Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

Article  PubMed  Google Scholar 

Smith, A. B. et al. Muscle-invasive bladder cancer: evaluating treatment and survival in the National Cancer Data Base. BJU Int. 114, 719–726 (2014).

Article  PubMed  Google Scholar 

Burger, M. et al. Epidemiology and risk factors of urothelial bladder cancer. Eur. Urol. 63, 234–241 (2013).

Article  PubMed  Google Scholar 

National Institutes of Health, National Cancer Institute. Cancer stat facts: bladder cancer. seer.cancer.gov, https://seer.cancer.gov/statfacts/html/urinb.html (2022).

Gupta, S. E. A. Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). J. Clin. Oncol. 40, 4577 (2022).

Article  Google Scholar 

Balar, A. V. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017).

Article  CAS  PubMed  Google Scholar 

Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).

Article  CAS  PubMed  Google Scholar 

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), https://www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.

FDA. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment (2020).

Rosenberg, J. E. A. Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. J. Clin. Oncol. 40, 4516 (2022).

Article  Google Scholar 

O’Donnell, P. H. et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J. Clin. Oncol. 41, 4107–4117 (2023).

Article  PubMed  Google Scholar 

Merck. Merck announces phase 3 KEYNOTE-A39/EV-302 trial met dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in certain patients with previously untreated locally advanced or metastatic urothelial cancer. Merck www.merck.com/news/merck-announces-phase-3-keynote-a39-ev-302-trial-met-dual-primary-endpoints-of-overall-survival-os-and-progression-free-survival-pfs-in-certain-patients-with-previously-untreated-locally-advanced/ (2023).

Dash, A. et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer 107, 506–513 (2006).

Article  CAS  PubMed  Google Scholar 

Galsky, M. D. et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J. Clin. Oncol. 29, 2432–2438 (2011).

Article  PubMed  Google Scholar 

Russell, B. M., Boussi, L. & Bellmunt, J. Management of advanced urothelial carcinoma in older and frail patients: have novel treatment approaches improved their care? Drugs Aging 39, 271–284 (2022).

Article  CAS  PubMed  Google Scholar 

Loehrer, P. J. Sr et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J. Clin. Oncol. 10, 1066–1073 (1992).

Article  PubMed  Google Scholar 

von der Maase, H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005).

Article  CAS  PubMed  Google Scholar 

von der Maase, H. et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J. Clin. Oncol. 18, 3068–3077 (2000).

Article  CAS  PubMed  Google Scholar 

Sternberg, C. N. et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur. J. Cancer 42, 50–54 (2006).

Article  CAS  PubMed  Google Scholar 

Sternberg, C. N. et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J. Clin. Oncol. 19, 2638–2646 (2001).

Article  CAS  PubMed  Google Scholar 

Bellmunt, J. et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J. Clin. Oncol. 30, 1107–1113 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bamias, A. et al. Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Ann. Oncol. 29, 361–369 (2018).

Article  CAS  PubMed  Google Scholar 

De Santis, M. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 30, 191–199 (2012).

Article  PubMed  Google Scholar 

Bellmunt, J., de Wit, R., Albanell, J. & Baselga, J. A feasibility study of carboplatin with fixed dose of gemcitabine in “unfit” patients with advanced bladder cancer. Eur. J. Cancer 37, 2212–2215 (2001).

Article  CAS  PubMed  Google Scholar 

Galsky, M. D. et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann. Oncol. 23, 406–410 (2012).

Article  CAS  PubMed  Google Scholar 

Powles, T. DANUBE post-hoc analysis: outcomes for durvalumab with or without tremelimumab by cisplatin eligibility and PD-L1 biomarker status in metastatic urothelial carcinoma. In 36th Annual EAU Congress, https://bladder.uroonco.uroweb.org/webcast/danube-post-hoc-analysis-outcomes-for-durvalumab-with-or-without-tremelimumab-by-cisplatin-eligibility-and-pd-l1-biomarker-status-in-metastatic-urothelial-carcinoma/ (Uroweb, 2021).

Grande, E. E. A. Overall survival (OS) by response to first-line (1L) induction treatment with atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with metastatic urothelial carcinoma (mUC): updated data from the IMvigor130 OS final analysis. J. Clin. Oncol. 41, 4503 (2023).

Article  Google Scholar 

Sridhar, S. S. et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up from the JAVELIN Bladder 100 trial in subgroups defined by 1L chemotherapy regimen and analysis of overall survival (OS) from start of 1L chemotherapy. J. Clin. Oncol. 41, 3486–3492 (2023).

Article  PubMed  PubMed Central  Google Scholar 

von der Maase, H., Andersen, L., Crino, L., Weinknecht, S. & Dogliotti, L. Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: a phase II clinical trial. Ann. Oncol. 10, 1461–1465 (1999).

Article  PubMed  Google Scholar 

Morales-Barrera, R. et al. Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function. Eur. J. Cancer 48, 1816–1821 (2012).

Article  CAS  PubMed  Google Scholar 

Mourey, L. E. A. Vefora, GETUG-AFU V06 study: randomized multicenter phase II/III trial of fractionated cisplatin (CI)/gemcitabine (G) or carboplatin (CA)/g in patients (pts) with advanced urothelial cancer (UC) with impaired renal function (IRF) — results of a planned interim analysis. J. Clin. Oncol. 38, 461 (2020).

Article  Google Scholar 

Douillard, J. Y. et al. Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. Br. J. Cancer 84, 1179–1184 (2001).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Calabro, F. et al. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer 115, 2652–2659 (2009).

Article  CAS  PubMed  Google Scholar 

Hussain, M., Vaishampayan, U., Du, W., Redman, B. & Smith, D. C. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J. Clin. Oncol. 19, 2527–2533 (2001).

Article  CAS  PubMed  Google Scholar 

Galsky, M. D. et al. Phase II trial of dose-dense doxorubicin plus gemcitabine followed by paclitaxel plus carboplatin in patients with advanced urothelial carcinoma and impaired renal function. Cancer 109, 549–555 (2007).

Article  CAS  PubMed  Google Scholar 

De Santis, M. et al. Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results of an international randomized phase II trial (JASINT1). Ann. Oncol. 27, 449–454 (2016).

Article  PubMed  Google Scholar 

Loriot, Y. Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis based on duration and cycles of 1L chemotherapy. J. Clin. Oncol. 39, 438 (2021).

Article  Google Scholar 

Raggi, D. et al. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann. Oncol. 27, 49–61 (2016).

Article  CAS  PubMed  Google Scholar 

Petrylak, D. P. et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial.Lancet 390, 2266–2277 (2017).

Article  CAS  PubMed  Google Scholar 

Nadal, R. & Bellmun, J. Management of metastatic bladder cancer.Cancer Treat Rev. 76, 10–21 (2019).