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

Not Applicable

Not yet recruiting

• Conditions: Lymphedema Arm

• Registration Number: NCT07045831
• Lead Sponsor: University Hospital, Ghent

Brief Summary

Title:

The LYMPH Trial - Microsurgical versus Conservative Therapy for Breast Cancer-Related Lymphedema

Purpose of the Study:

The LYMPH trial compares two treatments for chronic breast cancer-related lymphedema (BCRL)-a condition where fluid builds up and causes swelling, usually in the arm, after breast cancer treatment.

The study is testing whether microsurgical treatments (lymphatic surgery) are more effective than the current conservative therapy (called CDT) in improving quality of life for women with this condition.

What is BCRL? After surgery or radiotherapy for breast cancer, some women develop swelling in the arm (lymphedema) due to damaged lymphatic vessels. This condition can cause pain, heaviness, infections, reduced mobility, and emotional distress. It can also impact daily activities and work life.

Treatment Approaches:

Conservative Decongestion Therapy (CDT):

Includes manual lymphatic drainage (massage), compression bandaging/garments, skin care, and exercise.

It is currently the standard treatment, but it's time-consuming, lifelong, and does not cure the condition.

Microsurgical Treatment:

Lymphovenous Anastomosis (LVA): Creates tiny bypasses between lymphatic vessels and veins to drain excess fluid.

Vascularized Lymph Node Transfer (VLNT): Transfers healthy lymph nodes to the affected area to help restore drainage.

Sometimes liposuction is added to remove built-up fat caused by long-term lymphedema.

These surgeries aim to fix the underlying problem, not just manage the symptoms.

How the Study Works:

Participants:

280 women aged 18 or older who have had breast cancer and suffer from chronic BCRL.

Groups:

Participants are randomly assigned to one of two groups:

Group A: Receives lymphatic surgery. Group B: Continues with CDT.

Follow-Up:

All participants are followed for 2 years, with some follow-up continuing for up to 10 years. They complete questionnaires about quality of life, pain, arm swelling, and daily impact.

Crossover Option:

After the main follow-up (15 months), women in the CDT group may choose to switch to surgical treatment.

Goals and Benefits:

The main goal is to see whether women who have surgery report better quality of life than those who continue with CDT.

Other goals include measuring pain, arm swelling, infections, and the impact on daily life and costs.

This study also hopes to support broader access to lymphatic surgery, as many health insurers currently do not cover it.

Safety and Ethics:

All treatments are already used in clinical practice.

Risks of surgery (like infection or bleeding) are rare and manageable.

The study meets international ethical and safety standards.

Where is the Study Taking Place? The study is being carried out in more than 30 hospitals across Europe, North and South America, and Asia, including Belgium.

Why This Matters:

Chronic BCRL can have a serious impact on daily life and emotional well-being. By comparing two valid treatment options in a high-quality scientific study, this trial hopes to identify the most effective and sustainable way to help women live better after breast cancer.

Detailed Description

Background and Rationale

Breast cancer-related lymphedema (BCRL) is a common and chronic condition resulting from damage to the lymphatic system during breast cancer treatment (e.g., sentinel lymph node biopsy, axillary lymph node dissection, or radiotherapy). It can cause persistent arm swelling, pain, limited mobility, recurrent infections (such as erysipelas), and diminished quality of life (QoL).

The current standard of care, conservative complex physical decongestion therapy (CDT), is purely symptomatic, lifelong, and often ineffective in halting disease progression. CDT includes manual lymphatic drainage (MLD), compression therapy, skin care, and exercise. While beneficial, it does not address the underlying pathophysiology.

In contrast, microsurgical treatments such as lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) aim to restore lymphatic drainage. LVA involves connecting lymphatic vessels to small veins to bypass damaged areas, while VLNT introduces healthy lymph nodes into the affected area to re-establish lymphatic pathways. These procedures are promising but lack robust, multicenter randomized controlled trial (RCT) evidence to support their widespread adoption or reimbursement. The LYMPH Trial is designed to fill this critical evidence gap.

Study Objectives

Primary Objective:

To evaluate whether lymphatic microsurgery (LVA/VLNT ± liposuction), combined with CDT, improves lymphedema-specific QoL compared to CDT alone in patients with chronic BCRL, as measured by the Lymph-ICF-UL questionnaire at 15 months after randomization.

Secondary Objectives:

To assess additional QoL outcomes (LYMPH-Q, EQ-5D-5L)

To compare physical outcomes (e.g., arm volume, frequency of drainage, pain)

To evaluate healthcare use and indirect costs (Switzerland only)

To monitor safety and surgical complications

To explore long-term outcomes over a 10-year follow-up period

Study Design

This is a pragmatic, randomized, international, multicenter, superiority trial with two arms:

Arm A: Surgical treatment (LVA, VLNT, or both ± liposuction) plus standard CDT

Arm B: CDT alone

The trial will enroll 280 adult female patients with chronic BCRL, randomized 1:1. After completing primary endpoint assessments at 15 months, patients in the control group may cross over to receive surgery if desired. This design reflects real-world clinical settings and offers flexibility in intervention delivery while maintaining robust trial standards.

The trial will be conducted across \~35 specialized centers in Europe, North and South America, and Asia. All sites have demonstrated expertise in both CDT and microsurgical lymphedema treatment.

Inclusion Criteria

Female patients ≥18 years with prior breast cancer diagnosis

Clinical diagnosis of chronic BCRL (ISL Stage ≥1), lasting \>3 months

Completion of at least 3 months of CDT

Willingness and eligibility to undergo surgery

Ability to complete study questionnaires

Exclusion Criteria

Primary or non-BCRL lymphedema

Prior surgical treatment for BCRL on the affected side

Contraindications to surgery (per treating surgeon)

Intervention Details

Arm A - Surgery Group:

Patients will undergo microsurgery (LVA and/or VLNT, possibly with liposuction) at the discretion of the operating surgeon. Diagnostic imaging (ICG, MRI lymphangiography) will be used for planning. Surgical flexibility reflects routine clinical practice. CDT continues per standard care postoperatively. All surgical parameters will be documented.

Arm B - CDT Group:

Patients receive ongoing conservative treatment, including MLD, compression therapy, and exercise, as managed by trained physiotherapists. Treatment specifics are not standardized, reflecting usual care conditions.

Patients in Arm B can opt for surgery after 15 months or earlier under defined circumstances (e.g., clinical deterioration). Post-surgery follow-up follows the same visit schedule.

Assessments and Follow-Up

QoL questionnaires: Lymph-ICF-UL (primary), LYMPH-Q, EQ-5D-5L

Physical assessments: Arm volume measurements, pain (VAS)

Frequency of infections (erysipelas), lymphatic drainage

Healthcare use, employment impacts, patient burden

Cost data collection (Switzerland only)

Follow-up visits at baseline, post-op (if applicable), 3, 6, 9, 15, and 24 months

Extended follow-up annually up to 10 years for long-term outcomes

Outcomes

Primary Endpoint:

Lymphedema-specific QoL at 15 months (Lymph-ICF-UL)

Secondary Endpoints:

QoL (LYMPH-Q, EQ-5D-5L), pain (VAS)

Arm volume, drainage frequency

Adverse events, infections, surgical complications

Healthcare and societal burden (e.g., outpatient visits, absences from work)

Cost-effectiveness (Switzerland): QALYs, ICER

Statistical Considerations

A sample size of 280 ensures 252 evaluable participants, allowing 90% power to detect a clinically relevant 10-point difference in Lymph-ICF-UL (SD=21.9, α=0.05). The primary analysis will use ANCOVA, adjusted for baseline QoL and lymphedema stage. Secondary analyses include additional covariates (e.g., center effect, treatment interaction).

Sensitivity analyses will be performed on both the full analysis set (FAS) and per-protocol set (PPS), accounting for potential crossovers and missing data.

Risk-Benefit Assessment

Risks for surgical participants include typical perioperative complications such as infection or bleeding, though these are rare. Expected benefits may include symptom relief, fewer infections, reduced need for CDT, fewer outpatient visits, and improved functional and psychological wellbeing. All procedures used are already standard at experienced centers.

Control group patients will receive best available care (CDT). They are allowed to cross over to surgical treatment after 15 months, or earlier if necessary.

Ethical and Regulatory Oversight

Conducted in accordance with the Declaration of Helsinki, ICH-GCP, Swiss ClinO, and Human Research Act

Risk category A under ClinO Article 61 (interventions are standard practice)

Oversight by independent Data Safety Monitoring Board (DSMB)

Registered with ClinicalTrials.gov (NCT05890677) and Humanforschung Schweiz (BASEC ID: 2023-00733)

Conclusion

The LYMPH Trial addresses a major unmet need by rigorously comparing CDT and surgical treatment in a real-world setting. It focuses on patient-centered outcomes, cost-effectiveness, and long-term results. Its findings will inform clinical decision-making and potentially support policy changes toward broader surgical access for BCRL patients.

Study Timeline

• Status Verified: 2025-06
• Study First Submitted: 2025-06-23
• Study First Submitted QC: 2025-06-23
• Last Update Submitted: 2025-06-23
• Study First Posted: 2025-07-01
• Last Update Posted: 2025-07-01
• Study Start: 2025-08-01
• Primary Completion: 2039-12-31
• Study Completion: 2039-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 280

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Lymphedema-specific Quality of Life (QoL) at 15 months	15 months after randomization	Change in lymphedema-specific quality of life from baseline to 15 months post-randomization, measured using the Lymph-ICF-UL questionnaire (Upper Limb Module). This validated patient-reported outcome measure assesses impairments in function, activity limitations, and participation restrictions due to upper limb lymphedema across five domains: physical function, mental function, household activities, mobility, and life/social activities. Each of the 29 items is scored on a visual analogue scale (0-10), with higher scores indicating greater disability.

Secondary Outcome Measures

Name	Time	Method
Quality of Life - LYMPH-Q	Baseline, 3, 6, 9, 15, 24 months	Patient-reported outcomes using the LYMPH-Q Upper Extremity Module, which includes subscales for symptoms, function, appearance, psychological wellbeing, and care experience.
Frequency of Lymphatic Drainage Sessions	Cumulative at 3, 6, 9, 15, and 24 months	Number of professional lymphatic drainage sessions received per patient during each follow-up interval.
Surgical Complications	From surgery to 24 months (surgical arm only)	Incidence and severity of complications related to surgery (e.g., bleeding, infection, wound healing problems), graded using the Clavien-Dindo classification.
Pain Level	Baseline, 3, 6, 9, 15, 24 months	Self-reported pain in the affected arm using a Visual Analogue Scale (VAS), ranging from 0 (no pain) to 10 (worst pain imaginable).
Arm Volume Measurement	Baseline, 3, 6, 9, 15, 24 months	Change in affected arm volume as measured by standardized circumference measurements and calculated volume formulas.
Quality of Life (Additional Time Points)	3, 6, 9, and 24 months post-randomization	Change in lymphedema-specific QoL measured by the Lymph-ICF-UL at additional follow-up time points (3, 6, 9, 24 months).
Generic Quality of Life - EQ-5D-5L	Baseline, 3, 6, 9, 15, 24 months	Health-related quality of life assessed using the EQ-5D-5L instrument, generating utility values for economic evaluation (QALY calculation).
Burden on Patients	Cumulative from baseline to 24 months	Measures include number of outpatient visits, length of hospital stays, number of operative procedures, and work absences.
Frequency of Lymphangitic Events	From randomization to 24 months	Number of episodes of cellulitis/erysipelas or other lymphangitic infections requiring medical treatment.

Trial Locations

Locations (1)

Universitair Ziekenhuis; 🇧🇪 Gent, Oost-Vlaanderen, Belgium