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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.

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

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.

Surgical Intervention

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.

Conservative Complex Physical Decongestion Therapy

Elisabeth Kappos, PD Dr. med.

Andrea Pusic, Prof. Dr. med.

Erin Taylor, Dr. med.

Justin M. Sacks, Prof. Dr.

Eduardo Gonzalez, Dr. med.

Madeleine Mischitz, Dr.

Matthias Rab, Dr.

Phillip Blondeel, Prof. Dr.

Anne Karoline Groth, Dr. med.

Josh Vorstenbosch, MD PhD FRCSC

Anna Towers, Dr.

Kathryn V. Isaac, Asst. Prof. Dr.

Katrin Seidenstücker, Dr.

Raymund Horch, Prof. Dr.

Björn Behr, Prof. Dr. med.

Christoph Hirche, Prof. Dr. med.

Steffen Eisenhardt, Prof. Dr. med.

Gunther Felmerer, Prof. Dr. Med.

Ulrich Kneser, Prof. Dr. med.

Lukas Prantl, Prof. Dr. med.

Norbert Heine, Dr. med.

Efterpi Demiri, Prof. Dr. med.

Dimitrios Dionysiou, Dr. med.

Benedetto Longo, Dr. med.

Giuseppe Visconti, Dr. med.

Shao Shan Qiu, Dr.

Maximilian Vlad Muntean, Dr. med.

Gemma Pons, Dr.

Martin Halle, Dr. med.

Maria Mani, Dr. med.

Yves Harder, Prof. Dr. med.

Jan Plock, Prof. Dr. med.

Daniel Kalbermatten, Prof. Dr. med.

Pietro di Summa, PD Dr. med.

Florian Jung, Dr. med.

Nicole Lindenblatt, Prof. Dr. med.

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)

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.

Pragmatic, randomized, international, multicenter superiority trial

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

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

The LYMPH-ICF-UL-Questionnaire (Lymphedema Functioning Disability and health questionnaire for upper limb lymphedema) is a widely used, rigorously developed, and validated patient-reported outcome (PRO) instrument for chronic breast cancer-related lymphedema. It assesses the impairments in function, activity limitations and participation restrictions of patients with upper limb lymphedema (LE). 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. This questionnaire helps determine if lymphatic surgery improves quality of life and patient satisfaction compared to conservative therapy.

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).

The questionnaire is used to determine whether lymphatic surgery provides better quality of life and patient satisfaction compared to conservative therapy.

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.

The questionnaire is used to determine whether lymphatic surgery provides better quality of life and patient satisfaction compared to conservative therapy.

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.

It is used to determine whether lymphatic surgery provides better quality of life and patient satisfaction compared to conservative therapy.

Safety is assessed via a rigorous and detailed examination of (serious) adverse events.

For the surgery group only, safety is assessed via a rigorous and detailed examination of complications of surgery. Grading is according to the modified classification of Clavien-Dindo, categorizing them into five levels ranging from minor deviations to life-threatening events.

The assessment will cover both surgical stages in case of two-staged lymphedema (LE) surgery.

The frequency of lymphangitic events (erysipelas) is closely monitored. Lymphangitic events are defined as skin infections at the lymphedema site(s) which can be treated with oral or intravenous antibiotics. The type of antibiotic given, the application form, type of hospital stay and necessity of a surgery will be assessed.

Arm volume is determined by measuring the circumference of each arm at 10 cm intervals from the wrist to the axilla. The volume of each arm segment is calculated using a truncated cone model, and percentage edema volume is derived from the volume difference between the affected and unaffected arms. Both relative (relative to the unaffected arm) and absolute (volume reduction of the affected arm at the next measurement) volume change are calculated, corrected for BMI and differences between dominant and non-dominant arms.

The frequency of lymphatic drainage before the start of the study and between the study's follow-up visits is assessed.

To determine the burden on patients, the total number of breast-/arm-related operative procedures including the second stage intervention in case of two-staged surgery until the end of the 24-month follow-up is assessed by screening patient charts, interviewing patients during follow-up and corresponding with the family practitioners if indicated.

To determine the burden on patients, the length of lymphedema-related hospital stay(s) is recorded following the randomization until discharge and the cumulative number of days the patient is hospitalized until two years after randomization. This information is obtained from the hospital patient record database where available or manual chart review and from interviews of the patients during follow-up.

To determine the burden on patients, the number of LE-related outpatient visits including visits at family doctor, study site, emergency room or other specialist physicians is assessed from randomization until the 24 months follow-up.

To determine the burden on patients, the lymphedema-related change in the ability to work is assessed by the number of missed working days and hours until the 24 months follow-up and extended follow-up.

To perform an economic evaluation, information regarding the condition-related medical resource use, healthcare costs, indirect costs, productivity losses, and incremental cost-effectiveness (quality-adjusted life-years) is collected.

The information is based on the responses to the EQ-5D-5L questionnaire, the questions asked under burden on patients, and on other medical resource information recorded in the trial primarily for clinical purposes, at the respective visits. In addition, direct extraction of breast cancer-related lymphedema-related in- and outpatient costs, and corresponding key resource use parameters, are collected from the hospital administration systems of the participating Swiss sites, once at the 2 year follow-up visit .

Spots Global Cancer Trial Database for conservative complex physical decongestion therapy