The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema

Study Overview
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Brief Summary
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The goal of this randomized controlled trial is to compare the effectiveness and cost-effectiveness of lymphaticovenous anastomosis (LVA) with sham surgery for patients suffering from unilateral cancer-related lymphedema in either the upper or lower extremity. It aims to answer whether LVA is more effective than sham surgery in terms of improvement in Lymph-ICF score. A total of 110 participants will be allocated randomly into two groups at a 1:1 ratio. The first group will receive lymphaticovenous anastomosis (LVA), while the second group will undergo sham surgery.

Detailed Description
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One of the most debilitating side effects of cancer treatment is cancer-related lymphedema (CRL), with an overall incidence of 15.5%. To date, there is no definite cure for lymphedema. Conservative therapy, namely complex decongestive therapy is the golden standard for the treatment. Lymphaticovenous anastomosis (LVA) might be a promising treatment modality for patients with CRL, but available studies are small and the quality is lacking. No large-scale prospective or randomized studies have been published on the efficacy of LVA. The main objective of this randomized controlled trial is to assess whether LVA is more effective than sham surgery in terms of improvement in Lymph-ICF score, volume reduction, reduction of complex decongestive therapy, and cost-effectiveness. The study will take place in three centers in the Netherlands: Maastricht University Medical Center, Radboud University Medical Center, and Erasmus University Medical Center. The patients will be randomly distributed into two groups: the LVA group or the Sham group. Both procedures are performed under local anesthesia. Patients in both groups are subject to minor surgical complications (wound infection, bleeding, wound dehiscence). Special care will be taken to prevent damage to lymphatic vessels in the Sham group, to allow a future LVA operation once the study ends. The follow-up moments will be at 3, 6, 12, 18, and 24 months. Additionally, a subset of patients will partake in an annual extended follow-up, ongoing until the start of the analysis. Each follow-up moment will last 45 minutes in total. The patient also receives two digital questionnaires at each follow-up moment.

Official Title
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Effectiveness and Cost-effectiveness of Lymphaticovenous Anastomosis for Cancer Patients Who Suffer From Chronic Peripheral Lymphedema: a Randomized Controlled Trial

Conditions
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Lymphedema, Secondary, Lymphedema of Upper Limb, Lymphedema, Lower Limb, Lymphedema Arm, Lymphedema of Leg

Intervention / Treatment
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* Procedure: Lymphaticovenous anastomosis
* Procedure: Sham surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treated for cancer and underwent treatment of either axillary or inguinal lymph nodes or radiotherapy; Early stage lymphedema (ISL I-II) in the upper or lower extremity, and diagnosed by lymphoscintigraphy for the lower extremity; Unilateral lymphedema; Viable lymphatic vessels as determined by indocyanine green (ICG)Lymphography (stage II-III); Refractory lymphedema that underwent at least three months of conservative treatment; Informed consent. Exclusion Criteria: History of lymphatic reconstruction in the past 10 years; Late-stage lymphedema of the extremity (ISL classification ≥ II lymphedema) with evident fat deposition and/or fibrosis; Patients with active distant metastases, treated with palliative intent; Patients with the active treatment of primary cancer, i.e. surgery, radiotherapy, and/or chemotherapy. Note: patients receiving adjuvant targeted and/or endocrine treatment are eligible; Edema due to venous insufficiency, evaluated by venous duplex ultrasound of the deep and superficial venous system; Active infection in the lymphedematous extremity; Bilateral lymphedema; Lymphedema present in genital or breast area only; Primary lymphedema; Non-viable lymphatic system as determined by ICG Lymphography (stages IV and V).

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: Multicenter, double-blind, randomized sham-controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lymphaticovenous anastomosis (LVA)<br>Patients in this group will undergo lymphaticovenous anastomosis at one or more locations on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. Incisions will be made at the sites where lymphatic vessels are obstructed, ensuring no harm to the viable part of the lympahtic system. The locations will be determined prior to the surgery using ICG lymphography. The LVA(s) will be made in the subdermal plane with the aid of a surgical microscope. Generally, 1 to 4 LVAs are made. The LVA(s) is made using a surgical microscope and the operation will take approximately 60 to 90 minutes. | Procedure: Lymphaticovenous anastomosis<br>* Lymphaticovenous anastomosis (LVA) involves connecting a lymphatic vessel to a adjacent vein of similar size, thereby facilitating the ouflow of lymphatic fluid in patients suffering from secondary lymphedema<br>* Other names: Lymphatic-venous shunt;|
| Sham Comparator: Sham surgery<br>Patients in this group will undergo sham surgery at one location on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. The locations for LVA surgery will be determined prior to the surgery using ICG lymphography. However, the incision for the sham procedure will be made 2 centimeters medial or lateral to the predetermined site. This is done in order to avoid damage to the lymph vessels as to allow for future LVA surgery. After the incision, no LVA is made. Rather than performing the actual operation, the plastic surgeon will simulate the procedure by applying pressure in the surgical area. To mimic the approximate duration of a regular LVA procedure, the sham operation will take approximately 60 to 90 minutes. | Procedure: Sham surgery<br>* Sham surgery involves the process of surgery, including local anesthesia and incisions, but no LVA is made.<br>* Other names: Surgical placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the Lymph-ICF Score at 12 and 24 months | The Dutch version of the 'Lymphedema Functioning, Disability, and Health (Lymph-ICF) questionnaire is used. There are two versions of the Lymph-ICF; one for the upper extremity and one for the lower extremity. The questionnaires assess the impairments in function, activity limitations, and participation restrictions of patients with lymphedema. It is a validated, disease-specific questionnaire, consisting of items across 5 domains. Each item is scored on a VAS, ranging from 0 to 100. | Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in excess limb volume | The excess limb volume will be measured with BioImpedance Spectroscopy (BIS). With a bioimpedance device, the volume of the extremities can be measured together with the fluid in different compartments of the extremities. | Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 
| Change from baseline in extremity circumference measured by the Upper and Lower Extremity Lymphedema (UEL and LEL) indices | The extremity circumference will be measured using measuring tape according to the fixed measuring points of the UEL- and LEL-indices. The UEL- and LEL-indices are corrected for BMI. | Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 
| Change from baseline in the use of conservative treatment | Discontinuation of conservative treatment, being complex decongestive therapy, will be assessed with a patient diary to record the frequency of treatments received (i.e. skin therapy visits, number of compression garments, etc.). | Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 
| Postoperative complications | All postoperative complications for both treatment groups will be recorded to monitor safety. SAEs will be directly reported to the sponsor. | Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 
| Patency of the LVA | The patency of the LVAs will be measured with ICG lymphography | 12 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 
| Patient costs, QALYs, and incremental cost-effectiveness | Patients costs are registered by the patient in the patient diary. The QALY will be calculated using the EQ-5D-5L questionnaire. The EQ-5D is a questionnaire responsive to changes in health in cancer-patients after the conclusion of treatment. | , lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LVA, Lymphaticovenous anastomosis, Sham surgery, Microsurgery