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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.

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.

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

Lymphaticovenous anastomosis

Sham surgery involves the process of surgery, including local anesthesia and incisions, but no LVA is made.

Sham surgery

Alieske Kleeven, MSc

Stefan Hummelink, MSc, PhD

Yasmine Jonis, MSc

Shan Shan Qiu Shao, MSc, PhD

Dalibor Vasilic, MSc, PhD

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.

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.

Multicenter, double-blind, randomized sham-controlled trial

The researcher, research nurse and patients will be blinded. The blinded researcher and research nurse will perform the measurements during follow-up, as well as the assessment of the outcomes. Due to the nature of the study, the surgeon performing both procedures cannot be blinded.

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

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

The results will be published under an Open Access license, making them accesible to everyone at all times. Requests for sharing individual participant data (IPD) will be evaluated on a case-by-case basis, assessing them for suitable research purposes following the trial's completion.

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.

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.

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.

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.).

All postoperative complications for both treatment groups will be recorded to monitor safety. SAEs will be directly reported to the sponsor.

The patency of the LVAs will be measured with ICG lymphography

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema	NCT06082349	Lymphedema, Sec... Lymphedema of U... Lymphedema, Low... Lymphedema Arm Lymphedema of L...	Lymphaticovenou... Sham surgery	18 Years -	Maastricht University Medical Center
The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema	NCT06082349	Lymphedema, Sec... Lymphedema of U... Lymphedema, Low... Lymphedema Arm Lymphedema of L...	Lymphaticovenou... Sham surgery	18 Years -	Maastricht University Medical Center

Spots Global Cancer Trial Database for lymphaticovenous anastomosis