{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:27:30Z","timestamp":1791462450731,"version":"4.3.4"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) improve recurrence outcomes in stage III melanoma but can cause immune-related adverse events (irAEs) of varying severity. While some studies suggest irAEs correlate with improved survival, findings remain inconsistent. Optimal management of recurrent stage III melanoma after adjuvant ICI therapy is also unclear. Here, we evaluate the impact of irAEs on survival and describe subsequent treatments in patients with recurrent stage III melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and Methods<\/jats:title>\n                    <jats:p>We identified 171 patients with stage III melanoma treated with adjuvant ICIs since 2017. Clinical endpoints included overall survival, progression-free survival, distant metastasis-free survival, melanoma-specific survival, and time-to-irAE, which were analyzed using Kaplan\u2013Meier method, Cox model, and Fine\u2013Gray\u2019s method. Cox model with time-varying covariate modeling addressed immortal-time bias. Subgroup analysis examined survival by irAE type, grade, and treatment resumption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>irAEs occurred in 43.86% of patients, with dermatitis (17.64%), colitis (16.67%), and hypothyroidism (15.69%) the most common. irAE presence did not impact survival outcomes. Thirty-one grade 3+ irAEs occurred, which were linked to increased short-term melanoma-specific mortality. Immune-related hepatitis was associated with higher mortality risk in multivariable modeling. Recurrence or progression occurred in 28.65% of patients, with 38.78% located at a distal site. Among those who started additional medical treatment, 42.86% received dual-checkpoint inhibitor therapy and 14.29% enrolled in clinical trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings do not support an association between irAEs and survival in patients with stage III melanoma. However, specific types of events, particularly hepatitis, may increase mortality. Prospective studies are needed to clarify optimal treatment after recurrence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyaf393","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T13:06:13Z","timestamp":1764162373000},"source":"Crossref","is-referenced-by-count":1,"title":["Immune-related adverse events, survival outcomes, and next steps in patients with stage III melanoma: real-world experience at a National Cancer Institute-designated Comprehensive Cancer Center"],"prefix":"10.1093","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2655-6418","authenticated-orcid":false,"given":"Kevin G","family":"Zablonski","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarred M","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5663-8319","authenticated-orcid":false,"given":"Seunghee","family":"Margevicius","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie N","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-5218","authenticated-orcid":false,"given":"Pingfu","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Seibert","sequence":"additional","affiliation":[{"name":"School of Medicine, Case Western Reserve University , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-2799","authenticated-orcid":false,"given":"Maira A","family":"Bhatty","sequence":"additional","affiliation":[{"name":"School of Medicine, Case Western Reserve University , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mirsky","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Bruno","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Mangla","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S","family":"Hoehn","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke D","family":"Rothermel","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris Y","family":"Sheng","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, University Hospitals Seidman Cancer Center , Cleveland, OH 44106,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"2025121808015874400_oyaf393-B1","doi-asserted-by":"publisher","first-page":"9506","DOI":"10.1200\/JCO.2021.39.15_suppl.9506","article-title":"CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma","volume":"39","author":"Wolchok","year":"2021","journal-title":"J Clin Oncol"},{"key":"2025121808015874400_oyaf393-B2","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.3390\/cancers15041106","article-title":"Immunotherapy in melanoma: recent advances and future directions","volume":"15","author":"Knight","year":"2023","journal-title":"Cancers (Basel)"},{"key":"2025121808015874400_oyaf393-B3","doi-asserted-by":"publisher","first-page":"104808","DOI":"10.1016\/j.critrevonc.2025.104808","article-title":"T cell-mediated mechanisms of immune-related adverse events induced by immune checkpoint inhibitors","volume":"213","author":"Li","year":"2025","journal-title":"Crit Rev Oncol Hematol"},{"key":"2025121808015874400_oyaf393-B4","doi-asserted-by":"publisher","first-page":"e2002","DOI":"10.1002\/onco.13918","article-title":"Real-world clinical and economic outcomes in selected immune-related adverse events among patients with cancer receiving immune checkpoint inhibitors","volume":"26","author":"Zheng","year":"2021","journal-title":"Oncologist"},{"key":"2025121808015874400_oyaf393-B5","doi-asserted-by":"publisher","first-page":"1519082","DOI":"10.3389\/fphar.2025.1519082","article-title":"Immune-related adverse events with PD-1\/PD-L1 inhibitors: insights from a real-world cohort of 2523 patients","volume":"16","author":"Yan","year":"2025","journal-title":"Front Pharmacol"},{"key":"2025121808015874400_oyaf393-B6","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.intimp.2018.08.014","article-title":"Immune-related adverse events from combination immunotherapy in cancer patients: a comprehensive meta-analysis of randomized controlled trials","volume":"63","author":"Zhang","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"2025121808015874400_oyaf393-B7","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1001\/jamaoncol.2016.1051","article-title":"Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review","volume":"2","author":"Friedman","year":"2016","journal-title":"JAMA Oncol"},{"key":"2025121808015874400_oyaf393-B8","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-related adverse events associated with immune checkpoint blockage","volume":"378","author":"Postow","year":"2018","journal-title":"N Engl J Med"},{"key":"2025121808015874400_oyaf393-B9","doi-asserted-by":"publisher","first-page":"102134","DOI":"10.1016\/j.ctrv.2020.102134","article-title":"Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors\u2014a systematic review and meta-analysis","volume":"92","author":"Hussaini","year":"2021","journal-title":"Cancer Treat Rev"},{"key":"2025121808015874400_oyaf393-B10","doi-asserted-by":"publisher","first-page":"633032","DOI":"10.3389\/fonc.2021.633032","article-title":"Association of immune related adverse events with efficacy of immune-checkpoint inhibitors and overall survival in cancers: a systemic review and meta-analysis","volume":"11","author":"Fan","year":"2021","journal-title":"Front Oncol"},{"key":"2025121808015874400_oyaf393-B11","doi-asserted-by":"publisher","first-page":"976224","DOI":"10.3389\/fonc.2022.976224","article-title":"Patients with melanoma treated with immune checkpoint inhibitors who had non-thyroid endocrine and skin immune-related adverse events have better prognosis: a systematic review and meta-analysis","volume":"12","author":"Sun","year":"2022","journal-title":"Front Oncol"},{"key":"2025121808015874400_oyaf393-B12","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1111\/fcp.12966","article-title":"Association between immune-related adverse events and prognosis in patients treated with immune checkpoint inhibitors in melanoma: a surrogacy analysis","volume":"38","author":"Euvrard","year":"2024","journal-title":"Fundam Clin Pharmacol"},{"key":"2025121808015874400_oyaf393-B13","doi-asserted-by":"publisher","first-page":"102452","DOI":"10.1016\/j.ctrv.2022.102452","article-title":"Analysis of the association between prospectively collected immune-related adverse events and survival in patients with solid tumor treated with immune-checkpoint blockers, taking into account immortal-time bias","volume":"110","author":"Kfoury","year":"2022","journal-title":"Cancer Treat Rev"},{"key":"2025121808015874400_oyaf393-B14","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/S1470-2045(15)70122-1","article-title":"Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomized, doubled-blind, phase 3 trial","volume":"16","author":"Eggermont","year":"2015","journal-title":"Lancet Oncol"},{"key":"2025121808015874400_oyaf393-B15","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/S1470-2045(21)00065-6","article-title":"Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG\/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial","volume":"22","author":"Eggermont","year":"2021","journal-title":"Lancet Oncol"},{"key":"2025121808015874400_oyaf393-B16","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/ijc.34462","article-title":"Real-world clinical outcome and safety of adjuvant therapy in stage III melanoma patients: data from two academic Italian institutions","volume":"153","author":"De Falco","year":"2023","journal-title":"Int J Cancer"},{"key":"2025121808015874400_oyaf393-B17","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/01621459.1958.10501452","article-title":"Nonparametric estimation from incomplete observations","volume":"53","author":"Kaplan","year":"1958","journal-title":"J Am Stat Assoc"},{"key":"2025121808015874400_oyaf393-B18","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","article-title":"Regression models and life-tables","volume":"34","author":"Cox","year":"1972","journal-title":"J R Stat Soc Ser B Stat Methodol"},{"key":"2025121808015874400_oyaf393-B19","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A proportional hazards model for the subdistribution of a competing risk","volume":"94","author":"Fine","year":"1999","journal-title":"J Am Stat Assoc"},{"key":"2025121808015874400_oyaf393-B20","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1214\/aos\/1176350951","article-title":"A class of K-sample tests for comparing the cumulative incidence of a competing risk","volume":"16","author":"Gray","year":"1988","journal-title":"Ann Statist"},{"key":"2025121808015874400_oyaf393-B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/CJI.0000000000000300","article-title":"Immune-related adverse events and survival in solid tumors treated with immune checkpoint inhibitors: a systemic review and meta-analysis","volume":"43","author":"Petrelli","year":"2020","journal-title":"J Immunother"},{"key":"2025121808015874400_oyaf393-B22","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1016\/S1470-2045(24)00278-X","article-title":"Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a restrospective multicohort study","volume":"25","author":"Wan","year":"2024","journal-title":"Lancet Oncol"},{"key":"2025121808015874400_oyaf393-B23","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1002\/onco.13740","article-title":"Temporal trends and outcomes among patients admitted for immune-related adverse events: a single-center retrospective cohort study from 2011 to 2018","volume":"26","author":"Molina","year":"2021","journal-title":"Oncologist"},{"key":"2025121808015874400_oyaf393-B24","doi-asserted-by":"publisher","first-page":"3713","DOI":"10.1200\/JCO.24.00191","article-title":"Corticosteroids for immune-related adverse events and checkpoint inhibitor efficacy: analysis of six clinical trials","volume":"42","author":"Verheijden","year":"2024","journal-title":"J Clin Oncol"},{"key":"2025121808015874400_oyaf393-B25","doi-asserted-by":"publisher","first-page":"e2245596","DOI":"10.1001\/jamanetworkopen.2022.45596","article-title":"Association of immune-related adverse events, hospitalization, and therapy resumption with survival among patients with metastatic melanoma receiving single-agent or combination immunotherapy","volume":"5","author":"Watson","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2025121808015874400_oyaf393-B26","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1056\/NEJMoa1802357","article-title":"Adjuvant pembrolizumb versus placebo in resected stage III melanoma","volume":"378","author":"Eggermont","year":"2018","journal-title":"N Engl J Med"},{"key":"2025121808015874400_oyaf393-B27","doi-asserted-by":"publisher","first-page":"114146","DOI":"10.1016\/j.ejca.2024.114146","article-title":"Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma","volume":"207","author":"Luke","year":"2024","journal-title":"Eur J Cancer"},{"key":"2025121808015874400_oyaf393-B28","doi-asserted-by":"publisher","first-page":"4794","DOI":"10.1200\/JCO.23.01136","article-title":"Systemic therapy for melanoma: ASCO guidelines update","volume":"41","author":"Seth","year":"2023","journal-title":"J Clin Oncol"},{"key":"2025121808015874400_oyaf393-B29","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1038\/s41591-023-02498-y","article-title":"Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockage refractory metastatic melanoma: a randomized phase 2 trial","volume":"29","author":"VanderWalde","year":"2023","journal-title":"Nat Med"},{"key":"2025121808015874400_oyaf393-B30","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1245\/s10434-021-10910-5","article-title":"Talimogene laherparepvec (T-VEC) for the treatment of advanced locoregional melanoma after failure of immunotherapy: an international multi-institutional experience","volume":"29","author":"Carr","year":"2022","journal-title":"Ann Surg Oncol"},{"key":"2025121808015874400_oyaf393-B31","doi-asserted-by":"publisher","first-page":"4004","DOI":"10.1158\/1078-0432.CCR-25-0880","article-title":"FDA approval summary: lifileucel for unresectable or metastatic melanoma previously treated with an anti-PD-1-basediImmunotherapy","volume":"31","author":"Hu","year":"2025","journal-title":"Clin Cancer Res"},{"key":"2025121808015874400_oyaf393-B32","author":"Hodi"},{"key":"2025121808015874400_oyaf393-B33","author":"BioAtla"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/advance-article-pdf\/doi\/10.1093\/oncolo\/oyaf393\/65552013\/oyaf393.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/30\/12\/oyaf393\/65552013\/oyaf393.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/30\/12\/oyaf393\/65552013\/oyaf393.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T13:04:41Z","timestamp":1766063081000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/doi\/10.1093\/oncolo\/oyaf393\/8343550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":33,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyaf393","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,11,26]]},"article-number":"oyaf393"}}