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][1]) 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. ### Competing Interest Statement NL: Scientific advisor and consultant for Medical Microinstruments (MMI) Other authors: None declared. ### Clinical Trial ID: [NCT05890677][1] ### Funding Statement The funding of this study is provided by Science Foundation Investigator initiated clinical trials call 2022 (33IC30205817/1) as well as a Jubilee Award from Rising Tide Foundation and Krebsforschung Schweiz. The study protocol has undergone peer-review by the funding bodies. The financial support provided for this study did not influence its conceptualization, nor will it impact the study's execution, data analysis, interpretation, or the decision-making process regarding the submission of findings. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Ethikkommission Nordwest- und Zentralschweiz gave ethical approval for this work (202300733, 22.05.2023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Metadata describing the type, size and content of the datasets will be shared along with the study protocol and case report forms on public repositories adhering to the FAIR principles. Researchers who wish to reuse data may submit a project synopsis at dkf.unibas.ch/contact. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05890677&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F13%2F2024.02.13.24302744.atom