Effectiveness of Fluoroscopy-guided MLD for Treatment of BCRL

Study Overview
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Brief Summary
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The main scientific objective of this multicentric double-blinded randomised controlled trial entails examining the effectiveness of fluoroscopy-guided MLD versus traditional MLD 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

Detailed Description
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According to the International Society of Lymphology, lymphoedema needs to be treated with Decongestive Lymphatic Therapy (Consensus Document ISL 2013). 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 (Kärki et al 2009). 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 (Devoogdt et al 2010, Oremus et al 2012, Huang et al 2013, Ezzo et al 2015). 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 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. Therefore, the main scientific objective entails examining the effectiveness of fluoroscopy-guided MLD versus traditional MLD versus placebo MLD, applied as part of the intensive and maintenance phase of Decongestive Lymphatic Therapy, for the treatment of BCRL

Official Title
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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

Conditions
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Breast Neoplasm, Lymphedema

Intervention / Treatment
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* Other: Information
* Other: Skin care
* Other: Compression therapy
* Other: Fluoroscopy-guided MLD
* Other: Traditional MLD
* Other: Placebo MLD


Participation Criteria
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Eligibility Criteria
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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 breast cancer-related lymphoedema Chronic lymphoedema (>3 months present), stage I to IIb At least 5% difference between both arms and/ or hands, adjusted for dominance Written informed consent obtained 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 Active metastasis of the cancer Surgery of the lymphatic system in the past (lymph node transplantation, lymphovenous shunt) Cannot participate during the entire study period Mentally or physically unable to participate in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluoroscopy-guided MLD<br>Information, skin care, compression therapy, exercises and fluoroscopy-guided MLD 3 weeks (14 sessions of 60 minutes) of intensive treatment 6 months (18 sessions of 60 minutes) of maintenance treatment 6 months of follow-up | Other: Information<br>* During intensive phase: a leaflet with information about the lymphatic system and lymphoedema, clinical evaluation and conservative treatment of lymphoedema During maintenance phase: two informational sessions about self-management and about compression sleeves and other compression material<br>Other: Skin care<br>* The skin is hydrated during the session. If wounds are present, the wound is cared.<br>Other: Compression therapy<br>* During intensive phase: application of multi-layer, multi-component bandages During maintenance phase: wearing custom-made compression garment<br>Other: Fluoroscopy-guided MLD<br>* Fluoroscopy-guided MLD is applied on patient-specific lymphatic system (known from lymphofluoroscopy) by applying cleaning techniques on lymph nodes, resorption techniques to stimulate resorption of lymph by lymph capillaries and gliding technique to stimulate transport of lymph through lymph collectors<br>|
| Active Comparator: Traditional MLD<br>Information, skin care, compression therapy, exercises and traditional MLD 3 weeks (14 sessions of 60 minutes) of intensive treatment 6 months (18 sessions of 60 minutes) of maintenance treatment 6 months of follow-up | Other: Information<br>* During intensive phase: a leaflet with information about the lymphatic system and lymphoedema, clinical evaluation and conservative treatment of lymphoedema During maintenance phase: two informational sessions about self-management and about compression sleeves and other compression material<br>Other: Skin care<br>* The skin is hydrated during the session. If wounds are present, the wound is cared.<br>Other: Compression therapy<br>* During intensive phase: application of multi-layer, multi-component bandages During maintenance phase: wearing custom-made compression garment<br>Other: Traditional MLD<br>* Traditional MLD is applied without knowledge of the patient-specific lymphatic architecture. During MLD no cream or oil is used. A pressure with the hands up to 40 mmHg is applied. Drainage is performed at the level of the jugular and occipital region and the belly (in the depth). Draining techniques are applied on the retroclavicular lymph nodes, axillary lymph nodes, humeral lymph nodes and cubital lymph nodes. At the level of the hand, arm, shoulder and trunk, hand movements are applied to stimulate lymphatic transport through the lymph collectors. The therapist's hands perform 'pumping-movements' while stretching the skin.<br>|
| Placebo Comparator: Placebo MLD<br>Information, skin care, compression therapy, exercises and placebo MLD 3 weeks (14 sessions of 60 minutes) of intensive treatment 6 months (18 sessions of 60 minutes) of maintenance treatment 6 months of follow-up | Other: Information<br>* During intensive phase: a leaflet with information about the lymphatic system and lymphoedema, clinical evaluation and conservative treatment of lymphoedema During maintenance phase: two informational sessions about self-management and about compression sleeves and other compression material<br>Other: Skin care<br>* The skin is hydrated during the session. If wounds are present, the wound is cared.<br>Other: Compression therapy<br>* During intensive phase: application of multi-layer, multi-component bandages During maintenance phase: wearing custom-made compression garment<br>Other: Placebo MLD<br>* During placebo MLD a superficial massage with massage cream is performed on the patient's contralateral arm and on the belly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphoedema Volume at the Level of the Arm/ Hand | = the ratio at the different time points; The (inter-limb) ratio = Relative excessive lymphoedema volume of the arm/ hand = [(volume arm + volume hand affected side) / (corrected volume arm + corrected volume hand healthy side)]; Volume arm is determined by performing circumference measurements and calculating the volume with the formula of the truncated cone; Volume hand is determined by the water displacement method; The volume of the non-dominant hand/arm is on average 3.3% smaller than the dominant hand/arm, therefore is the volume of the arm at the healthy side corrected for hand dominance | Primary endpoint = After 3 weeks of intensive treatment | 
| Stagnation of Fluid at Level of the Shoulder/ Trunk | Ratio PWC% at the different time intervals = PWC% affected side / PWC% healthy side Measured with the MoistureMeterD compact at the level of shoulder and trunk where after a mean ratio PWC% is calculated | Primary endpoint = After 3 weeks of intensive treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extracellular Fluid in the Upper Limb | L-Dex score, measured with Impedimed BIS device at the different time points Amount of extracellular fluid = represented by L-Dex score This outcome is calculated and displayed on the Impedimed BIS device, and represents the difference in the amount of extracellular fluid in the affected upper limb compared to the unaffected upper limb. Normal L-Dex scores range between -10 and +10. A score outside this range, represents lymphedema. A higher number, represents a worse score. | After 3 weeks of intensive treatment, 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Thickness of Cutis and Subcutis of Arm and Trunk Measured With Ultrasound | Analyses for change in thickness of cutis + subcutis were performed: Relative excessive thickness of the cutis+subcutis (inter-limb ratio of cutis+subcutis in mm) = Thickness of cutis+subcutis (mm) affected side / thickness of cutis+subcutis (mm) healthy side Arm: Reference points 1, 2, 3, 5, 6, 7 where after a mean ratio thickness of cutis+subcutis is calculated | After 3 weeks of intensive treatment and 6 months of maintenance treatment and 6 months of follow-up | 
| Problems in Functioning Related to Development of Breast Cancer-related Lymphoedema | Different scores are obtained from the questionnaire. Each of the 29 questions has to be scored on a 11-point Likert scale between 0 and 10 (instead of a VAS between 0 and 100). The total score of the Lymph-ICF-UL is equal to the sum of the scores on the questions divided by the total number of answered questions and multiplied by 10. In addition, a score is determined for each of the five domains of the Lymph-ICFUL: (1) physical function, (2) mental function, (3) household activities, (4) mobility activities, and (5) life and social activities. Thus, the total score on the Lymph-ICF-UL and the score on the five domains range between 0 and 100. The higher the score, the more problems in functioning. | After 3 weeks of intensive treatment, 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Elasticity of Skin and Subcutaneous Tissue of Arm and Trunk Using the SkinFibrometer | Induration force is presented in Newton (N) by the device. Relative difference in skin elasticity (induration force inter-limb ratio) = Skin elasticity affected side / skin elasticity healthy side Arm: Reference points 1, 2, 3, 5, 6, 7 where after a mean induration ratio is calculated | After 3 weeks of intensive treatment, 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Quality of Life Score | At the end of each assessment, subjects are asked to fill in the questionnaire individually Questionnaire counts 16 + 1 questions, which relate to the following 5 domains: physical symptoms; physical wellbeing, psychological symptoms; existential wellbeing and support A Likert scale with 11 possibilities (0-10) is used for the 16 questions and part D is an open question Each question corresponds to a score between 0 (very bad) and 10 (excellent); a total score and 5 different domain scores are calculated (each between 0 and 10) A lower score indicates a lower Quality of Life | After 3 weeks of intensive treatment and 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Number of Episodes of Erysipelas | At each clinical evaluation, it was asked to the patient if they had had an episode of erysipelas (which is an infection) between today and the previous evaluation. The numbers of episodes were counted, and the causes of this episode of erysipelas were described. The numbers of episodes were compared between the groups. | Between baseline and the end of the follow-up phase (12 months) | 
| Overall Treatment Satisfaction | The number patients presented as a percentage that indicated that their complaints have been slightly (3), much (2) or very much improved (1) during 12 months of time | Between baseline and the end of the follow-up phase (12 months) | 
| Manual Lymphatic Drainage (MLD)-Specific Treatment Satisfaction | The mean rating of the perceived effect of the manual lymph drainage (MLD) that patients received during the study (between 0-10). The higher the score, the higher the satisfaction about the effect of the manual lymph drainage received. | Between baseline and the end of the follow-up phase (12 months) | 
| Local Tissue Water at the Level of the Arm and Trunk | Ratio PWC% at the different time intervals = PWC% affected side / PWC% healthy side Measured with the MoistureMeterD compact at different measurement points where after a mean ratio PWC% is calculated Arm: Reference points 1, 2, 3, 5, 6, 7 where after a mean ratio PWC% is calculated | After 3 weeks of intensive treatment phase, after 1, 3, 6 months of maintenance treatments and after 6 months of follow-up | 
| Thickness of the Cutis and Subcutis of the Arm and Trunk Evaluated by Palpation (Pinch Test) | In total, six reference points (located at the hand (1 reference point) and arm (5 reference points)) are being evaluated and scored (0 or 1) A reference point is scored with 1 in case the skin fold thickness at the affected side is increased compared to the reference point at the non-affected side The final outcome for the arm score is the (cumulated) total score of six reference points 1, 2, 3, 5, 6, 7 (range 0-6), a higher score indicates more presence of thickened skin | After 3 weeks of intensive treatment, 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Hardness (Fibrosis) of the Skin at the Level of the Arm and Trunk Evaluated Through Palpation | In total, six reference points (located at the hand (1 reference point) and arm (5 reference points)) are being evaluated and scored (0 or 1) A reference point is scored with 1 in case fibrosis of the skin is present The final outcome for the arm score is the (cumulated) total score of six reference points 1, 2, 3, 5, 6, 7 (range 0-6), a higher score indicates more presence of fibrosis | After 3 weeks of intensive treatment, 1, 3, 6 months of maintenance treatment and 6 months of follow-up | 
| Lymphatic Architecture and Function | Total dermal backflow score (0-39). The higher the score, the more dermal backflow is present Amount of efferent lymphatics leaving dermal backflow areas Presence of visible lymph nodes after the break Raw data is currently still being analyzed in order to be able to report on the described outcome measures. At present (March 2022) these analyses are not yet performed. Therefore these results will be reported later on this year (anticipated date: July 2022). | After 3 weeks of intensive treatment and 6 months of maintenance treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, lymphedema, manual lymph drainage, near infrared fluorescence imaging