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This study compares first\u2010line ILI\/ILP, ICI, and TVEC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first\u2010line ILI\/ILP, ICI, or TVEC for unresectable melanoma ITM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 551 patients were treated, with ILI\/ILP (<jats:italic>n<\/jats:italic>\u00a0=\u00a0356), ICI (<jats:italic>n<\/jats:italic>\u00a0=\u00a0125), and TVEC (<jats:italic>n<\/jats:italic>\u00a0=\u00a070) with median follow\u2010up of 5.5 years. Tumor burden was highest with ILI\/ILP and lowest with TVEC (<jats:italic>p<\/jats:italic> =\u00a0.002). Breslow thickness was lowest with TVEC (<jats:italic>p<\/jats:italic> =\u00a0.007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI\/ILP and ICI (<jats:italic>p<\/jats:italic> =\u00a0.01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; <jats:italic>p<\/jats:italic> =\u00a0.029) and a longer local progression\u2010free survival (PFS) (hazard ratio [HR], 0.40; <jats:italic>p<\/jats:italic> =\u00a0.003). ILI\/ILP had shorter local PFS (HR, 1.72; <jats:italic>p<\/jats:italic> =\u00a0.012), PFS (HR, 1.79; <jats:italic>p<\/jats:italic> &lt;\u00a0.001), distant metastasis\u2010free survival (DMFS) (HR, 1.75; <jats:italic>p<\/jats:italic> =\u00a0.014), overall survival (HR, 1.82; <jats:italic>p<\/jats:italic> =\u00a0.009), and melanoma\u2010specific survival (HR, 2.29; <jats:italic>p<\/jats:italic> =\u00a0.004). Stage IIIB disease had longer DMFS (HR, 0.24; <jats:italic>p<\/jats:italic> &lt;\u00a0.001) compared to IIIC\/D.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>TVEC as first\u2010line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI\/ILP and ICI, TVEC should be considered as first\u2010line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.35636","type":"journal-article","created":{"date-parts":[[2024,11,10]],"date-time":"2024-11-10T03:02:12Z","timestamp":1731207732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A comparison of isolated limb infusion\/perfusion, immune checkpoint inhibitors, and intralesional therapy as first\u2010line treatment for patients with melanoma in\u2010transit metastases"],"prefix":"10.1002","volume":"131","author":[{"given":"Danielle K.","family":"DePalo","sequence":"first","affiliation":[{"name":"Department of Cutaneous Oncology Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8121-7559","authenticated-orcid":false,"given":"Michelle M.","family":"Dugan","sequence":"additional","affiliation":[{"name":"Department of Cutaneous Oncology Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syeda Mahrukh Hussnain","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Department of Cutaneous Oncology Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Ollila","sequence":"additional","affiliation":[{"name":"University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4277-8692","authenticated-orcid":false,"given":"Tina J.","family":"Hieken","sequence":"additional","affiliation":[{"name":"Mayo Clinic Comprehensive Cancer Center  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Block","sequence":"additional","affiliation":[{"name":"Mayo Clinic Comprehensive Cancer Center  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2303-3468","authenticated-orcid":false,"given":"Winan J.","family":"van Houdt","sequence":"additional","affiliation":[{"name":"Netherlands Cancer Institute  Amsterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel W. 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