{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:01:33Z","timestamp":1790402493863,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape. Methods: This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien\u2013Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). Results: A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group (p = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group (p = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group (p = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group (p = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS (p = 0.01) and DSS (p = 0.007) but not local DFS (p = 0.13) and distant DFS (p = 0.21). Conclusions: Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.<\/jats:p>","DOI":"10.3390\/jpm14050442","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T05:28:06Z","timestamp":1713850086000},"page":"442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Isolated Limb Perfusion and Immunotherapy in the Treatment of In-Transit Melanoma Metastases: Is It a Real Synergy?"],"prefix":"10.3390","volume":"14","author":[{"given":"Marco","family":"Rastrelli","sequence":"first","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Russano","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-3971","authenticated-orcid":false,"given":"Francesco","family":"Cavallin","sequence":"additional","affiliation":[{"name":"Independent Statistician, 36020 Solagna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-8014","authenticated-orcid":false,"given":"Paolo","family":"Del Fiore","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Pacilli","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), School of Medicine, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Di Prata","sequence":"additional","affiliation":[{"name":"Surgery Department, San Martino Hospital, 32100 Belluno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo Riccardo","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Vecchiato","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-2594","authenticated-orcid":false,"given":"Luigi","family":"Dall\u2019Olmo","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Mocellin","sequence":"additional","affiliation":[{"name":"Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Balch, C.M., Atkins, M.B., Garbe, C., Gershenwald, J.E., Halpern, A.C., Kirkwood, J.M., McArthur, G.A., Thompson, J.F., and Sober, A.J. (2020). Cutaneous Melanoma, Springer.","DOI":"10.1007\/978-3-319-46029-1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1097\/CMR.0000000000000740","article-title":"The role of regional chemotherapy for advanced limb melanoma in the era of potentially effective systemic therapies","volume":"31","author":"Read","year":"2021","journal-title":"Melanoma Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s11912-022-01216-0","article-title":"Management of In-Transit Metastases","volume":"24","author":"Queiroz","year":"2022","journal-title":"Curr. Oncol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1097\/00000658-195810000-00009","article-title":"Chemotherapy of cancer: Regional perfusion utilizing an extracorporeal circuit","volume":"148","author":"Creech","year":"1958","journal-title":"Ann. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1097\/01.sla.0000146147.89667.ed","article-title":"One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases","volume":"240","author":"Brunstein","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1634\/theoncologist.2009-0325","article-title":"Isolated limb perfusion for malignant melanoma: Systematic review on effectiveness and safety","volume":"15","author":"Ferrandiz","year":"2010","journal-title":"Oncologist"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sevilla-Ortega, L., Ferr\u00e1ndiz-Pulido, L., Palaz\u00f3n-Carri\u00f3n, N., \u00c1lamo de la Gala, M.d.C., de Toro-Salas, R., Garnacho-Montero, J., Marcos-Rodr\u00edguez, J.A., Agudo Mart\u00ednez, A., Araji-Tiliani, O., and Calvo-Mor\u00f3n, M.C. (2021). Role of Isolated Limb Perfusion in the Era of Targeted Therapies and Immunotherapy in Melanoma. A Systematic Review of The Literature. Cancers, 13.","DOI":"10.3390\/cancers13215485"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S356","DOI":"10.1245\/s10434-015-4856-x","article-title":"Isolated Limb Perfusion with Melphalan and Tumour Necrosis Factor \u03b1 for In-Transit Melanoma and Soft Tissue Sarcoma","volume":"22","author":"Smith","year":"2015","journal-title":"Ann. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.soc.2005.12.004","article-title":"Isolated limb perfusion in regional melanoma","volume":"15","author":"Noorda","year":"2006","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1245\/s10434-010-1104-2","article-title":"Long-term results of melphalan-based isolated limb perfusion with or without low-dose TNF for in-transit melanoma metastases","volume":"17","author":"Rossi","year":"2010","journal-title":"Ann. Surg. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ejca.2018.04.014","article-title":"The effect of age on outcomes after isolated limb perfusion for advanced extremity malignancies","volume":"100","author":"Smith","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1245\/s10434-017-5803-9","article-title":"Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients","volume":"24","author":"Madu","year":"2017","journal-title":"Ann. Surg. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1097\/CMR.0000000000000177","article-title":"Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases","volume":"25","author":"Deroose","year":"2015","journal-title":"Melanoma Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1200\/JCO.2005.05.5152","article-title":"Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020","volume":"24","author":"Cornett","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1097\/00008390-199910000-00009","article-title":"Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: A multicentre randomized phase II study","volume":"9","author":"Eggermont","year":"1999","journal-title":"Melanoma Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/jso.23552","article-title":"Isolated limb perfusion for in-transit melanoma metastases: Melphalan or TNF-melphalan perfusion?","volume":"109","author":"Hoekstra","year":"2014","journal-title":"J. Surg. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1200\/JCO.1998.16.9.2906","article-title":"Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: Results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593","volume":"16","author":"Koops","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1056\/NEJMoa1408868","article-title":"Combined vemurafenib and cobimetinib in BRAF-mutated melanoma","volume":"371","author":"Larkin","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1056\/NEJMoa1406037","article-title":"Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma","volume":"371","author":"Long","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejca.2022.03.041","article-title":"The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases\u2014A multicenter cohort study","volume":"169","author":"Holmberg","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e000440","DOI":"10.1136\/jitc-2019-000440","article-title":"Efficacy of immune checkpoint inhibitors for in-transit melanoma","volume":"8","author":"Tie","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/jso.25400","article-title":"A systematic review and meta-analysis of locoregional treatments for in-transit melanoma","volume":"119","author":"Read","year":"2019","journal-title":"J. Surg. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.ejso.2022.01.027","article-title":"Isolated limb perfusion for locally advanced melanoma in the immunotherapy era","volume":"48","author":"Davies","year":"2022","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Holmberg, C.-J., Mattsson, J., and Bagge, R.O. (2023). Effects of the Introduction of Modern Immunotherapy on the Outcome of Isolated Limb Perfusion for Melanoma In-Transit Metastases. Cancers, 15.","DOI":"10.3390\/cancers15020472"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1245\/s10434-018-6513-7","article-title":"Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond","volume":"25","author":"Gershenwald","year":"2018","journal-title":"Ann. Surg. Oncol."},{"key":"ref_27","unstructured":"(2024, March 09). Eastern Cooperative Oncology Group (ECOG) System. Available online: https:\/\/ecog-acrin.org\/resources\/ecog-performance-status\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1245\/s10434-006-9040-x","article-title":"Isolated limb perfusion with melphalan and tumor necrosis factor alpha for advanced melanoma and soft-tissue sarcoma","volume":"14","author":"Hayes","year":"2007","journal-title":"Ann. Surg. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0277-5379(82)90235-8","article-title":"Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions","volume":"18","author":"Wieberdink","year":"1982","journal-title":"Eur. J. Cancer Clin. Oncol."},{"key":"ref_30","first-page":"518","article-title":"Proposed classification of complications of surgery with examples of utility in cholecystectomy","volume":"111","author":"Clavien","year":"1992","journal-title":"Surgery"},{"key":"ref_31","unstructured":"R Core Team (2023). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1245\/s10434-018-07143-4","article-title":"Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma","volume":"26","author":"Belgrano","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3109\/02656736.2013.802374","article-title":"Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma","volume":"29","author":"Olofsson","year":"2013","journal-title":"Int. J. Hyperth."},{"key":"ref_34","first-page":"A4741","article-title":"Tumour response after hyperthermic isolated limb perfusion for locally advanced melanoma","volume":"61","author":"Paulsen","year":"2014","journal-title":"Dan. Med. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/jso.22121","article-title":"Isolated limb perfusion with TNF-alpha and melphalan for distal parts of the limb in soft tissue sarcoma patients","volume":"105","author":"Deroose","year":"2012","journal-title":"J. Surg. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1001\/archsurg.140.11.1115","article-title":"Predictors of outcome after hyperthermic isolated limb perfusion: Role of tumor response","volume":"140","author":"Aloia","year":"2005","journal-title":"Arch. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ejca.2021.04.032","article-title":"Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases","volume":"152","author":"Zaremba","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.jss.2021.05.054","article-title":"A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients","volume":"268","author":"Guadagni","year":"2021","journal-title":"J. Surg. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1158\/2326-6066.CIR-17-0356","article-title":"Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade","volume":"6","author":"Ariyan","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Justesen, T.F., Orhan, A., Raskov, H., Nolsoe, C., and G\u00f6genur, I. (2022). Electroporation and Immunotherapy-Unleashing the Abscopal Effect. Cancers, 14.","DOI":"10.3390\/cancers14122876"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/5\/442\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:32:31Z","timestamp":1760106751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/5\/442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,23]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["jpm14050442"],"URL":"https:\/\/doi.org\/10.3390\/jpm14050442","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,23]]}}}