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

Not Applicable

Recruiting

• Conditions: Lymphedema, Secondary; Lymphedema of Upper Limb; Lymphedema, Lower Limb; Lymphedema Arm; Lymphedema of Leg

• Registration Number: NCT06082349
• Lead Sponsor: Maastricht University Medical Center

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2023-10-03
• Study First Submitted QC: 2023-10-09
• Study First Posted: 2023-10-13
• Study Start: 2023-12-18
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-14
• Last Update Posted: 2024-05-16
• Primary Completion: 2029-03-01
• Study Completion: 2029-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 110

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change from Baseline in the Lymph-ICF Score at 12 and 24 months	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).	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.

Secondary Outcome Measures

Name	Time	Method
Change from baseline in extremity circumference measured by the Upper and Lower Extremity Lymphedema (UEL and LEL) indices	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).	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.
Change from baseline in excess limb volume	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).	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.
Patency of the LVA	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).	The patency of the LVAs will be measured with ICG lymphography
Patient costs, QALYs, and incremental cost-effectiveness	, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).	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.
Change from baseline in the use of conservative treatment	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).	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.).
Postoperative complications	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).	All postoperative complications for both treatment groups will be recorded to monitor safety. SAEs will be directly reported to the sponsor.

Trial Locations

Locations (3)

Radboud University Medical Center; 🇳🇱 Nijmegen, Gelderland, Netherlands

Maastricht University Medical Center; 🇳🇱 Maastricht, Limburg, Netherlands

Erasmus University Medical Center; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands