The LYMPH Trial - Surgical Versus Conservative Complex Physical Decongestion Therapy for Chronic Breast Cancer-Related Lymphedema

Study Overview
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Brief Summary
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The aim of this study is to test whether lymphatic surgery provides better QoL (assessed with the Lymph-ICF-UL, (Lymphedema Functioning Disability and health questionnaire for upper limb lymphedema)) 15 months after randomization (and therefore about one year after surgery) compared to conservative treatment only for patients with chronic lymphedema (LE)

Detailed Description
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To date, conservative complex physical decongestion therapy (CDT) is the gold standard for BCRL (breast cancer related lymphedema) and includes manual lymphatic drainage, local compression with bandages and garments, physical exercises and meticulous skin care. It is, however, too often ineffective to prevent stage progression in curing BCRL and purely symptomatic. Lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) are two surgical techniques that, in contrast to CDT, are able to actually address the underlying causes and eventually restore the lymphatic drainage. LVA achieves this by creating numerous bypasses between lymphatic vessels and venules allowing the drainage of excessive fluid within the subcutaneous tissues into the venous system, while VLNT usually brings functioning lymph nodes to an area devoid of lymph nodes or with dysfunctional lymph nodes, thus enabling the spontaneous development of new lymphatic pathways. Both techniques have shown very promising results with low complication rates and improved Quality of Life (QoL) for the patients. However, no multicentric randomized controlled trial (RCT) has yet prospectively evaluated the superiority of these surgical techniques over CDT alone, limiting patient's access to most effective treatment available. Requests for cost reimbursement must still be submitted to insurance companies in most countries and are often rejected, thus delaying surgical treatment and resulting in prolonged suffering of affected patients. This is untenable seeing as affected patients suffer from a heavy physical, psychological and financial burden. This pragmatic, randomized, multicenter trial aims to establish a solid scientific basis assessing the superiority of surgical treatment over CDT alone.

Official Title
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The LYMPH Trial - Surgical Versus Conservative Complex Physical Decongestion Therapy for Chronic Breast Cancer-Related Lymphedema: A Pragmatic, Randomized, Multicenter Superiority Trial

Conditions
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Lymphedema, Breast Cancer

Intervention / Treatment
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* Procedure: Surgical Intervention
* Procedure: Conservative Complex Physical Decongestion Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Patients ≥ 18 years of age with prior treatment of breast cancer. At least one of the following prior breast cancer treatments: sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), radiotherapy (RT) of chest wall or axilla or breast cancer surgery. Clinical diagnosis of chronic BCRL as defined by the ISL (inter-limb difference of >10% in volume or excess volume between the affected and non-affected limbs present for more than 3 months). Minimum of 3 months CDT. Ability to complete the QoL questionnaires. Exclusion Criteria: No indication for lymphatic surgery according to clinical judgment of the treating surgeon (individual reasons will be specifically documented). Primary congenital LE or non-breast cancer-related LE. Need for immediate LE surgery according to clinical judgement by a specialist due to far progressed LE stage.

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
Interventional Model Description: Pragmatic, randomized, international, multicenter superiority trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A : Surgical Group<br>According to the pragmatic study design, neither the diagnostic workup nor the surgery will be standardized in order to offer surgeons considerable leeway on how to perform lymphatic surgery, which resembles the flexibility in usual care. The key aspects of the preoperative workup and the surgery including the number of LVAs (Lymphovenous Anastomosis), harvesting of lymph nodes (donor site), time of surgery, and practical details will be registered. | Procedure: Surgical Intervention<br>* LVA (Lymphovenous Anastomosis) and VLNT (Vascularised Lymph Node Transfer) are two advanced microsurgical techniques that are increasingly implemented in clinical practice in specialized centers and that are already carried out after health insurance application according to local standard of care. They have been studied in their respective mode of action as well as in their effectiveness in treating chronic BCRL (Breast Cancer-Related Lymphedema) in a multitude of mostly observational and single center studies with highly encouraging results. Patients in the interventional arm A will receive surgery with one of the two approaches or a combination of both, in a one or two-stage method, at the discretion of the treating surgeon. Depending on local standards one or both of the above might be combined with liposuction to the affected arm in a one or two-stage approach as well.<br>|
| Active Comparator: Group B: Conservative Complex Physical Decongestion Therapy (control group)<br>CDT (Conservative Complex Physical Decongestion Therapy) will be performed as in usual care, following the pragmatic study design. The key aspects like frequency of lymphatic drainage, time when lymphatic drainage is performed and time and class of compressive garments are used will be documented. CDT incorporates two stages of treatment. The first treatment phase (intensive phase) entails skincare, MLD (manual lymphatic drainage), exercises aimed at improvement of mobility/range of motion in the shoulder, elbow or wrist joints, and compression therapy through bandaging. Most patients undergo this phase shortly after the diagnosis of LE. CDT in the second phase (maintenance phase) aims to maintain the achieved limb volume/ circumference reduction through compression with therapeutic elastic compression garment for the arm. Skincare, mobility exercises and MLD is continued in this phase if needed | Procedure: Conservative Complex Physical Decongestion Therapy<br>* Patients randomized to the control arm will receive CDT (Conservative Complex Physical Decongestion Therapy), which currently is considered as the best available standard of care. For this, patients will be referred to one of the dedicated LE (physical/skin) therapy clinics, if not already treated by one, according to their place of residence for continuation of standard conservative therapy. Recommendations to the procedures and treatment frequency of the conservative therapy will be made, but CDT will be done at the discretion of the treating physiotherapist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life Questionnaire (Lymph-ICF-UL) | One of the most widely used PRO (patient reported outcome) instruments in chronic BCRL (breast cancer related lymphedema) is the LYMPH-ICF-UL-Questionnaire (Lymphedema Functioning Disability and health questionnaire for upper limb lymphedema), a rigorously developed and validated PRO instrument specific to BCRL. This questionnaire assesses the impairments in function, activity limitations and participation restrictions of patients with upper LE (limb lymphedema). It is a validated questionnaire, consisting of 29 items (questions) across five different domains. Each item is scored on a VAS (visual analog scale) ranging from 0 to 10. The total score on the LYMPH-ICF is equal to the sum of the item scores divided by the total number of answered items. A higher score on the Lymph-ICF indicates a greater impact on the functioning in daily life related to upper limb LE. | two time assessment at baseline and 15 month after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life Questionnaire (Lymph-ICF-UL) | One of the most widely used PRO (patient reported outcome) instruments in chronic BCRL (breast cancer related lymphedema) is the LYMPH-ICF-UL-Questionnaire (Lymphedema Functioning Disability and health questionnaire for upper limb lymphedema), a rigorously developed and validated PRO instrument specific to BCRL. This questionnaire assesses the impairments in function, activity limitations and participation restrictions of patients with upper LE (limb lymphedema). It is a validated questionnaire, consisting of 29 items (questions) across five different domains. Each item is scored on a VAS (visual analog scale) ranging from 0 to 10. The total score on the LYMPH-ICF is equal to the sum of the item scores divided by the total number of answered items. A higher score on the Lymph-ICF indicates a greater impact on the functioning in daily life related to upper limb LE. | 13 time assessment up to 10 years after randomization | 
| Change in Quality of Life Questionnaire (LYMPH-Q) | The Lymph-Q Upper Extremity Module is a new PROM (patient-reported outcome measure) developed to assess patient reported outcomes of BCRL in a concept-driven approach. The complete questionnaire contains 68 questions covering the patient-relevant topics Health-related quality of life (arm appearance, arm function, arm symptoms, psychological), experience of care (information), and treatment (arm sleeve). | 15 time assessment up to 10 years after randomization | 
| Change in Quality of Life Questionnaire (EuroQol EQ-5D-5L) | The 5-level EQ-5D version (EQ-5D-5L) consists of the EQ-5D descriptive system that comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions (5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems) resulting in a 1-digit number that expresses the level for that dimension. The digits for each dimension can be combined into a 5-digit number that describes the patient's health state. | 15 time assessment up to 10 years after randomization | 
| Change in Pain score (visual analog scale) | The pain score consists of a VAS (visual analog scale) ranging from 0 (i.e. no pain) to 10 (i.e. worst pain). The VAS was published by the Yale University | 7 time assessment up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphatic surgery, breast cancer related lymphedema, sentinel lymph node biopsy, axillary lymph node dissection, manual lymphatic drainage, conservative complex physical decongestion therapy