{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:21:55Z","timestamp":1790922115520,"version":"4.1.0"},"reference-count":43,"publisher":"Harborside Press, LLC","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Although intermediate clinical endpoints (ICEs) may expedite completion of randomized controlled trials (RCTs) evaluating perioperative systemic treatments for localized muscle-invasive bladder cancer (MIBC), no validated surrogate for overall survival (OS) has been established. We aimed to assess the surrogacy of pathologic complete response (pCR), pathologic objective response (pOR), and disease-free survival (DFS) for OS.\n                    <jats:bold>Patients and Methods:<\/jats:bold>\n                    We analyzed 4,828 patients with MIBC (cT2\u2013T4N0M0) who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) across 29 European centers (2001\u20132024). The inverse probability of treatment weighting (IPTW) approach was used to adjust for confounding between NAC and RC-only groups. Surrogacy was evaluated using: (1) adapted Prentice criteria to test whether each ICE remained a significant predictor of OS while the treatment effect disappeared in IPTW-adjusted multivariable Cox models; (2) the proportion of treatment effect explained (PTE); and (3) an emulated 2-stage meta-analytic framework to estimate the pseudo\u2013trial-level R\n                    <jats:sup>2<\/jats:sup>\n                    between treatment effects on each ICE and OS across 1,000 replicates of 5 random clusters. The surrogate threshold effect (STE) was calculated for ICEs demonstrating strong surrogacy (R\n                    <jats:sup>2<\/jats:sup>\n                    \u22650.7).\n                    <jats:bold>Results:<\/jats:bold>\n                    Overall, 1,288 (26.7%) patients received NAC followed by RC and 3,540 (73.3%) underwent RC alone. In IPTW-adjusted Cox regression analyses including NAC and each ICE separately, pCR (hazard ratio [HR], 0.32; 95% CI, 0.24\u20130.41;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.001), pOR (HR, 0.26; 95% CI, 0.21\u20130.31;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.001), and DFS (HR, 5.17; 95% CI, 4.56\u20135.86;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.001) were independent predictors of OS. The PTE was 0.42 (95% CI, 0.22\u20130.54), 0.48 (95% CI, 0.24\u20130.58), and 0.84 (95% CI, 0.66\u20130.96) for pCR, pOR, and DFS, respectively. At the pseudo\u2013trial level, the R2 was 0.22 (95% CI, 0.20\u20130.25), 0.33 (95% CI, 0.31\u20130.36), and 0.83 (95% CI, 0.81\u20130.84) for the correlation between treatment effects on pCR, pOR, and DFS and OS, respectively. The STE was 0.82 (95% CI, 0.81\u20130.84) for DFS.\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    We observed uncertainty regarding the surrogacy of pCR and pOR in patients undergoing RC with or without NAC for localized MIBC. Only DFS consistently mediated the treatment effect on OS, supporting its use as a surrogate for RCT dimensioning when a recurrence or death risk reduction of \u226518% is expected.\n                  <\/jats:p>","DOI":"10.6004\/jnccn.2026.7014","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:52:25Z","timestamp":1781614345000},"source":"Crossref","is-referenced-by-count":2,"title":["Surrogacy of Intermediate Clinical Endpoints for Overall Survival in Patients With Localized Muscle-Invasive Bladder Cancer"],"prefix":"10.6004","volume":"24","author":[{"given":"Pietro","family":"Scilipoti","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology\/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy"},{"name":"Vita-Salute San Raffaele University, Milan, Italy"},{"name":"GRC 5 Predictive Onco-Uro Group, Department of Urology, Pitie-Salpetriere Hospital, AP-HP, Sorbonne University, Paris, France Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"de Angelis","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology\/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy"},{"name":"Vita-Salute San Raffaele University, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance","family":"Thibault","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hopital Europ\u00e9en Georges Pompidou, APHP Centre, Institut du Cancer Paris CARPEM, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"\u015alusarczyk","sequence":"additional","affiliation":[{"name":"Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"del Giudice","sequence":"additional","affiliation":[{"name":"Department of Maternal Infant and Urologic Sciences, \u201cSapienza\u201d University of Rome, Policlinico Umberto I Hospital, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Contieri","sequence":"additional","affiliation":[{"name":"Department of Urology, Humanitas Clinical and Research Institute IRCCS, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Hurle","sequence":"additional","affiliation":[{"name":"Department of Urology, Humanitas Clinical and Research Institute IRCCS, Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Daniel","family":"Subiela","sequence":"additional","affiliation":[{"name":"Departament of Urology, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, Universidad de Alcala, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Simone","sequence":"additional","affiliation":[{"name":"Department of Urology, \u201cRegina Elena\u201d National Cancer Institute, IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Proietti","sequence":"additional","affiliation":[{"name":"Department of Urology, \u201cRegina Elena\u201d National Cancer Institute, IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Urology, The Jikei University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrokh","family":"Shariat","sequence":"additional","affiliation":[{"name":"Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria"},{"name":"Department of Urology, University of Texas Southwestern, Dallas, TX"},{"name":"Department of Urology, Weill Cornell Medical College, New York, NY"},{"name":"Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Zamboni","sequence":"additional","affiliation":[{"name":"Department of Urology, Spedali Civili of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazareno","family":"Suardi","sequence":"additional","affiliation":[{"name":"Department of Urology, Spedali Civili of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunya","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhisa","family":"Fujii","sequence":"additional","affiliation":[{"name":"Institute of Science Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Bertolo","sequence":"additional","affiliation":[{"name":"Department of Urology, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Antonelli","sequence":"additional","affiliation":[{"name":"Department of Urology, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliott","family":"Diamant","sequence":"additional","affiliation":[{"name":"Department of Urology, Henri Mondor Hospital, University of Paris Est Cr\u00e9teil, Cr\u00e9teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Vordos","sequence":"additional","affiliation":[{"name":"Department of Urology, Henri Mondor Hospital, University of Paris Est Cr\u00e9teil, Cr\u00e9teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Etienne","family":"Gabriel","sequence":"additional","affiliation":[{"name":"GRC 5 Predictive Onco-Uro Group, Department of Urology, Pitie-Salpetriere Hospital, AP-HP, Sorbonne University, Paris, France Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Th\u00e9o","family":"Harber","sequence":"additional","affiliation":[{"name":"Department of Urology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-B\u00e9nite, 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Bogdan","family":"Borz","sequence":"additional","affiliation":[{"name":"Department of Urology, Cochin Hospital, APHP, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Verhoest","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Mauger De Varennes","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Rennes, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Surlemont","sequence":"additional","affiliation":[{"name":"Department of Urology, Rouen University Hospital, Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Ghenassia","sequence":"additional","affiliation":[{"name":"Department of Urology, Rouen University Hospital, Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Masson-Lecomte","sequence":"additional","affiliation":[{"name":"Department of Urology, Saint Louis Hospital, APHP, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Peyrottes","sequence":"additional","affiliation":[{"name":"Department of Urology, Saint Louis Hospital, APHP, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Lebacle","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Bic\u00eatre-Paris Sud-Saclay University, Le Kremlin Bic\u00eatre, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Beniac","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Bic\u00eatre-Paris Sud-Saclay University, Le Kremlin Bic\u00eatre, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"L\u00e9on","sequence":"additional","affiliation":[{"name":"Department of Urology, Clinique Pasteur, Royan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Larr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Urology, Reims University Hospital, Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayek","family":"Taha","sequence":"additional","affiliation":[{"name":"Department of Urology, Reims University Hospital, Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautier","family":"Marcq","sequence":"additional","affiliation":[{"name":"Department of Urology, Claude Huriez Hospital, Lille, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evanguelos","family":"Xylinas","sequence":"additional","affiliation":[{"name":"Department of Urology, Bichat-Claude Bernard Hospital, APHP, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Allory","sequence":"additional","affiliation":[{"name":"UMR 144 CNRS, Institut Curie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Bajeot","sequence":"additional","affiliation":[{"name":"Department of Urology, Toulouse University Hospital, University of Toulouse Ut3, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doriane","family":"Prost","sequence":"additional","affiliation":[{"name":"Department of Urology, Paris Saint-Joseph Hospital, Paris, 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