in the superficial lymphatic vessels. After the measurement, video sequences are 
analyzed using the ICG dedicated software IC-CALC 2.0. This programme counts the number of pixels 
in function of time, reaching a target threshold of grey scale in a region of interest (ROI) delimitated 
by a selected surface drawn on the image (9). 
 
4.2 Drug accountability 
Patients receive 3 times (baseline, after 3 weeks and after 6 months) intradermal injection of 0.2 ml 
ICG/ aqua in first and fourth webspace.  
The purpose of the baseline lymphofluoroscopy is to have knowledge about the lymphatic transport 
at baseline. This is important to investigate whether fluoroscopy-guided MLD result in a better 
improvement of lymphatic transport than traditional MLD or placebo MLD, after the intensive phase 
of Decongestive Lymphatic Therapy and/ or the maintenance phase of Decongestive Lymphatic 
Therapy. In the group receiving fluoroscopy-guided MLD, de baseline lymphofluoroscopy is also 
necessary to investigate the superficial lymphatic architecture. 
 

 
 
Page 15 of 33 
 
 
4.3 Subject compliance 
Not applicable. No specific procedures to determine subject compliance with the medication are 
necessary, since the injections will be performed by the vascular surgeon after informed consent.  
 
4.4 Concomitant medication (non-IMP) 
Not applicable. In the present study, the application of medication (ICG) is not the intervention. It is 
applied in order to be able to perform the intervention, i.e. fluoroscopy-guided MLD. Patients of both 
control groups also receive an injection because change of lymphatic architecture and lymphatic 
transport is one of our secondary outcomes that we aim to compare between the 3 groups and this 
after 3 weeks of intensive treatment and after 6 months of treatment. 
 
5. Selection and withdrawal of subjects 
 
5.1 Inclusion criteria 
- 
Age >18y (since the treatment with MLD and the investigation using ICG is not dangerous for 
pregnant women, women with child bearing age are included) 
- 
Women/ men with unilateral breast cancer related lymphedema. 
- 
Chronic lymphoedema (>3 months present), stage I to IIb concomitantly with signs of pitting 
- 
At least 5% difference between both arms and/ or hands, adjusted for dominance 
- 
Written informed consent obtained 
 
5.2 Exclusion criteria 
- 
Allergy for iodine; sodiumiodine, ICG 
- 
Increased activity of the thyroid gland; benign tumors of the thyroid gland 
- 
Age <18y 
- 
Oedema of the upper limb from other causes 
- 
Surgery of the lymphatic system in the past (lymph node transplantation, lymphovenous 
shunt) 
- 
Bilateral axillary lymph node dissection 
- 
Cannot participate during the entire study period 
- 
Mentally or physically unable to participate in the study 

 
 
Page 16 of 33 
 
 
5.3 Selection of participants 
Patients with breast cancer-related lymphoedema (BCRL) are recruited in the University Hospitals 
Leuven (lymphoedema center, multidisciplinary breast center, department of vascular surgery) (N=90), 
in the University Hospital Sint-Pieter (lymphoedema center) (N=10), in the Antwerp University Hospital 
(multidisciplinary breast center) (N=41), in AZ Groeninge Kortrijk (Center of Oncology) (N=35). Patients 
who are participating in Brussels, can choose whether they prefer to receive the treatments (14x 
during the intensive phase and 18x during the maintenance phase) in the hospital in Brussels or in a 
private practice for physiotherapy situated in Liège. However, all investigations will be performed in 
the hospital itself. Furthermore, we would like to include a fifth study center located in Flanders to 
improve recruitment, UZ Gent (department of Radiotherapy) (N=25). Note considering practical issue: 
in case of lack of sufficient space at the department of Radiotherapy to provide the treatments, the 
private cabinet of one of the project’s researchers of UZ Gent (dr. Monten) can be used as well 
(location: Amand Casier de Terbekenlaan 43, 9030 Gent). 
For an additional investigation within this project, regarding analysis of the validity and reliability of 
the Lymph-ICF questionnaire with NRS scale in patients with breast cancer-related lymphoedema, 
which is the questionnaire being used as assessment tool to evaluate the change of problems in 
functioning related to the development of BCRL (= one of the secondary endpoints), a total of 30 extra 
patients with breast cancer-related lymphoedema will be recruited in the Lymphovenous Center of UZ 
Leuven. To realize the same investigation for the French version of the questionnaire, a total of 30 
patients with breast cancer-related lymphoedema (meeting the same inclusion criteria) will be 
recruited in the Centre for Lymphoedema of CHU UCL Namur, site Mont-Godinne. 
To boost the recruitment of patients, we will submit a short communication about the existence of the 
study in waiting rooms for patients of the participating centres and in health-related websites and/or 
(weekly or monthly) newsletters/magazines distributed in Flanders (i.e. Think Pink, Vlaamse kanker 
liga, Kom Op Tegen Kanker, Stichting tegen kanker, Visie CM, METRO, Deze Week, De Zondag, Goed 
Gevoel, Libelle, Flair). 
 
5.4 Randomisation procedure/Code Break 
After baseline assessment, patients are randomised in one of the three treatment groups. 
Randomisation is performed by someone different form the assessors or therapists of the study. 
Before randomization, the patient receives an ID. Randomisation is performed using an excel-file and 
the order of the randomization is determined by the ID number. 
 

 
 
Page 17 of 33 
 
 
5.5 Withdrawal of subjects 
Patients have the right to withdraw from the study at any point in time at its own request. This has no 
effect on the patient. The patient will not be replaced but will be asked to participate in the follow-up 
measurements (3 weeks after the intensive treatment and 1, 3 and 6 months after the start of the 
maintenance treatment and at the end of the follow-up phase, this is 6 months after the end of the 
maintenance phase). 
When patients withdraw from the study as the result of (serious) adverse events (which we do not 
expect) they will be followed on a regular base by the department of Vascular Surgery of UZ Leuven, 
in the Lymphoedema Clinic of University Hospital Sint-Pieter, by the Multidisciplinary Breast Clinic of 
Antwerp University Hospital, by the Centre of Oncology of AZ Groeninge Kortrijk and by the 
Department of Radiotherapy of UZ Gent (depending where the patient was included). Patients are not 
withdrawn from the study when they fail to come to the physical therapy sessions, since we apply the 
intention-to-treat principle. 
 
5.6 Expected duration of trial 
Month 1: 1st of December 2015: start of trial  
Month 3-38: recruiting and inclusion of 201 patients and baseline assessment 
We estimate that around one patient with arm lymphoedema is included each week in UH 
Leuven (0.75/week), one patient is included in UH Sint-Pieter each two weeks (0.5/week) and 
one patient is included in UH Antwerp each 3 weeks (0.3/week). So the inclusion period will 
reach month 38 of the project. If we reach this frequency of inclusion, at the end of month 12 
of the project, 81 patients will be included (32 patients in UH Leuven, 16 patients in UH 
Antwerp and 26 patients in UH Sint-Pieter). 
Go/ no go: if the assumed frequency of inclusion is not reached the first 6 months of the 
inclusion period (16 patients in UH Leuven, 8 patients in UH Antwerp and 13 patients in UH 
Sint-Pieter), we have to change the strategy of recruitment (through other hospitals, patient 
groups, physical therapists, …). 
Month 22: September 2017: By the end of this month, the sub-investigation about reliability 
and validity of the Lymph-ICF questionnaire, which is the questionnaire being used to 
determine the change of problems in functioning related to the development of BCRL as 
secondary endpoint, needs to be fulfilled (2nd aim of PhD Tessa De Vrieze). This means that by 
the end of this month, data concerning this aim needs to be analysed from at least 30 patients. 
To speed up this recruitment, 30 patients who are 1) visiting the Lymphovenous Center UZ 
Leuven, 2) are meeting the inclusion criteria, and 3) have given written informed consent, will 

 
 
Page 18 of 33 
 
 
be recruited in the Lymphovenous Center UZ Leuven, additional to the patients who are 
participating the EFforT-trial. 
Month 37: December 2018: By the end of this month, the sub-investigation about reliability 
and validity of the French version Lymph-ICF questionnaire, which is the questionnaire being 
used to determine the change of problems in functioning related to the development of BCRL 
as secondary endpoint, needs to be fulfilled (3rd aim of PhD Tessa De Vrieze). This means that 
by the end of this month, data concerning this aim needs to be analysed from at least 30 
French-speaking patients. To speed up this recruitment, 30 patients who are 1) visiting the 
Centre for Lymphoedema CHU UCL Namur site Mont-Godinne, 2) are meeting the inclusion 
criteria, and 3) have given written informed consent, will be recruited in the Centre for 
Lymphoedema CHU UCL Namur site Mont-Godinne, however these patients are not 
participating in the interventional EFfoRT-BCRL trial. 
Month 38: January 2019: end of inclusion period = milestone 1: analysing and interpreting 
data concerning relation between the different baseline measurements 
Month 1-45 baseline and follow-up assessments 
Month 45: August 2019: last treatment = milestone 2: start analyses and interpretation (cfr 
infra) 
March 2020: last measurements of follow-up period  
Month 45-48: statistical analyses and interpretation of data concerning effect of fluoroscopy-guided 
MLD compared to traditional MLD or placebo MLD for the treatment of BCRL. 
Month 48: November 2019: end of statistical analyses and interpretations = milestone 3 
Month 45-48: utilisation period. 
Month 48: November 2019: end of the project = milestone 4 
6. Trial Procedures 
 
6.1 By visit 
All treatments are performed in the lymphoedema centre of the University Hospitals Leuven, in the 
lymphoedema centre of the University Hospital Sint-Pieter, in the Multidisciplinary Breast Clinic of the 
Antwerp University Hospital, in the Centre of Oncology of AZ Groeninge Kortrijk or in the Department 
of Radiotherapy of UZ Gent. 

 
 
Page 19 of 33 
 
 
Patients who are participating in Brussels, can choose whether they prefer to receive the treatments 
in the hospital in Brussels itself or in a private practice for physiotherapy situated in Liège if the distance 
between domicile and the hospital seems too significant. However, all investigations will be performed 
in the hospital in Brussels. Practice for physiotherapy situated in Liège: 
Le Centre Paramédical "Les Prés d'Or" 
Chaussée des Prés 33 
 4020 Liège 
All patients receive during 3 weeks 15 sessions of intensive treatment for the lymphoedema. 
Thereafter they receive during 6 months (18 sessions) maintenance treatment. 
Intensive treatment 
All groups receive information, skin care, multi-layer bandaging and exercises. 
Additionally the three groups receive MLD. The intervention group receives additionally fluoroscopy-
guided MLD, the first control group receives traditional MLD and the second control group receives 
placebo MLD.  
The content and duration of the treatment in the three groups is based on the current reimbursement 
of physical therapy applied in patients with lymphoedema of at least 5% difference. 
The patients receive each week 5 sessions of treatment. The session with skin care, bandaging and 
exercises last for 30 minutes. The session with MLD also last for 30 minutes. So, the total duration of 
both sessions is 60 minutes and they receive 15 sessions of standard treatment and 15 sessions of MLD 
in total. All treatments are performed by physical therapists experienced in treatment of patients with 
lymphoedema. 
 
Content of each treatment modality: 
Information: the patient receive a leaflet with information about the lymphatic system and 
lymphoedema, clinical evaluation and conservative treatment of lymphoedema 
Skin care: The skin is hydrated during the session. If  wounds are present, the wound is cared 
for.  
Multi-layer bandaging: This bandage consists of different layers: a cotton tube embraces the 
limb and protects the skin; the cotton wool decreases the pressure under the bandage or 
protects the skin against injuries from the bandages; padding with structure creates a 
massage-effect under the bandage; inelastic (low-stretch) bandages, also applied from distal 
to proximal and in a criss-cross pattern, provide an axial rotation of the whole bandage and an 
improvement of the lymphatic transport. The bandage is applied after hydrating the skin, the 

 
 
Page 20 of 33 
 
 
patient performs than exercises. After exercising, MLD is applied on the shoulder and trunk. 
After MLD, the bandage is applied again. Patients have to wear the multi-layer bandage daily 
during day and night. Patients are also taught to bandage themselves. In case of slipping down 
of the bandage or in case of pain the patient has to change the bandage herself. 
Exercise therapy: Patients have to perform upper limb exercises while wearing the multi-layer 
bandage. They have to perform these exercises a second time at home and twice daily during 
the weekend. They are advised to use the arm as normal as possible. 
Fluoroscopy-guided MLD: The lymphatic system is stimulated optimally with the new method 
of MLD. The therapist applies hand movements of higher pressure (up to 80 mmHg) which 
consist of following techniques: 
o Cleaning techniques to empty the lymph nodes at the level of the clavicular, axilla, 
humerus and elbow 
o Resorption technique to create resorption of lymph by the lymph capillaries 
o Gliding technique alongside the skin to stimulate transport of lymph through the 
lymph collectors or to stimulate transport of lymph through the interstitium. 
MLD is also based on the assessment by fluoroscopy. During the drainage session, the therapist 
has to consider the photo of the patient (= the lymph mapping) and her lymphatic transport, 
obtained by the lymphofluoroscopy. 
Traditional MLD: MLD with drainage of the jugular and occipital region, emptying 
retroclavicular lymph nodes, axillary lymph nodes, humeral lymph nodes and cubital lymph 
nodes, stimulating lymph collectors on the trunk, shoulder, arm and hand, without knowledge 
of the patient-specific lymphatic architecture. A pressure with the hands up to 40 mmHg is 
applied and to stimulate lymphatic transport through the lymph collaterals, the therapist’s 
hands perform ‘pump-movements’ while stretching the skin. 
Placebo MLD: deep massage by performing relaxing transverse movements on the muscles of 
the ipsilateral neck, shoulder, arm and belly. We give following explanation to the patients 
about the effect of the treatment: ‘After axillary lymph node dissection, the superficial 
lymphatic network partially disappears (i.e. axillary web syndrome). Lymph transport mainly 
happens through the deep lymphatic network that is surrounded by the muscles. By relaxing 
the muscles lymphatic transport through the deep lymphatic network will improve.’ 
Patients are taught to stimulate their lymphatic transport and are asked to repeat the self-
drainage daily at home. 
Maintenance treatment 
Immediately after the intensive treatment, the maintenance treatment is started for 6 months. 
All patients (intervention and control 1 and 2 group) have to: 

 
 
Page 21 of 33 
 
 
- 
continue skin care 
- 
wear a custom-made compression sleeve 
- 
perform twice a day exercises at home (same as during intensive treatment) 
- 
follow two informational sessions: one session about self-management and one session about 
compression sleeves and other compression material. 
The intervention group receives additionally fluoroscopy-guided MLD, the control 1 group receives 
traditional MLD and the control 2 group receives placebo MLD. Each session lasts for 30 minutes, with 
a frequency decreasing from 2 times a week to one each two weeks (M1: 2x/week, M2: 1x/week, M3-
4: 1x/2 weeks, M5-6 1x/ month, 18 sessions in total). Patients are asked to continue the self-MLD once 
a day at home. 
6.2 Laboratory tests 
Not applicable.  
6.3 Other investigations 
Ultrasonography at the level of the shoulder and trunk to detect stagnation of lymph at the level of 
the shoulder and trunk. 
7. Assessment of efficacy 
 
All assessments are performed in the Lymphoedema Centre of UZ Leuven, in the Lymphoedema Clinic 
of UZ Sint-Pieter, in the Multidisciplinary Breast Clinic of UZA, in the Centre of Oncology of AZ 
Groeninge Kortrijk or in the Department of Radiotherapy of UZ Gent. All assessments are performed 
by someone who is blinded for the allocation to the treatment groups. 
Primary outcome parameters are: 
- 
Change of lymphoedema volume of arm and hand 
- 
Change of stagnation (measured with tissue dielectric constant and with bio-impedance 
analyses) of fluid at the level of shoulder/ trunk 
Secondary outcome parameters are: 
- 
Number of responders after intensive treatment (>30% decrease of lymphoedema volume) 
and after maintenance treatment (<10% increase of lymphoedema volume) 
- 
Change of tissue elasticity at level of arm/ shoulder/ trunk 
- 
Change of extracellular fluid in the arm 
- 
Change of tissue dielectric constant at the level of the arm 
- 
Change of thickness and reflectivity of cutis and subcutis of arm/ shoulder/ trunk 
- 
Change of lymphatic architecture and function 

 
 
Page 22 of 33 
 
 
- 
Change of problems in functioning related to the development of BCRL. 
- 
Change of quality of life 
- 
Number of episodes of erysipelas 
- 
Adverse events associated from MLD 
- 
Cost associated with the disease (lymphoedema) and its treatment 
Following clinical outcome parameters are measured before and after 3 weeks of intensive treatment, 
after 1, 3 and 6 months of maintenance treatment and after 6 months of follow-up: arm and hand 
volume and arm circumferences of both arms, extracellular fluid in the arm, problems in functioning 
related to the development of lymphedema, health-related quality of life and treatment compliance 
are measured. 
Lymphatic architecture and function, thickness and consistency of cutis and subcutis and venous blood 
circulation in arm and trunk are measured before and after the intensive treatment and after 6 months 
of maintenance treatment. 
The first 30 patients are measured twice to check test-retest reliability of the clinical measurements 
(except lymphofluoroscopy). To correct for changes outside of lymphoedema, all clinical assessments 
are performed on the affected side and on the healthy side as well.  
Arm volume (10 min): measured with an arm volumeter: the first 30 patients receive an arm 
volume measurement with the volumeter of Belgrado (in publication), with the volumeter of 
Gebruers (10) and with the volumeter of Damstra (11); based on comparison of test-retest 
reliability and time-efficiency of the different techniques, measurement of arm volume is 
chosen 
 
Hand volume (10 min): measured with a hand volumeter (12) 
Arm circumferences (10 min): measured with a circumference measurement device 
(perimeter) (13) 
Tissue elasticity (5 min): measured with the tonometer (14) and SkinFibrometer 
Water content in the arm/ shoulder/ trunk (5 min): measured with MoistureMeter (15) 
Water content in the arm/ shoulder/ trunk (10 min): measured with BioImpedance 
Spectroscopy (16) 
Problems in functioning related to development of arm lymphoedema (15 min): measured 
with 
the 
Functioning 
Disability 
and 
Health 
questionnaire 
(Lymph-ICF) 
(17)  
*An additional sub-investigation is linked to this questionnaire by analysing the validity and 
reliability of the Dutch as well as the French versions of this questionnaire. In order to realise 
this analysis in time (regarding one of the PhD’s pre-planned time schedule), 30 additional 

 
 
Page 23 of 33 
 
 
patients, who 1) are meeting the inclusion criteria, and 2) have given written informed consent, 
will be recruited in the Lymphovenous Center UZ Leuven regarding the investigation of the 
Dutch version, and 30 additional patients who 1) are meeting the inclusion criteria, and 2) have 
given written informed consent, will be recruited in the Centre for Lympholoedema of CHU 
UCL Namur site Mont-Godinne regarding the investigation of the French version. To determine 
reliability and validity, all patients are asked to complete following documents/questionnaires 
during (ICF) and after their consultation: 
1) Informed Consent document 
2) Lymph-ICF Questionnaire with Numeric Rating Scale (this questionnaire has to be filled in 
twice to analyse test-retest reliability; once at the hospital and a second time at home, 24h 
hours after completing the first one (for this second “blanco” questionnaire an addressed 
and stamped envelope will be provided) 
3) SF-36 Questionnaire (a general questionnaire regarding “general Quality of Life” 
(investigation of validity of the Lymph-ICF questionnaire) 
4) Questionnaire regarding content validity of the Lymph-ICF ((1) Was each question of the 
Lymph-ICF understandable? (2) Was the scoring system clear? and (3) Were all complaints 
related to your lymphoedema mentioned in the Lymph-ICF?) 
5) Questionnaire regarding medical and socio-demographic data of the participants in order 
to determine the characteristics of the study sample. 
Information regarding circumference measurements of the upper limb, received during the 
consultation will be used to calculate and analyze the amount of lymphoedema present in each 
patient 
at 
the 
time 
of 
completing 
the 
questionnaires. 
**For patients participating the EFforT-trial, these questionnaires are completed during the 
assessment which takes place 1 month after the start of the maintenance phase (see 3.5 study 
diagram). 
 
Health-related quality of life (15 min): measured with McGill quality of life questionnaire (in 
publication) 
Skin thickness and reflectivity at level of arm/ shoulder/ trunk (15 min): measured by 
ultrasonography (18) 
 
Lymphatic architecture and function (2.5 hours): measured by lymphofluoroscopy (see above) 
(8, 19) 
 
 
Treatment compliance (5 min): measured with a self-developed questionnaire. 
 

 
 
Page 24 of 33 
 
 
Costs associated lymphoedema and its treatment (10 min): measured with a self-developed 
questionnaire. 
 
Episodes of erysipelas: measured with a self-developed questionnaire 
 
Adverse events from MLD: measured with a self-developed questionnaire 
 
Patient-related data (such as age, body length and weight and physical activity level (with FPACQ)) 
(20), breast cancer treatment- related data (such as type of surgery, type of adjuvant treatment, 
number and level of axillary lymph nodes dissected) and lymphoedema related data (such as duration 
of the oedema and pitting) are collected before the start of the treatment programme. 
Body weight is measured at each measurement session. 
 
8. Assessment of Safety 
8.1 Specification, timing and recording of safety parameters 
We will involve an external safety board to determine subject safety during the study. 
They will perform their first analyses after 6 months of inclusion of patients and again 6 months later. 
Thereafter, analyses are performed after 2 years, 3 years and 4 years. 
They will analyse adverse events related to the assessment (especially with lymphofluoroscopy) and 
to the treatment of lymphoedema (especially the MLD). 
 
8.2 Procedures for recording and reporting adverse events (AE) 
8.2.1 Definitions in Law of May 7, 2004 concerning experiments on the human person 
 
Adverse reaction (AR): all untoward and unintended responses to an investigational medicinal product 
or to an experiment and, when an investigational product is concerned, related to any dose 
administered;  
Adverse event (AE): any untoward medical occurrence in a patient or subject of the treated group 
during an experiment, and which does not necessarily have a causal relationship with this treatment 
Unexpected adverse reaction (UAR): an adverse reaction, the nature or severity of which is not 
consistent with the information on the experiment, and, when a clinical trial is concerned, with the 
applicable product information (e.g. investigator's brochure for an unauthorised investigational 

 
 
Page 25 of 33 
 
 
product or the patient leaflet joined to the summary of product characteristics for an authorised 
product); 
Serious adverse event (SAE) or serious adverse reaction (SAR): any untoward medical occurrence or 
effect that results in death, is life-threatening, requires hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or 
birth defect, and this, when it is a clinical trial, at any dose;  
Suspected unexpected serious adverse reaction (SUSAR): is an AR that is serious and unexpected 
(meaning that nature or severity of the AR is not consistent with the Investigational Medicinal Product 
reference safety information, which is the Investigator’s Brochure) and is judged by either the 
investigator or the sponsor as having a reasonable suspected causal relationship with the 
investigational medicinal product. 
 
8.2.2 Notification of adverse events 
 
The investigator shall report all serious adverse events immediately, after first knowledge, to the 
sponsor except for those that the protocol or investigator's brochure identifies as not requiring 
immediate reporting. The immediate report shall be followed by detailed, written reports. The 
immediate and follow-up reports shall identify subjects by code numbers.  
Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety 
evaluations shall be reported to the sponsor according to the reporting requirements and within the 
terms specified in the protocol 
For reported deaths of a subject, the investigator shall supply the sponsor and the accredited ethics 
committee with any additional information requested. 
The sponsor shall keep detailed records of all adverse events which are reported to him by the 
investigator or investigators. These records shall be submitted to the minister if the experiment is 
being conducted in Belgium, if he so requests. 
 
8.2.3 Notification of serious adverse reactions 
 
The sponsor shall ensure that all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening is recorded and reported as soon as possible to the minister, 
to the competent authorities in all the Member States concerned in the case of a trial, and to the 
competent ethics committee, and in any case no later than seven days after knowledge by the sponsor 

 
 
Page 26 of 33 
 
 
of such a case, and that relevant follow-up information is subsequently communicated within an 
additional eight days. 
All other suspected unexpected serious adverse reactions shall be reported to the minister, to the 
competent authorities of all Member States concerned in the case of a clinical trial and to the ethics 
committee concerned as soon as possible but within a maximum of fifteen days of first knowledge by 
the sponsor. 
The sponsor shall also inform the other investigators. 
Once a year throughout the experiment, the sponsor shall provide the minister and the ethics 
committee in Belgium and those of the member States in whose territory the trial is conducted in the 
case of a multicentre trial, with a listing of all suspected serious adverse reactions which have occurred 
over this period and a report of the subjects' safety. 
Regarding those adverse events and serious adverse reactions the Principal Investigator will take all 
reasonable measures, in consultation with Sponsor, to protect subjects at risk following the occurrence 
of such events. 
8.2.4 Adverse events that do not require reporting 
No AE’s or SAE’s are expected nor after the subcutaneous injection of ICG, neither associated with 
the treatment of lymphoedema. 
AE will be reported during the entire trial period, i.e. 7 months (3 weeks intensive phase and 6 
months maintenance phase) 
 
8.3 Treatment stopping rules 
Not applicable. No AE’s or SAE’s are expected nor after the subcutaneous injection of ICG, neither 
associated with the treatment of lymphoedema. 
 
8.4 Data monitoring committee (DMC) 
Not applicable. 
 
There are no indications for setting up a data monitoring committee, such as: 
- 
Life-threatening disease 
- 
Patient population (e.g. pediatric population) 
- 
Prior knowledge or strong suspicion that a treatment under consideration has the potential to 
harm patients 
- 
Complex study design 
 

 
 
Page 27 of 33 
 
 
9. Statistics 
9.1 Sample size 
 
The required sample size for the study is 192 subjects or 64 subjects per group to detect a difference 
of 15% in the reduction of lymphoedema volume at the level of the arm/ hand (first primary 
outcome) or at the level of the shoulder/ trunk (second primary outcome) between the three groups. 
This is based on an alpha of 0.0125 and a power of 80%. The effect size is determined from clinical 
results of the Leuven Lymphovenous Center and by consulting experts in the field of lymphology, 
with the estimated reduction of 35% (±25%) for the traditional MLD group and an estimated 
reduction of 50% (±25%) for the fluoroscopy guided MLD group, and of 20% (±25%) for the placebo 
MLD group. Based on a previous longitudinal study with breast cancer patients (21), a dropout rate 
of 5% is estimated (or 9 patients). 
73 patients with unilateral BCRL were followed in the Leuven Lymphovenous Center between 
November 2011 and November 2013. Patients firstly received intensive decongestive lymphatic 
therapy with skin care, bandaging, exercises and traditional MLD. Thereafter they received 
maintenance decongestive lymphatic therapy with skin care, compression sleeve, exercises and 
traditional MLD. Lymphoedema volume of the arm reduced 36% (±28%) on average after intensive 
treatment on average. 
According to different experts in the field of lymphology (the principle and sub-investigators of this 
study), an additional reduction of the lymphoedema volume of 15% is clinically relevant. This can be a 
reduction of the lymphoedema volume at the level of the arm/ hand OR at the level of the shoulder/ 
trunk. The group with fluoroscopy-guided MLD is compared to the group with traditional MLD, and the 
group with fluoroscopy-guided MLD is compared to placebo MLD. This explains why an alpha level of 
1.25% was chosen (and not 5%) (= 2 times Bonferoni correction). In literature, data on change of 
lymphoedema volume at the level of the shoulder/ trunk is missing.  
 
 
9.2 Randomisation 
Patients in the intervention group will receive standard physical therapy + fluoroscopy-guided MLD 
Patients in the control 1 group will receive standard physical therapy + traditional MLD 
Patients in the control 2 group will receive standard physical therapy + placebo MLD 

 
 
Page 28 of 33 
 
 
Randomisation is performed by someone different form the assessors or therapists of the study. 
Before randomization, the patient receives an ID. Randomisation is performed using an excel-file and 
the order of the randomization is determined by the ID number. 
The assessments are performed by someone who is blinded to the allocation to the treatment groups. 
Patients are also blinded to the allocation to the treatment group 
 
 
9.3 Analysis 
 
Month 45-48: statistical analyses and interpretation of data concerning effect of fluoroscopy-guided 
MLD compared to traditional MLD or placebo MLD for the treatment of BCRL. 
Month 48: November 2019: end of statistical analyses and interpretations = milestone 3 
The statistical department of KU Leuven is counselled about the statistical analyses. 
Following hypotheses will be tested: 
- Patients receiving fluoroscopy-guided MLD during the intensive or maintenance phase of 
decongestive lymphatic therapy will have a significantly: 
o greater reduction of lymphoedema volume at the level of the hand/ arm 
o less stagnation of lymph at the level of the shoulder/ trunk 
o greater response 
o greater reduction of extracellular fluid in the arm 
o greater reduction of tissue dielectric constant in the arm 
o greater improvement of tissue elasticity 
o greater reduction of problems in functioning related to lymphoedema 
o greater improvement of health related quality of life improvement of lymphatic 
function 
o greater change of cutis and subcutis consistency 
o greater decrease of cutis and subcutis thickness 
o more improvement of lymphatic transport 
than patients receiving traditional MLD or placebo MLD. 
 
Data will be analyzed according the intention to treat principle. A 1.25% level of significance is applied. 
 

 
 
Page 29 of 33 
 
 
10. Quality assurance 
Experienced assessors will perform all lymphofluoroscopic evaluations after informed consent. 
Injections will be given under sterile conditions. 
Physical therapy will be given by experienced physical therapists. 
The safety board will collect all adverse events and will supervise the safety of the patients. 
11. Direct access to source data and documents 
It will be specified, (or reference is made to another written agreement) that the investigator(s) and 
the institution(s) will permit trial-related monitoring, audits, EC review, and regulatory inspections 
(where appropriate) by providing direct access to source data and other documents (ie patients’ case 
sheets, blood test reports, X-ray reports, histology reports etc).  
12. Ethics and regulatory approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (2013), 
the principles of GCP and in accordance with all applicable regulatory requirements. This protocol 
and related documents will be submitted for review to Ethics Committee of the University 
Hospitals Leuven, University Hospital Antwerp, to UMC Sint-Pieter, to AZ Groeninge Kortrijk, to 
UZ Gent and to the Federal Agency for medicinal products for Clinical Trial Authorisation. 
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, 
or their legal representatives, to participate in the Study. The Participating Site shall obtain a 
signed informed consent form (ICF) for all patients prior to their enrollment and participation in 
the Study in compliance with all applicable laws, regulations and the approval of the (local) Ethics 
Committee, if required. The Participating Site shall retain such ICFs in accordance with the 
requirements of all applicable regulatory agencies and laws. 
The Investigator and the Participating Site shall treat all information and data relating to the Study 
disclosed to Participating Site and/or Investigator in this Study as confidential and shall not 
disclose such information to any third parties or use such information for any purpose other than 
the performance of the Study. The collection, processing and disclosure of personal data, such as 
patient health and medical information is subject to compliance with applicable personal data 
protection and the processing of personal data (Directive 95/46/EC and Belgian law of December 
8, 1992 on the Protection of the Privacy in relation to the Processing of Personal Data). 
Data are anonymous. The table with the data of the study do not contain information that can be 
linked to the patient (such as name, date of birth). All documents to collect patient-specific data 
for the study contain a patient-specific code (and not the name of the patient). The overview of 

 
 
Page 30 of 33 
 
 
the different codes and related name and date of birth of the patient is kept by the principle 
investigator. 
13. Data Handling 
The data will be stored on a shared file (on UZ data). Only the principle investigator, sub-investigators 
and project co-workers (after permission from the principle investigator) have access to the file. The 
access is secured by a login and password. 
14. Data Management 
All documents concerning the organization of the project (such as documents concerning approval by 
the Ethical Committee), may be – after permission of the persons who has to sign - signed 
electronically. Each site will retain all study related documents according to storage and record 
retention principles of good clinical practices. 
15. Translational research 
Not applicable 
16. Publication Policy 
 
Possible publications are: 
- 
Protocol study: Nele Devoogdt first author and Sarah Thomis last author 
- 
PhD student 1 
o Effect intensive treatment: on clinical parameters 
o Effect intensive treatment: changing lymphatic architecture and lymph transport 
o Comparison of arm volume measured with 3 devices: Gebruers, Belgrado, Damstra 
o Responsiveness of Lymph-ICF 
o Economic analyses of current conservative treatment of lymphoedema analyse  
- 
PhD student 2 
o Effect maintenance treatment: on clinical parameters 
o Effect maintenance treatment: changing lymphatic architecture and lymph transport 
o Reliability and validity of the French version of the Lymph-ICF 
o Comparison of extracellular fluid measured with 2 devices: Impedimed versus Bodystat 
Quadscan 
o Economic analyses old conservative treatment of lymphoedema versus new one 
 
On every publication, PhD student is first author and Nele Devoogdt (principle investigator) is last 
author. 
All sub-investigators are mentioned on every publication as co-authors. 
Adding co-authors, change of the order of co-authors will be discussed with all investigators. 

 
 
Page 31 of 33 
 
 
If an investigator wants to make an extra publication with existing data, he/ she has to discuss this with 
all investigators. 
 
17. Insurance/Indemnity 
 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, UH 
Leuven shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance. 
18. Financial Aspects 
 
This study is financed by the Agency for Innovation by Science and Technology, applied Biomedical 
Research. In order to arrange such financing a separate collaboration agreement has been agreed 
between UH Leuven and the beneficiaries.  
For patients, participating in the study will be cost free. Neither the assessment of the patient 
(clinically, 
echography, 
fluoroscopy) 
nor 
the 
treatment 
with 
MLD 
will 
be 
charged.  
The standard physical therapy sessions however are on doctor’s prescription. One part will be 
reimbursed  by the social services. The other part is paid by the patient. At the end of the study the 
patient will receive a compensation for participating in the study which is equivalent to the amount 
she/ he had to pay herself/ himself for the physical therapy sessions (by giving gift cards). 
 
 
 

 
 
Page 32 of 33 
 
 
19. References 
 
1. 
Pusic AL, Cemal Y, Albornoz C, Klassen A, Cano S, Sulimanoff I, et al. Quality of life among breast 
cancer patients with lymphedema: a systematic review of patient-reported outcome instruments and 
outcomes. J Cancer Surviv. 2013;7(1):83-92. 
2. 
The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the 
International Society of Lymphology. Lymphology. 2013;46(1):1-11. 
3. 
Karki A, Anttila H, Tasmuth T, Rautakorpi UM. Lymphoedema therapy in breast cancer patients: 
a systematic review on effectiveness and a survey of current practices and costs in Finland. Acta Oncol. 
2009;48(6):850-9. 
4. 
Devoogdt N, Van Kampen M, Geraerts I, Coremans T, Christiaens MR. Different physical 
treatment modalities for lymphoedema developing after axillary lymph node dissection for breast 
cancer: a review. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):3-9. 
5. 
Huang TW, Tseng SH, Lin CC, Bai CH, Chen CS, Hung CS, et al. Effects of manual lymphatic 
drainage on breast cancer-related lymphedema: a systematic review and meta-analysis of randomized 
controlled trials. World J Surg Oncol. 2013;11:15. 
6. 
Oremus M, Dayes I, Walker K, Raina P. Systematic review: conservative treatments for 
secondary lymphedema. BMC Cancer. 2012;12:6. 
7. 
Belgrado JP. Lymphofluoroscopie associée à un traitment physique.  Symposium of 
International Lymphoedema Framework; Montpellier2012. 
8. 
Tan IC, Maus EA, Rasmussen JC, Marshall MV, Adams KE, Fife CE, et al. Assessment of lymphatic 
contractile function after manual lymphatic drainage using near-infrared fluorescence imaging. Arch 
Phys Med Rehabil. 2011;92(5):756-64 e1. 
9. 
Belgrado JP, Vandermeeren L, Valsamis JB, Vandekerhoven S, Sinegre A, Giacalone G, et al. 
Drainage lymphatique manuel de l' imagerie à la pratique 'evidence-based'.  Congrès de Axxon2013. 
10. 
Gebruers N, Truijen S, Engelborghs S, De Deyn PP. Volumetric evaluation of upper extremities 
in 250 healthy persons. Clin Physiol Funct Imaging. 2007;27(1):17-22. 
11. 
Damstra RJ, Glazenburg EJ, Hop WC. Validation of the inverse water volumetry method: A new 
gold standard for arm volume measurements. Breast Cancer Res Tr. 2006;99(3):267-73. 
12. 
Farrell K, Johnson A, Duncan H, Offenbacker T, Curry C. The intertester and intratester 
reliability of hand volumetrics. J Hand Ther. 2003;16(4):292-9. 
13. 
Devoogdt N, Lemkens H, Geraerts I, Van Nuland I, Flour M, Coremans T, et al. A new device to 
measure upper limb circumferences: reliability and validity. Int Angiol. 2010;(in publication). 
14. 
Moseley A, Piller N. Reliability of bioimpedance spectroscopy and tonometry after breast 
conserving cancer treatment. Lymphat Res Biol. 2008;6(2):85-7. 
15. 
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