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

Introduction: Up to one fifth of breast cancer survivors will develop chronic breast cancer-related lymphedema (BCRL). To date complex physical decongestion therapy (CDT) is the gold standard of treatment. However, it is mainly symptomatic and often ineffective in preventing BCRL progression. Lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) are microsurgical techniques that aim to restore lymphatic drainage. This international randomized trial aims to evaluate advantages of microsurgical interventions plus CDT vs CDT alone for BCRL treatment. Methods and analysis: The effectiveness of LVA and/or VLNT in combination with CDT, which may be combined with liposuction, versus CDT alone will be evaluated in routine practice across the globe. BCRL patients will be randomly allocated to either surgical or conservative therapy. The primary endpoint of this trial is the patient-reported quality of life (QoL) outcome lymphedema-specific QoL, which will be assessed 15 months after randomization. Secondary endpoints are further patient reported outcomes (PROs), arm volume measurements, economic evaluations, and imaging at different timepoints. A long-term follow-up will be conducted up to 10 years after randomization. A total of 280 patients will be recruited in over 20 sites worldwide. Ethics and dissemination: This study will be conducted in compliance with the Declaration of Helsinki and the ICH-GCP E6 guideline. Ethical approval has been obtained by the lead Ethics Committee Ethikkommission Nordwest- und Zentralschweiz (2023-00733, 22.05.2023). Ethical approval from local authorities will be sought for all participating sites. Regardless of outcomes, the findings will be published in a peer-reviewed medical journal. Metadata detailing the dataset type, size and content will be made available, along with the full study protocol and case report forms, in public repositories in compliance with the FAIR principles. Trial registration: The trial is registered at https://clinicaltrials.gov (ID: NCT05890677) and on the Swiss National Clinical Trials Portal (SNCTP, BASEC project-ID: 2023-00733) at https://kofam.ch/de. The date of first registration was 23.05.2023. Strengths and limitations of this study: -This is a pragmatic, randomized, international, multicentre, superiority trial, which has the potential to impact the clinical practice of therapy for patients with chronic BCRL. -The pragmatic design will reflect clinical practice, thereby directly providing applicable results. -A comprehensive long-term follow-up will be conducted, extending up to 10 years, to assess and analyze long-term outcomes. -Patient advocates were intensely involved throughout the trial design. -To date, no multicentric RCT has compared microsurgical techniques (LVA and VLNT) possibly combined with liposuction with CDT alone, thereby limiting access of the patients to available treatment options. -The assessment of treatment quality (both conservative and surgical) at various sites is challenging due to potential variations resulting from the pragmatic design, which may influence the outcomes of the study.