Added Value of Reconstructive Lymphatic Surgery to Usual Care in Lymphoedema

Study Overview
=================
Brief Summary
-----------------
The primary objective of this research proposal is to investigate in patients with lymphoedema of the upper limb or lower limb (P) the added value of reconstructive lymphatic surgery (I) to the decongestive lymphatic therapy (usual care) (C) on the lymphoedema-specific quality of life (QoL) (O) at 18 months post-surgery/ no surgery (T) Consequently, a multicentre pragmatic randomised controlled trial is performed to give an answer on following research question: 'Is, in addition to usual care - i.e. decongestive lymphatic therapy -, reconstructive lymphatic surgery (intervention group) superior to no surgery (control group), for the treatment of upper or lower limb lymphoedema?'

Detailed Description
-----------------
Lymphoedema is a chronic and often debilitating condition caused by lymphatic insufficiency. It leads to swelling of the limb and an increased risk of infection. It can be classified as primary (congenital) or secondary (acquired) lymphoedema. Lymphoedema is very burdensome for the patient and therefore is it often associated with mental problems for example frustration and stress. In addition, because of the increase in volume of the limb, patients also develop physical problems, such as pain, heaviness, loss of strength, and develop functional problems, such as problems with household, mobility or social activities. These mental, physical and functional problems all have a negative impact on quality of life and have an influence on the ability to work. Consensus exist that the first choice of treatment is a conservative treatment. This conservative treatment consists of skin care, compression therapy (i.e. multilayer bandaging and compression garments), exercises and lymph drainage. Reconstructive lymphatic surgery is another option, also often performed: i.e. lymphovenous anastomoses, on the one hand, and a lymph node transfer, on the other hand. By (partially) restoring the lymphatic transport, the reconstructive lymphatic surgery may possibly lead to a larger decrease of the lymphoedema volume and therefore greater discontinuation of the compression garment. Consequently, patients will have an improvement in functioning and quality of life. Currently, scientific evidence for reconstructive lymphatic surgery for the treatment of lymphoedema is missing. Therefore, the aim of this trial is to investigate the added value of reconstructive lymphatic surgery of the lymphatic system in addition to the conservative treatment, for the treatment of lymphoedema.

Official Title
-----------------
Comparison of Reconstructive Lymphatic Surgery Versus no Surgery, Additional to Decongestive Lymphatic Therapy (Usual Care), for the Treatment of Iymphoedema, Through a Multicentre Randomised Controlled Trial

Conditions
-----------------
Lymphedema, Lymphoedema of Leg, Lymphedema Arm

Intervention / Treatment
-----------------
* Other: Usual care
* Procedure: Reconstructive lymphatic surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Unilateral or bilateral, primary or secondary lymphoedema of the upper or lower limb If cancer-related lymphoedema, approval for participation in study from oncological specialist (patient participation has to be discussed during Multidisciplinary Oncological Consult); approval if: estimated cancer-related survival is ≥3 years oncological safety is guaranteed: for instance, time interval since radiotherapy/ chemotherapy is ≥3 months Lymphoedema stage 1 to 2b Objective diagnosis of lymphoedema: ≥ 5% volume difference OR ≥ 2 minor/ 1 major criteria on lymphoscintigraphy OR presence of IndoCyanineGreen (ICG) dermal backflow Score on Lymph-ICF questionnaire at screening: ≥ 25 / 100 (= moderate level of problems in functioning related to the development of lymphoedema) History of at least 6 months of decongestive lymphatic therapy (DLT) until minimal pitting Age ≥ 18 years Exclusion Criteria: Participants with history of liposuction, lymphovenous anastomosis, lymph node transfer Pregnant participants Severe obese participants: BMI>35 Estimated cancer-related survival is <3 years and oncological safety is not guaranteed (e.g. interval since radiotherapy/ chemotherapy is <3 months) In case of lower limb lymphoedema: presence of chronic venous insufficiency C4, C5, C6; deep venous thrombosis; post-thrombotic syndrome Allergy for ICG, iodine, penicillin and sulphonamides; increased activity of thyroid gland; benign tumour in thyroid; heparin use and severe renal insufficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reconstructive lymphatic surgery<br>The intervention treatment is reconstructive lymphatic surgery and consists of the application of lymphovenous anastomosis (LVA), lymph node transfer (LNT) or a combination of both. The choice of reconstructive technique(s) is determined by the surgeon and is based on the algorithm for reconstructive lymphatic surgery of lymphoedema. Additionally, all patients receive usual care (i.e. maintenance decongestive lymphatic therapy) | Other: Usual care<br>* Home physical therapist performs usual care and educates the patient to perform self-management Usual care: M1-6: 6 months of maintenance decongestive lymphatic therapy (DLT) (by patient and home physical therapist): week 1-2: no physical therapy; patient performs limb elevation, muscle contractions and wears the bandage (intervention group)/ compression garment (control group) week 3-4: start physical therapy, 2 days/ week: exercises, skin care & manual lymph drainage (MLD), education; self-management by patient and wearing compression garment 14-16h/day (4 sessions) M2-6: 1 day/ week physical therapist: exercises, skin care & MLD, and self-management by patient and wearing compression garment 14-16h/day (20 sessions) M7-12: 6 months of maintenance DLT by patient (self-management) and home physical therapist: - 1 day/week physical therapist: skin care, MLD, exercises (26 sessions) Month 13-18: 6 months of maintenance DLT by patient Month 19-36: 18 months of follow-up<br>Procedure: Reconstructive lymphatic surgery<br>* For the procedure of LVA: - Aim: making anastomoses of lymph vessels at the capillary level with a diameter of 0.3 to 0.8 mm, to redirect lymph to venous stream directly For the procedure of LNT: - Aim: Placed lymph nodes act as sponge to absorb lymphatic fluid and direct it into the vascular network; Placed lymph nodes induce lymphangiogenesis<br>|
| Active Comparator: No surgery<br>All patients receive usual care (i.e. maintenance decongestive lymphatic therapy) | Other: Usual care<br>* Home physical therapist performs usual care and educates the patient to perform self-management Usual care: M1-6: 6 months of maintenance decongestive lymphatic therapy (DLT) (by patient and home physical therapist): week 1-2: no physical therapy; patient performs limb elevation, muscle contractions and wears the bandage (intervention group)/ compression garment (control group) week 3-4: start physical therapy, 2 days/ week: exercises, skin care & manual lymph drainage (MLD), education; self-management by patient and wearing compression garment 14-16h/day (4 sessions) M2-6: 1 day/ week physical therapist: exercises, skin care & MLD, and self-management by patient and wearing compression garment 14-16h/day (20 sessions) M7-12: 6 months of maintenance DLT by patient (self-management) and home physical therapist: - 1 day/week physical therapist: skin care, MLD, exercises (26 sessions) Month 13-18: 6 months of maintenance DLT by patient Month 19-36: 18 months of follow-up<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphoedema-specific QoL (or problems in functioning related to development of lymphoedema) | evaluated with the Dutch or French version of the Lymph-ICF questionnaire for upper or lower limb lymphoedema | at 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphoedema-specific QoL (or problems in functioning related to development of lymphoedema) | evaluated with the Dutch or French version of the Lymph-ICF questionnaire for upper or lower limb lymphoedema | at 1, 3, 6, 12 (short term) and 24, 36 (longer term) months | 
| General health-related QoL | evaluated with the EuroQol-5D-5L questionnaire | at 1, 3, 6, 12, 18, 24, 36 months | 
| Limb volume | evaluated using circumference measures (ml) | at 1, 3, 6, 12, 18 (key secondary outcome), 24, 36 months | 
| Failure to reduce the hours a day of wearing the compression stocking | failure is defined as not able to continue the reduction of the hours of wearing the compression garment as stated by the protocol | at 12, 18, 24, 36 months | 
| The hours of wearing the compression garment during one week | evaluated with the International Compression Club (ICC) questionnaire ('dosage score' between 0-168h) | at 12, 18 (key secondary outcome), 24, 36 months | 
| The experience of the compression garment | evaluated with the International Compression Club (ICC) questionnaire ('comfort score' between 0-10 and 'complication score' between 0-10) | at 1, 3, 6, 12, 18, 24, 36 months | 
| The physical activity level | evaluated with the International Physical Activity Questionnaire (IPAQ) - short form (MET-hours/week) | at 1, 3, 6, 12, 18, 24, 36 months | 
| The need for intensive treatment due to an increase in lymphoedema volume | through interview | at 6, 12, 18, 24, 36 months | 
| Body weight | measured using a balance | at 1, 3, 6, 12, 18, 24, 36 months | 
| Work capacity | evaluated with the Work Productivity and Activity Impairment (WPAI-GH) questionnaire | at 1, 3, 6, 12, 18, 24, 36 months | 
| Work ability | evaluated with the Quickscan 18 (short form) questionnaire | at 1, 3, 6, 12, 18, 24, 36 months | 
| Infection during the previous 18 months (yes/no) | through interview | at 18, 36 months (adverse events are collected during each clinical assessment but the amount of infections as secondary outcome are taken together for statistical analyses per 18 months) | 
| Complications of surgery | through interview | at 1, 3, 6, 12, 18, 24, 36 months | 
| Recurrence of cancer (yes/no) | through medical file | at 36 months | 
| Lymphatic transport | through lymphoscintigraphy | at 18 months | 
| Costs related to lymphoedema and its treatment during previous 18 months | through interview | at 18, 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Reconstructive lymphatic surgery, Decongestive lymphatic therapy, Lymphovenous anastomosis, Lymph node transfer