{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T05:08:52Z","timestamp":1791954532608,"version":"4.3.4"},"reference-count":53,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"ZonMw Veelbelovende Zorg","award":["80-86200-98-26020"],"award-info":[{"award-number":["80-86200-98-26020"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2024,4,2]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cancer-related lymphoedema is one of the most debilitating side-effects of cancer treatment with an overall incidence of 15.5%. Patients may suffer from a variety of symptoms, possibly resulting in a diminished health-related quality of life (HRQoL). A microsurgical technique known as lymphaticovenous anastomosis (LVA) might be a promising treatment option. The objective of this study is to evaluate whether LVA is effective and cost-effective compared with sham surgery in improving the HRQoL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>A multicentre, double-blind, randomised sham-controlled trial conducted in three university hospitals in the Netherlands. The study population comprises 110 patients over the age of 18 years with unilateral, peripheral cancer-related lymphoedema, including 70 patients with upper limb lymphoedema and 40 patients with lower limb lymphoedema. A total of 55 patients will undergo the LVA operation, while the remaining 55 will undergo sham surgery. The follow-up will be at least 24 months. Patients are encouraged to complete the follow-up by explaining the importance of the study. Furthermore, patients may benefit from regular monitoring moments for their lymphoedema. The primary outcome is the HRQoL. The secondary outcomes are the limb circumference, excess limb volume, changes in conservative therapy, postoperative complications, patency of the LVA and incremental cost-effectiveness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study was approved by the Medical Ethical Committee of Maastricht University Medical Center on 20 September 2023 (NL84169.068.23). The results will be presented at scientific conferences and published in peer-reviewed medical journals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06082349\">NCT06082349<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-086226","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T03:45:49Z","timestamp":1713239149000},"page":"e086226","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["The N-LVA Study: effectiveness and cost-effectiveness of lymphaticovenous anastomosis (LVA) for patients with cancer who suffer from chronic peripheral lymphoedema \u2013 study protocol of a multicentre, randomised sham-controlled trial"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct06082349","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06082349","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2905-653X","authenticated-orcid":false,"given":"Alieske","family":"Kleeven","sequence":"first","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Department of Plastic, Reconstructive, and Hand Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7508-8986","authenticated-orcid":false,"given":"Yasmine M J","family":"Jonis","sequence":"additional","affiliation":[{"name":"Department of Plastic, Reconstructive, and Hand Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands"},{"name":"Department of Plastic Surgery, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanneke","family":"Tielemans","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2796-729X","authenticated-orcid":false,"given":"Sander","family":"van Kuijk","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merel","family":"Kimman","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"van der Hulst","sequence":"additional","affiliation":[{"name":"Department of Plastic, Reconstructive, and Hand Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalibor","family":"Vasilic","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hummelink","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan Shan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Plastic, Reconstructive, and Hand Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"2025121509453393000_14.4.e086226.1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41572-019-0072-5","article-title":"Cancer-associated secondary Lymphoedema","volume":"5","author":"Rockson","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"2025121509453393000_14.4.e086226.2","unstructured":"Sleigh BC MB . Lymphedema. StatPearls Publishing, 2023."},{"key":"2025121509453393000_14.4.e086226.3","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.15238"},{"key":"2025121509453393000_14.4.e086226.4","doi-asserted-by":"crossref","DOI":"10.3390\/jcm9103200","article-title":"The quality of life and Psychosocial implications of cancer-related lower-extremity Lymphedema: A systematic review of the literature","volume":"9","author":"Bowman","year":"2020","journal-title":"J Clin Med"},{"key":"2025121509453393000_14.4.e086226.5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.5306\/wjco.v5.i3.241","article-title":"Breast cancer-related Lymphedema: symptoms, diagnosis, risk reduction, and management","volume":"5","author":"Fu","year":"2014","journal-title":"World J Clin Oncol"},{"key":"2025121509453393000_14.4.e086226.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.4899"},{"key":"2025121509453393000_14.4.e086226.7","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1055\/s-0036-1572538","article-title":"Quality of life in patients with breast cancer-related Lymphedema and Reconstructive breast surgery","volume":"32","author":"Penha","year":"2016","journal-title":"J Reconstr Microsurg"},{"key":"2025121509453393000_14.4.e086226.8","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2022.1671","article-title":"Association of lower extremity Lymphedema with physical functioning and activities of daily living among older survivors of colorectal, endometrial, and ovarian cancer","volume":"5","author":"Zhang","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2025121509453393000_14.4.e086226.9","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25458"},{"key":"2025121509453393000_14.4.e086226.10","unstructured":"C B . Treatment of breast cancer-related Lymphedema using combined Autologous breast reconstruction and Autologous lymph node transplantation. In: Aldona J. S , ed. Breast Reconstruction - Current Perspectives and State of the Art Techniques. 2013."},{"key":"2025121509453393000_14.4.e086226.11","doi-asserted-by":"crossref","first-page":"336","DOI":"10.3747\/co.27.7225","article-title":"Cancer-related Lymphedema: clinical pearls for providers","volume":"27","author":"Chaput","year":"2020","journal-title":"Curr Oncol"},{"key":"2025121509453393000_14.4.e086226.12","doi-asserted-by":"publisher","DOI":"10.21037\/gs.2017.11.04"},{"key":"2025121509453393000_14.4.e086226.13","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2020.24373","article-title":"Development and validation of a risk model for breast cancer\u2013related Lymphedema","volume":"3","author":"Kwan","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2025121509453393000_14.4.e086226.14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.41.8574"},{"key":"2025121509453393000_14.4.e086226.15","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.11785"},{"key":"2025121509453393000_14.4.e086226.16","doi-asserted-by":"crossref","DOI":"10.3390\/cancers14225667","article-title":"The prevalence of lower limb and genital Lymphedema after prostate cancer treatment: a systematic review","volume":"14","author":"Clinckaert","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2025121509453393000_14.4.e086226.17","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2407-9-47","article-title":"Risk factors for lower limb Lymphedema after lymph node dissection in patients with ovarian and uterine carcinoma","volume":"9","author":"Tada","year":"2009","journal-title":"BMC Cancer"},{"key":"2025121509453393000_14.4.e086226.18","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.ejso.2020.01.033","article-title":"Risk factors for late-onset lower limb Lymphedema after gynecological cancer treatment: a multi-institutional retrospective study","volume":"46","author":"Yoshihara","year":"2020","journal-title":"Eur J Surg Oncol"},{"key":"2025121509453393000_14.4.e086226.19","doi-asserted-by":"crossref","first-page":"227","DOI":"10.35772\/ghm.2020.01022","article-title":"Lymphedema secondary to Melanoma treatments: diagnosis, evaluation, and treatments","volume":"2","author":"Ari\u00e9","year":"2020","journal-title":"Glob Health Med"},{"key":"2025121509453393000_14.4.e086226.20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ejogrb.2017.02.021","article-title":"Lymphedema after treatment for endometrial cancer - A review of prevalence and risk factors","volume":"211","author":"Lindqvist","year":"2017","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2025121509453393000_14.4.e086226.21","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1080\/0284186X.2021.1905175","article-title":"Factors associated with Melanoma-related limb Lymphoedema","volume":"60","author":"Gjorup","year":"2021","journal-title":"Acta Oncologica"},{"key":"2025121509453393000_14.4.e086226.22","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ijrobp.2018.08.036","article-title":"Timing of Lymphedema after treatment for breast cancer: when are patients most at risk","volume":"103","author":"McDuff","year":"2019","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"2025121509453393000_14.4.e086226.23","first-page":"143","article-title":"Surgical management of Lymphedema","volume":"117","author":"Kareh","year":"2020","journal-title":"Mo Med"},{"key":"2025121509453393000_14.4.e086226.24","doi-asserted-by":"crossref","DOI":"10.3389\/fsurg.2018.00023","article-title":"Supermicrosurgery: history, applications, training and the future","volume":"5","author":"Badash","year":"2018","journal-title":"Front Surg"},{"key":"2025121509453393000_14.4.e086226.25","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-005-0518-5"},{"key":"2025121509453393000_14.4.e086226.26","first-page":"171","article-title":"Replantation and Reconstructive Microvascular surgery. part II","volume":"58","author":"O\u2019Brien","year":"1976","journal-title":"Ann R Coll Surg Engl"},{"key":"2025121509453393000_14.4.e086226.27","first-page":"172","article-title":"Lymphovenous anastomosis for the treatment of Lymphedema: a systematic review of the literature and meta-analysis","volume":"53","author":"Nacchiero","year":"2020","journal-title":"Lymphology"},{"key":"2025121509453393000_14.4.e086226.28","doi-asserted-by":"crossref","DOI":"10.1097\/GOX.0000000000004529","article-title":"Outcomes of Lymphovenous anastomosis for lower extremity Lymphedema: a systematic review","volume":"10","author":"Verhey","year":"2022","journal-title":"Plast Reconstr Surg Glob Open"},{"key":"2025121509453393000_14.4.e086226.29","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1089\/lrb.2017.0067","article-title":"Effect of Lymphaticovenous anastomosis in breast cancer-related Lymphedema: a review of the literature","volume":"16","author":"Cornelissen","year":"2018","journal-title":"Lymphat Res Biol"},{"key":"2025121509453393000_14.4.e086226.30","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/micr.30514","article-title":"Efficacy and safety assessment of Lymphovenous anastomosis in patients with primary and secondary Lymphoedema: A systematic review of prospective evidence","volume":"39","author":"Rosian","year":"2019","journal-title":"Microsurgery"},{"key":"2025121509453393000_14.4.e086226.31","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2019-035337","article-title":"Improving the quality of life of patients with breast cancer-related Lymphoedema by Lymphaticovenous anastomosis (LVA): study protocol of a Multicentre randomised controlled trial","volume":"10","author":"Wolfs","year":"2020","journal-title":"BMJ Open"},{"key":"2025121509453393000_14.4.e086226.32","doi-asserted-by":"crossref","unstructured":"Jonis YMJ , Wolfs JAGN , Hummelink S , et al . The 6 month interim analysis of a randomized controlled trial assessing the quality of life in patients with breast cancer related Lymphedema undergoing Lymphaticovenous anastomosis vs. conservative therapy. Sci Rep 2024;14. doi:10.1038\/s41598-024-52489-3","DOI":"10.1038\/s41598-024-52489-3"},{"key":"2025121509453393000_14.4.e086226.33","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials","volume":"346","author":"Chan","year":"2013","journal-title":"BMJ"},{"key":"2025121509453393000_14.4.e086226.34","doi-asserted-by":"publisher","DOI":"10.2522\/ptj.20130285"},{"key":"2025121509453393000_14.4.e086226.35","doi-asserted-by":"publisher","DOI":"10.2522\/ptj.20100087"},{"key":"2025121509453393000_14.4.e086226.36","unstructured":"NvvDe V. R lymfoedeem . Multidisciplinaire evidence-based Richtlijn. 2014."},{"key":"2025121509453393000_14.4.e086226.37","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25513"},{"key":"2025121509453393000_14.4.e086226.38","unstructured":"HPM V . Oedeem en Oedeemtherapie: Bohn Stafleu Van Loghum. 2011."},{"key":"2025121509453393000_14.4.e086226.39","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1097\/PRS.0b013e3182a4d626","article-title":"A prospective analysis of 100 consecutive Lymphovenous bypass cases for treatment of extremity Lymphedema","volume":"132","author":"Chang","year":"2013","journal-title":"Plast Reconstr Surg"},{"key":"2025121509453393000_14.4.e086226.40","doi-asserted-by":"publisher","DOI":"10.1097\/SAP.0b013e318208fd75"},{"key":"2025121509453393000_14.4.e086226.41","doi-asserted-by":"publisher","DOI":"10.1097\/SAP.0b013e3182275d23"},{"key":"2025121509453393000_14.4.e086226.42","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2010.0020"},{"key":"2025121509453393000_14.4.e086226.43","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8510(90)90421-9"},{"key":"2025121509453393000_14.4.e086226.44","unstructured":"iMTA . iMTA medical consumption questionnaire. 2022. Available: https:\/\/www.imta.nl\/questionnaires\/imcq\/"},{"key":"2025121509453393000_14.4.e086226.45","unstructured":"iMTA . IMTA productivity cost questionnaire. 2023."},{"key":"2025121509453393000_14.4.e086226.46","unstructured":"Hakkaart van Roijen LP , Kanters T . Kostenhandleiding Voor Economische Evaluaties in de Gezondheidszorg: Methodologie en Referentieprijzen - Herziene Versie 2024. Zorginstituut Nederland; 2024."},{"key":"2025121509453393000_14.4.e086226.47","doi-asserted-by":"publisher","DOI":"10.1007\/s11136-011-9903-x"},{"key":"2025121509453393000_14.4.e086226.48","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.jval.2016.01.003","article-title":"Dutch tariff for the five-level version of EQ-5D","volume":"19","author":"M. Versteegh","year":"2016","journal-title":"Value in Health"},{"key":"2025121509453393000_14.4.e086226.49","unstructured":"Richtlijn Voor Het Uitvoeren Van Economische Evaluaties in de Gezondheidszorg - Herziene Versie 2024. Zorginstituut Nederland; 2024."},{"key":"2025121509453393000_14.4.e086226.50","unstructured":"General data protection regulation (GDPR). 2018."},{"key":"2025121509453393000_14.4.e086226.51","unstructured":"Uitvoeringswet Algemene Verordening Gegevensbescherming (UAVG)."},{"key":"2025121509453393000_14.4.e086226.52","unstructured":"WMA DECLARATION OF HELSINKI . Ethical principles for medical research involving human subjects. 2013."},{"key":"2025121509453393000_14.4.e086226.53","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1564608"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-086226","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T17:45:42Z","timestamp":1765820742000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-086226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4,15]]},"published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1136\/bmjopen-2024-086226"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-086226","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]}}}