PMID- 37811690 OWN - NLM STAT- MEDLINE DCOM- 20231106 LR - 20231129 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 10 IP - 10 DP - 2023 Oct 9 TI - Immunotherapy for advanced or metastatic urothelial carcinoma. PG - CD013774 LID - 10.1002/14651858.CD013774.pub2 [doi] LID - CD013774 AB - BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I(2) = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I(2) = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I(2) = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I(2) = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I(2) = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I(2) = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I(2) = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I(2) = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I(2) = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively. CI - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Maisch, Philipp AU - Maisch P AD - Department of Urology, Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany. AD - Department of Urology and Pediatric Urology, University Hospital Ulm, University of Ulm, Ulm, Germany. FAU - Hwang, Eu Chang AU - Hwang EC AD - Department of Urology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Korea, South. FAU - Kim, Kwangmin AU - Kim K AD - Graduate school, Yonsei University Wonju College of Medicine, Wonju, Korea, South. FAU - Narayan, Vikram M AU - Narayan VM AD - Department of Urology, Emory University, Atlanta, Georgia, USA. FAU - Bakker, Caitlin AU - Bakker C AD - Health Sciences Libraries, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Kunath, Frank AU - Kunath F AD - Department of Urology and Pediatric Urology, Klinikum Bayreuth, Bayreuth, Germany. AD - UroEvidence@Deutsche Gesellschaft fur Urologie, Berlin, Germany. FAU - Dahm, Philipp AU - Dahm P AD - Urology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA. AD - Department of Urology, University of Minnesota, Minneapolis, Minnesota, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20231009 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Immune Checkpoint Inhibitors) SB - IM UOF - doi: 10.1002/14651858.CD013774 MH - Humans MH - *Carcinoma, Transitional Cell/drug therapy MH - Disease Progression MH - Immune Checkpoint Inhibitors/therapeutic use MH - Immunotherapy/adverse effects MH - Systematic Reviews as Topic MH - *Urinary Bladder Neoplasms/drug therapy PMC - PMC10561349 COIS- PM declares no conflicts of interest. ECH is a Contact Editor for Cochrane Urology; however, he was not involved in the editorial process of this review. KK declares no conflicts of interest. VN is a Contact Editor for Cochrane Urology; however, he was not involved in the editorial process of this review. CB is the Information Specialist for Cochrane Urology; however, she was not involved in the editorial process of this review. FK is a Contact Editor for Cochrane Urology; however, he was not involved in the editorial process of this review. PD is the Co-ordinating Editor of Cochrane Urology; however, he was not involved in the editorial process of this review. EDAT- 2023/10/09 12:42 MHDA- 2023/10/23 01:18 PMCR- 2024/10/09 CRDT- 2023/10/09 06:42 PHST- 2024/10/09 00:00 [pmc-release] PHST- 2023/10/23 01:18 [medline] PHST- 2023/10/09 12:42 [pubmed] PHST- 2023/10/09 06:42 [entrez] AID - CD013774.pub2 [pii] AID - 10.1002/14651858.CD013774.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2023 Oct 9;10(10):CD013774. doi: 10.1002/14651858.CD013774.pub2.