{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:07:09Z","timestamp":1788966429317,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Urothelial carcinoma predominantly affects older patients, who often exhibit frailty, comorbidities, renal impairment, and reduced physiological reserve. We evaluated overall survival (OS) and progression-free survival (PFS) with first-line immune-based strategies in patients aged \u226565 years with advanced or metastatic urothelial carcinoma. The aim was to characterize treatment effects within this age-defined subgroup, not to determine whether age modifies treatment efficacy compared with younger patients. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized trials published from January 2015 to May 2026 reporting age-specific survival outcomes. Combination regimens were compared with platinum-based chemotherapy using random-effects models. Results: Combination strategies improved OS versus chemotherapy (HR 0.79, 95% CI 0.64\u20130.96), although heterogeneity was substantial (I2 = 69.7%) and the prediction interval crossed the null (0.48\u20131.27). Class-specific HRs were 0.56 (95% CI 0.26\u20131.20) for ADC plus ICI, 0.85 (0.77\u20130.95) for ICI plus chemotherapy, and 0.91 (0.34\u20132.42) for dual-checkpoint inhibition. PFS favoured experimental treatment but remained imprecise (HR 0.54, 95% CI 0.27\u20131.08; I2 = 89.5%). Excluding ADC plus ICI trials attenuated the OS effect (HR 0.88, 95% CI 0.80\u20130.96), indicating that the pooled estimate was influenced by these trials. ICI monotherapy did not improve OS. Conclusions: First-line immune-based combinations improved survival in selected patients aged \u226565 years, but benefit varied across treatment classes and should not be considered uniform across regimens. These findings do not establish whether age modifies treatment efficacy. Age-specific safety data were insufficient to define the benefit\u2013risk profile of individual strategies.<\/jats:p>","DOI":"10.3390\/cancers18182924","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:02:48Z","timestamp":1788962568000},"page":"2924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First-Line Immune Checkpoint Inhibitors in Older Patients with Advanced Urothelial Carcinoma: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8943-2963","authenticated-orcid":false,"given":"Dalila","family":"Incognito","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. Barresi\u201d, School of Specialization in Medical Oncology, University of Messina, 98122 Messina, Italy"},{"name":"Translational Molecular Medicine and Surgery, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6435-8522","authenticated-orcid":false,"given":"Andrea","family":"D\u2019Arienzo","sequence":"additional","affiliation":[{"name":"Oncology Unit, \u201cSanta Maria Delle Grazie\u201d Hospital, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0684-6683","authenticated-orcid":false,"given":"Sergio","family":"Facchini","sequence":"additional","affiliation":[{"name":"Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9244-8263","authenticated-orcid":false,"given":"Chiara","family":"Barraco","sequence":"additional","affiliation":[{"name":"Oncology Unit, \u201cSanta Maria Delle Grazie\u201d Hospital, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0924-2163","authenticated-orcid":false,"given":"Antonio","family":"Picone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8598-0323","authenticated-orcid":false,"given":"Antonella","family":"Nicastro","sequence":"additional","affiliation":[{"name":"Oncology Unit, \u201cSanta Maria Delle Grazie\u201d Hospital, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-3126","authenticated-orcid":false,"given":"Giuliana","family":"Ciappina","sequence":"additional","affiliation":[{"name":"Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Applied Biology and Experimental Medicine, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giordana","family":"Di Mauro","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. Barresi\u201d, School of Specialization in Medical Oncology, University of Messina, 98122 Messina, Italy"},{"name":"Translational Molecular Medicine and Surgery, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-3572","authenticated-orcid":false,"given":"Antonio","family":"Ieni","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adult and Childhood \u201cGaetano Barresi\u201d, University of Messina, 98121 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"},{"name":"Division of Medical Oncology, \u201cG. Martino\u201d University Hospital, University of Messina, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Facchini","sequence":"additional","affiliation":[{"name":"Oncology Unit, \u201cSanta Maria Delle Grazie\u201d Hospital, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10732748231152322","DOI":"10.1177\/10732748231152322","article-title":"Impact of age at diagnosis of bladder cancer on survival: A Surveillance, Epidemiology, and End Results-based study 2004\u20132015","volume":"30","author":"Lin","year":"2023","journal-title":"Cancer Control"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.eururo.2023.03.029","article-title":"Epidemiology of bladder cancer in 2023: A systematic review of risk factors","volume":"84","author":"Jubber","year":"2023","journal-title":"Eur. 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