The LYMPH Trial - Microsurgical Versus Conservative Treatment of Chronic Breast Cancer Associated Lymphedema

Official title

The LYMPH Trial - Comparing Microsurgical With Conservative Treatment of Chronic Breast Cancer Associated Lymphedema: Study Protocol of a Pragmatic Randomized International Multicentre Superiority Trial

Overview

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)

Detailed description

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.

Interventions

• Procedure Surgical Intervention
  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 singl
• Procedure Conservative Complex Physical Decongestion Therapy
  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

Primary outcome measures

• Change in Quality of Life Questionnaire (Lymph-ICF-UL) [Time frame: two time assessment at baseline and 15 month after randomization]

Secondary outcome measures (11)

• Change in Quality of Life Questionnaire (Lymph-ICF-UL) [Time frame: 13 time assessment up to 10 years after randomization]
• Change in Quality of Life Questionnaire (LYMPH-Q) [Time frame: 15 time assessment up to 10 years after randomization]
• Change in Quality of Life Questionnaire (EuroQol EQ-5D-5L) [Time frame: 15 time assessment up to 10 years after randomization]
• Change in Pain score (visual analog scale) [Time frame: 7 time assessment up to 2 years after randomization]
• Assessment of (serious) adverse events [Time frame: 7 time assessment up to 2 years after randomization]
• Assessment of surgical complications [Time frame: 7 time assessment up to 2 years after randomization]
• Assessment of lymphangitic events (erysipelas) [Time frame: 7 time assessment up to 2 years after randomization]
• Assessment of arm volume [Time frame: 15 time assessment up to 10 years after randomization]
• Assessment of the frequency of lymphatic drainage [Time frame: 15 time assessment up to 10 years after randomization]
• Assessment of the burden on patients [Time frame: 9 time assessment up to 10 years after randomization]
• Assessment of the economics (for Switzerland) [Time frame: 9 time assessment up to 10 years after randomization]

Eligibility criteria

Inclusion criteria

• Written informed consent.
• Patients ≥ 18 years of age.
• Former diagnosis of breast cancer.
• Clinical diagnosis of chronic Breast Cancer-Related Lymphedema (BCRL) (persisting for more than 3 months) classified as ≥ Stage 1, according to ISL.
• Minimum of 3 months Conservative Complex Physical Decongestion Therapy.
• Ability to complete the QoL questionnaires.
• Willingness to undergo surgery.

Exclusion criteria

• No indication for lymphatic surgery according to clinical judgment of the treating surgeon (individual reasons will be specifically documented).
• Primary congenital Lymphedema or non-BCRL.
• Previous surgical BCRL treatment on the side intended for intervention.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 9 centers

• BG Universitätsklinikum Bergmannsheil Bochum — Bochum
• Sana Kliniken Düsseldorf — Düsseldorf
• Uniklinikum Erlangen — Erlangen
• KEM Evang. Kliniken Essen-Mitte — Essen
• BG Klinik Frankfurt am Main — Frankfurt
• Universitätsklinikum Freiburg, Klinik für Plastische und Handchirurgie — Freiburg im Breisgau
• BG Klinik Ludwigshafen — Ludwigshafen am Rhein
• Klinikum Nürnberg — Nuremberg
• … and 1 more center

Switzerland · 6 centers

• University Hospital Basel — Basel
• Centre Hospitalier Universitaire Vaudois — Lausanne
• Kantonsspital Aarau — Aarau
• Hôpitaux Universitaires de Genève — Geneva
• Kantonsspital Winterthur — Winterthur
• Klinik für Plastische, Rekonstruktive, Aesthetische und Handchirurgie — Zurich

United States · 4 centers

• Yale School of Medicine — New Haven
• Harvard Medical School — Boston
• Washington University School of Medicine in St. Louis — St Louis
• Mayo Clinic — Rochester

Austria · 2 centers

• University Clinics St.Pölten — Sankt Pölten
• Krankenhaus Göttlicher Heiland GmbH — Vienna

Belgium · 2 centers

• Brussels University Hospital — Brussels
• University of Ghent — Ghent

Canada · 2 centers

• McGill University, Royal Victoria Hospital — Montreal
• University of British Columbia, Gordon and Leslie Diamond Health Care Centre — Vancouver

Italy · 2 centers

• Policlinico Tor Vergata: Fondazione PTV — Rome
• Policlinico Universitario Fondazione Agostino Gemelli — Rome

Sweden · 2 centers

• Karolinska Institutet, K1 Molekylär medicin och kirurgi — Stockholm
• Department of Plastic and Reconstructive Surgery Uppsala University Hospital — Uppsala

Brazil · 1 center

• Hospital Erasto Gaertner — Paraná

Greece · 1 center

• Papageorgiou Hospital of Thessaloniki — Thessaloniki

Israel · 1 center

• Rambam Health Clinic, ISR — Haifa

Netherlands · 1 center

• Maastricht University Medical Center — Maastricht

Romania · 1 center

• Institute of Oncology ''Prof. Dr. Ion Chiricuță'' of Cluj-Napoca — Cluj-Napoca

Spain · 1 center

• Hospital de la Santa Creu i Sant Pau — Barcelona

Taiwan · 1 center

• Kaohsiung Chang Gung Memorial Hospital — Kaohsiung City

Publications

• Kappos EA, Haas Y, Schulz A, Peters F, Savanthrapadian S, Stoffel J, Katapodi MC, Mucklow R, Kaiser B, Haumer A, Etter S, Cattaneo M, Staub D, Ribi K, Shaw J, Handschin TM, Eisenhardt S, Visconti G, Franceschini G, Scardina L, Longo B, Vetter M, Zaman K, Plock JA, Scaglioni M, Gonzalez EG, Quildrian SD, Felmerer G, Mehrara BJ, Ayala JM, Pons G, Kalbermatten DF, Sacks JM, Halle M, Muntean MV, Taylo PMID 39961719

Identifiers

NCT: NCT05890677 · 2023-00733; mu21kappos

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗