Advertisement

Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options

Open AccessPublished:July 21, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102072

      Highlights

      • Survival outcomes for patients with stage IV UC and distant metastases remain poor.
      • Platinum-based chemotherapy remains the standard of care for untreated, advanced UC.
      • First-line treatment options that provide a long-term survival benefit are needed.
      • New data supports improved survival outcomes with immune checkpoint inhibitors.

      Abstract

      Background

      Patients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of <5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients.

      Methods

      The websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents.

      Results

      For advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible.

      Conclusions

      After having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.

      Keywords

      Introduction

      Bladder cancer ranks as the ninth most common malignancy worldwide, with more than 165,000 deaths reported in 2012 [
      • Wong M.C.S.
      • Fung F.D.H.
      • Leung C.
      • Cheung W.W.L.
      • Goggins W.B.
      • Ng C.F.
      The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection.
      ]. The highest incidence rates occur in Southern Europe, Western Europe, and North America, although mortality rates are highest in Western Asia and Northern Africa [
      • Wong M.C.S.
      • Fung F.D.H.
      • Leung C.
      • Cheung W.W.L.
      • Goggins W.B.
      • Ng C.F.
      The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection.
      ]. Urothelial carcinoma (UC; also known as transitional cell carcinoma) accounts for 90% of all bladder cancers in Western Europe and the United States; squamous cell bladder cancer due to schistosomiasis infections is more common in Africa [
      • Wong M.C.S.
      • Fung F.D.H.
      • Leung C.
      • Cheung W.W.L.
      • Goggins W.B.
      • Ng C.F.
      The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection.
      ].
      An initial diagnosis of non–muscle-invasive bladder cancer occurs in approximately 70% of patients [
      • Lavaud P.
      • Hamilou Z.
      • Loriot Y.
      • Massard C.
      Durvalumab in urothelial cancers.
      ]. Treatment at the non–muscle-invasive stage includes transurethral resection of bladder tumor often followed by intravesical chemotherapy or intravesical bacillus Calmette-Guérin immunotherapy [
      • Lavaud P.
      • Hamilou Z.
      • Loriot Y.
      • Massard C.
      Durvalumab in urothelial cancers.
      ]. Approximately 25% of patients with bladder cancer will be diagnosed with muscle-invasive disease [
      • Bukhari N.
      • Al-Shamsi H.O.
      • Azam F.
      Update on the treatment of metastatic urothelial carcinoma.
      ]. Treatment of muscle-invasive bladder cancer includes surgery (cystectomy) combined with adjuvant or neo-adjuvant cisplatin-based chemotherapy [
      • Lavaud P.
      • Hamilou Z.
      • Loriot Y.
      • Massard C.
      Durvalumab in urothelial cancers.
      ], or synchronous chemoradiotherapy as an alternative to cystectomy [
      • James N.D.
      • Hussain S.A.
      • Hall E.
      • Jenkins P.
      • Tremlett J.
      • Rawlings C.
      • et al.
      Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.
      ], whereas patients with unresectable, locally advanced disease receive chemotherapy [
      • Bellmunt J.
      • Petrylak D.P.
      New therapeutic challenges in advanced bladder cancer.
      ]. Among patients newly diagnosed with bladder cancer, approximately 5% will have metastatic disease and, historically, outcomes for these patients have been very poor; the 5-year survival rate for those with stage IV disease and distant metastases is <5% [

      National Institutes of Health/National Cancer Institute. Surveillance Epidemiology and End Results (SEER) program, Cancer Stat Facts: Bladder Cancer. 2018. https://seer.cancer.gov/statfacts/html/urinb.html [accessed November 11, 2019].

      ].
      The current standard of care for the first-line treatment of advanced UC (locally advanced or metastatic, stage IV disease) is platinum-based combination chemotherapy [

      Bellmunt J. Treatment of metastatic urothelial cancer of the bladder and urinary tract. 2019. https://www.uptodate.com/contents/treatment-of-metastatic-urothelial-cancer-of-the-bladder-and-urinary-tract. [accessed September 21, 2019].

      ]. Patients with good performance status, adequate renal function, and no comorbidities are candidates for cisplatin-based regimens. However, approximately 40% of patients are not fit enough to receive cisplatin-containing therapy; options for these patients include carboplatin-based regimens. Myelosuppression, nephrotoxicity, and ototoxicity are common adverse events associated with cisplatin-based regimens [

      Bellmunt J. Treatment of metastatic urothelial cancer of the bladder and urinary tract. 2019. https://www.uptodate.com/contents/treatment-of-metastatic-urothelial-cancer-of-the-bladder-and-urinary-tract. [accessed September 21, 2019].

      ], which can have a negative impact on health-related quality of life (HRQoL).
      Evidence suggests that patients who receive cisplatin-based regimens have better survival outcomes than patients who receive carboplatin-based regimens [
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • Kerst J.M.
      • Leahy M.
      • Maroto P.
      • 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.
      ,
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      ]. However, as cisplatin can have a negative impact on HRQoL, there is a need to investigate alternative treatments that have improved benefit-risk profiles for cisplatin-eligible patients. Based on the results of single-arm, phase II studies [
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      ,
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Vuky J.
      • Powles T.
      • 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.
      ], atezolizumab (anti–programmed cell death ligand 1 [PD-L1]) and pembrolizumab (anti–programmed death 1 [PD-1) were approved by the US Food and Drug Administration (FDA) in 2017 for the first-line treatment of cisplatin-ineligible patients with stage IV UC and high tumor PD-L1 expression, or for patients not eligible for any platinum-based therapy regardless of PD-L1 status. In 2018, the European Medicines Agency (EMA) approved atezolizumab and pembrolizumab for the first-line treatment of cisplatin-ineligible patients with stage IV UC and high tumor PD-L1 expression. The anti–PD-L1 agents atezolizumab, avelumab, and durvalumab, as well as the anti–PD-1 agents nivolumab and pembrolizumab, are approved for the second-line treatment of locally advanced or metastatic UC, regardless of PD-L1 status [
      • Ghate K.
      • Amir E.
      • Kuksis M.
      • Hernandez-Barajas D.
      • Rodriguez-Romo L.
      • Booth C.M.
      • et al.
      PD-L1 expression and clinical outcomes in patients with advanced urothelial carcinoma treated with checkpoint inhibitors: a meta-analysis.
      ]. These agents are currently being evaluated as first-line therapies for metastatic UC, alone and in combination with chemotherapy or other agents, including inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (ipilimumab and tremelimumab).
      Given the availability of new therapies, it is important to understand the profiles and clinical outcomes of different treatment options for patients with advanced UC. As there is currently no comprehensive review of first-line management strategies for advanced UC, we conducted a review of available treatment guidelines, a systematic literature review of clinical outcomes with chemotherapy, and a recent review of the literature for studies of immuno-oncology (IO) agents in order to fill this gap in evidence.

      Methods

      Review of treatment guidelines

      To identify national and international treatment guidelines for UC, we reviewed the guidelines published by selected Health Technology Assessment bodies (the websites of 11 Health Technology Assessment agencies from seven countries were searched) and the websites of recognized professional/national associations. For national guidelines, those published in English that provided treatment recommendations by disease stage and line of therapy were selected. Documents detailing disease management guidelines for the first-line treatment of advanced UC were obtained from the websites of the American Society for Clinical Oncology (ASCO), American Urological Association (AUA), Canadian Health Service (CHS), European Association of Urology (EAU), European Society for Medical Oncology (ESMO), National Institute for Health and Care Excellence (NICE), and National Comprehensive Cancer Network (NCCN).

      Systematic literature review

      In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, systematic literature reviews (SLRs) were conducted to identify research reporting evidence of the efficacy, safety, and HRQoL outcomes associated with first-line chemotherapy for advanced UC. The titles and abstracts of reports published in English between January 1990 and November 2018 were searched, using the terms detailed in Table A.1, in the following databases: Medline and Medline in-process (via PubMed.com), Embase and Embase in-process (via Embase.com), Cochrane Central Register of Controlled Trials (CENTRAL), Centre for Reviews and Dissemination (CDSR), and Database of Abstracts of Reviews of Effects (DARE). Meeting abstracts from ASCO, AUA, EAU, ESMO, and the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) conferences held between 2013 and 2018 were also searched for relevant presentations. ClinicalTrials.gov, the European Clinical Trials Database (EudraCT), the EMA, and the US FDA were also searched to identify relevant clinical trials.
      Study selection criteria for the SLRs are reported in Table A.2. Titles and abstracts were assessed against the predefined selection criteria for inclusion in the review. The full-text publication of all included abstracts was then assessed by one reviewer, and all excluded full-text publications were confirmed by a second reviewer. Reference lists of systematic reviews and meta-analyses were reviewed to ensure that all relevant publications were identified in the search of databases. Information was extracted from full-text articles and independently validated. Logic checks and validation were performed on the extracted data for additional quality assurance.
      Studies included in the SLRs were assessed for bias using NICE-recommended standardized scoring systems, which included a checklist to assess the quality of clinical efficacy and safety data specific to randomized controlled trials (RCTs), and Downs’ and Black’s checklist to assess the methodological quality of non-randomized studies [
      • Downs S.H.
      • Black N.
      The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
      ]. Only studies with > 25 enrolled patients were included in the SLRs.

      Review of evidence for IO agents

      A literature search was conducted to identify evidence from completed and ongoing trials evaluating IO agents as first-line therapies for advanced UC. A search of PubMed, major oncology congresses, and ClinicalTrials.gov was undertaken, from June 2015 through June 2020. The search terms included bladder cancer, urothelial carcinoma, immune checkpoint inhibitor, anti–PD-1, anti–PD-L1, anti–CTLA-4, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and tremelimumab.

      Results

      Treatment guidelines for advanced UC

      Seven guideline documents pertaining to the treatment of UC were identified in Canada, Europe, the United Kingdom, and the United States (Table 1) [

      Alberta Health Services. Muscle invasive and locally advanced/metastatic bladder cancer clinical practice guideline GU-002 version 5. 2013. http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu002-bladder.pdf. [accessed November 11, 2019].

      ,
      • Bellmunt J.
      • Orsola A.
      • Leow J.J.
      • Wiegel T.
      • De Santis M.
      • Horwich A.
      • et al.
      Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      European Association of Urology (EAU). Muscle-invasive and metastatic bladder cancer. Summary of changes. 2020. 2020. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=summary-of-changes. [accessed June 15, 2020].

      ,
      • Milowsky M.I.
      • Rumble R.B.
      • Booth C.M.
      • Gilligan T.
      • Eapen L.J.
      • Hauke R.J.
      • et al.
      Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
      ,

      National Institute for Health and Care Excellence. Bladder cancer: diagnosis and management, NICE guideline. 2015. https://www.nice.org.uk/guidance/ng2. [accessed November 11, 2019].

      ,

      Princess Margaret Cancer Centre. Princess Margaret Cancer Centre clinical practice guidelines. 2012. http://www.uhn.ca/PrincessMargaret/Health_Professionals/Programs_Departments/Genitourinary_GU/Documents/CPG_GU_Urothelial.pdf. [accessed November 11, 2019].

      ,

      European Society for Medical Oncology (ESMO). eUpdate - bladder cancer treatment recommendations 2019. https://www.esmo.org/guidelines/genitourinary-cancers/bladder-cancer/eupdate-bladder-cancer-treatment-recommendations3. [accessed June 15, 2020].

      ,
      • Flaig T.W.
      • Spiess P.E.
      • Agarwal N.
      • Bangs R.
      • Boorjian S.A.
      • Buyyounouski M.K.
      • et al.
      Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.
      ] National Comprehensive Cancer Network (NCCN) guidelines were updated in March of 2020 [
      • Flaig T.W.
      • Spiess P.E.
      • Agarwal N.
      • Bangs R.
      • Boorjian S.A.
      • Buyyounouski M.K.
      • et al.
      Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.
      ], but recommendations remain unchanged for the first-line treatment of locally advanced or metastatic (stage IV) UC (Table 1). The European Society for Medical Oncology (ESMO) guidelines were published in 2014 [
      • Bellmunt J.
      • Orsola A.
      • Leow J.J.
      • Wiegel T.
      • De Santis M.
      • Horwich A.
      • et al.
      Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up.
      ] and were last updated in December of 2019 [

      European Society for Medical Oncology (ESMO). eUpdate - bladder cancer treatment recommendations 2019. https://www.esmo.org/guidelines/genitourinary-cancers/bladder-cancer/eupdate-bladder-cancer-treatment-recommendations3. [accessed June 15, 2020].

      ].
      Table 1Guidelines for the first-line treatment of advanced UC.
      ReferenceYearPopulationRecommendation for First-line Treatment
      NCCN
      • Flaig T.W.
      • Spiess P.E.
      • Agarwal N.
      • Bangs R.
      • Boorjian S.A.
      • Buyyounouski M.K.
      • et al.
      Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.
      2020Locally advanced or metastatic (stage IV) UCCisplatin eligible
      • Gemcitabine + cisplatin
      • DDMVAC with growth factor support
      Cisplatin ineligible

      Preferred:
      • Gemcitabine + carboplatin
      • Atezolizumab (tumors expressing PD-L1 or ineligible for platinum-containing chemotherapy)
      • Pembrolizumab (tumors expressing PD-L1 or ineligible for platinum-containing chemotherapy)
      Other recommended regimens:
      • Gemcitabine or gemcitabine + paclitaxel
      Certain circumstances:
      • Ifosfamide, doxorubicin, gemcitabine (for patients with good kidney function and PS)
      ESMO
      • Bellmunt J.
      • Orsola A.
      • Leow J.J.
      • Wiegel T.
      • De Santis M.
      • Horwich A.
      • et al.
      Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      European Society for Medical Oncology (ESMO). eUpdate - bladder cancer treatment recommendations 2019. https://www.esmo.org/guidelines/genitourinary-cancers/bladder-cancer/eupdate-bladder-cancer-treatment-recommendations3. [accessed June 15, 2020].

      2020Advanced unresectable or metastatic UCCisplatin eligible
      • Gemcitabine + cisplatin
      • MVAC with G-CSF
      • Dose-dense MVAC
      • Paclitaxel + cisplatin + gemcitabine
      Cisplatin ineligible (poor PS, impaired renal function, or comorbidities)
      • Gemcitabine + carboplatin
      • Atezolizumab (PD-L1-positive tumors)
      • Pembrolizumab (PD-L1-positive tumors)
      Platinum ineligible (PS ≤ 2 + poor renal function)
      • Clinical trial
      • Best supportive care
      EAU

      European Association of Urology (EAU). Muscle-invasive and metastatic bladder cancer. Summary of changes. 2020. 2020. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=summary-of-changes. [accessed June 15, 2020].

      2020Advanced or metastatic UCCisplatin eligible
      • Gemcitabine + cisplatin
      • MVAC or high-dose MVAC
      • Paclitaxel, cisplatin, and gemcitabine
      Cisplatin ineligible
      • Gemcitabine + carboplatin
      • Pembrolizumab (PD-L1-positive tumors)
      • Atezolizumab (PD-L1-positive tumors)
      • Alternative regimens
      Platinum ineligible (PS ≥ 2)
      • Pembrolizumab (PD-L1-positive tumors)
      • Atezolizumab (PD-L1-positive tumors)
      • Best supportive care
      ASCO/EAU
      • Milowsky M.I.
      • Rumble R.B.
      • Booth C.M.
      • Gilligan T.
      • Eapen L.J.
      • Hauke R.J.
      • et al.
      Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
      2016Metastatic muscle-invasive UCCisplatin eligible
      • Gemcitabine + cisplatin
      • MVAC or high-dose MVAC with G-CSF
      • Carboplatin and non-platinum combination chemotherapy is not recommended
      Cisplatin ineligible
      • Carboplatin-containing combination chemotherapy, preferably gemcitabine + carboplatin
      • Single agents
      CADTH

      Princess Margaret Cancer Centre. Princess Margaret Cancer Centre clinical practice guidelines. 2012. http://www.uhn.ca/PrincessMargaret/Health_Professionals/Programs_Departments/Genitourinary_GU/Documents/CPG_GU_Urothelial.pdf. [accessed November 11, 2019].

      2012Advanced, unresectable metastatic UCCisplatin eligible
      • Sequential gemcitabine + cisplatin, plus paclitaxel
      Cisplatin ineligible
      • Gemcitabine + carboplatin
      CHS

      Alberta Health Services. Muscle invasive and locally advanced/metastatic bladder cancer clinical practice guideline GU-002 version 5. 2013. http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu002-bladder.pdf. [accessed November 11, 2019].

      2013Metastatic UCCisplatin eligible
      • Gemcitabine + cisplatin
      • MVAC
      Cisplatin ineligible
      • Gemcitabine + carboplatin
      • Single-agent gemcitabine (if expected to poorly tolerate platinum agents)
      NICE

      National Institute for Health and Care Excellence. Bladder cancer: diagnosis and management, NICE guideline. 2015. https://www.nice.org.uk/guidance/ng2. [accessed November 11, 2019].

      2015Locally advanced or metastatic UCCisplatin eligible
      • Gemcitabine + cisplatin
      • Accelerated MVAC with G-CSF
      Cisplatin ineligible
      • Gemcitabine + carboplatin
      ASCO, American Society of Clinical Oncology; CADTH, Canadian Agency or Drugs and Technologies in Health; CHS, Canadian Health Service; DDMVAC, dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin; EAU, European Association of Urology; ECOG, Eastern Cooperative Oncology Group; ESMO, European Society of Medical Oncology; G-CSF, granulocyte colony-stimulating factor; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Care Excellence; PS, performance status; UC, urothelial carcinoma.
      All guidelines recommended platinum-based chemotherapy as first-line treatment. Cisplatin-based chemotherapy is preferred for patients who have good performance status, adequate renal function, and absence of comorbidities (eg, impaired cardiac status, neuropathy, hearing loss). Specifically, gemcitabine plus cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) are recommended for cisplatin-eligible patients. Carboplatin-based regimens (eg, gemcitabine plus carboplatin) are recommended in cases where cisplatin is contraindicated.
      Along with gemcitabine plus carboplatin, preferred regimens for cisplatin-ineligible patients in the current NCCN guidelines include atezolizumab or pembrolizumab for patients with high tumor PD-L1 expression or for those not eligible for any platinum-based chemotherapy, regardless of PD-L1 expression. In the recently updated ESMO guidelines, gemcitabine plus carboplatin remains the preferred regimen for cisplatin-ineligible patients; however, atezolizumab or pembrolizumab are recommended for cisplatin-ineligible patients with PD-L1-positive tumors. High PD-L1 expression for atezolizumab is defined as positive PD-L1 staining of tumor-infiltrating immune cells (ICs) of ≥ 5% as a proportion of the total tumor cell (TC) and IC area (VENTANA SP142 Assay), while for pembrolizumab, high PD-L1 expression is defined as positive PD-L1 staining of TCs plus ICs ≥ 10% as a proportion of the total TC area (combined positive score [CPS] ≥ 10) (PD-L1 IHC 223 pharmDx assay).

      Efficacy of first-line chemotherapy for advanced UC

      Of the 4492 publications identified in the searches for efficacy and safety studies on first-line chemotherapy for unresectable stage IV UC, 31 RCTs (with evidence reported in 46 publications) met the inclusion criteria and were included in the results (Fig. 1A).
      Figure thumbnail gr1
      Fig. 1PRISMA flow diagram of study selection. (A) Clinical and safety studies for the first-line treatment of urothelial carcinoma. (B) HRQoL analyses studies. CENTRAL, Cochrane Central Register of Controlled Trials; CDSR, Centre for Reviews and Dissemination; DARE, Database of Abstracts of Reviews of Effects; PRO, patient-reported outcomes; SLR, systematic literature review.
      Most RCTs compared various treatment schedules of platinum-based chemotherapies according to cycle length and dose density (Table 2). For example, studies that evaluated gemcitabine plus cisplatin evaluated different gemcitabine doses (cisplatin 70 mg/m2 + gemcitabine 250–2500 mg/m2 every 14, 21, or 28 days) [
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ,
      • Haggag R.
      • Farag K.
      • Abu-Taleb F.
      • Shamaa S.
      • Zekri A.R.
      • Elbolkainy T.
      • et al.
      Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update.
      ]. MVAC chemotherapy was most often administered at the standard doses of 30 mg/m2 methotrexate, 3 mg/m2 vinblastine, 70 mg/m2 cisplatin, and 30 mg/m2 doxorubicin, but some trials reported dose ranges of methotrexate 34–60 mg/m2, vinblastine 3.4–4 mg/m2, doxorubicin 34–60 mg/m2, and cisplatin 25–100 mg/m2 every 14, 23, or 28 days. Carboplatin was administrated at area under the curve 4.5, 5, or 6–250, 300, and 400 mg/m2 doses.
      Table 2Clinical evidence from RCTs of first-line chemotherapy for advanced UC.
      ReferenceInterventionPopulationNFollow-up

      Median (Range)
      Objective Response Rate

      % (95% CI)
      Progression-free Survival

      Median (95% CI)
      Overall Survival

      Median (95% CI)
      Grade 3+ AEs

      (most frequent hematologic)
      Bamias et al. 2004
      • Bamias A.
      • Aravantinos G.
      • Deliveliotis C.
      • Bafaloukos D.
      • Kalofonos C.
      • Xiros N.
      • et al.
      Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
      Docetaxel + cisplatin + G-CSFUnresectable, metastatic, or recurrent UC

      ECOG PS 0–2
      11125.3 mo

      (3.2–51)
      Overall: 37.4% (27.4–48.1)
      P = 0.017 for MVAC versus docetaxel + cisplatin; however, P = 0.100 when all randomized patients were analyzed and non-assessable patients were considered non-responders.


      ITT: 30.6%
      NR9.3 mo

      (7.9–10.7)
      Neutropenia (19.2%), anemia (5.8%), neutropenic sepsis (3.8%), thrombocytopenia (0.9%)
      MVAC + G-CSF109Overall: 54.2% (42.9–65.2)
      P = 0.017 for MVAC versus docetaxel + cisplatin; however, P = 0.100 when all randomized patients were analyzed and non-assessable patients were considered non-responders.


      ITT: 41.3%
      14.2 mo

      (12.5–15.9)

      P = 0.026
      Neutropenia (35.9%), neutropenic sepsis (11.7%), anemia (7.8%), thrombocytopenia (5.8%)
      Bamias et al. 2013
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      DD-MVAC (14 d) + G-CSFUnresectable, metastatic, or recurrent urothelial TCC

      ECOG PS 0–1
      6352.1 mo

      (0.1– 82.5)
      60.0%8.5 mo19.0 moNeutropenia (19.7%), anemia (11.5%), thrombocytopenia (8.2%)
      DD gemcitabine + cisplatin (14 d) + G-CSF6365.3%

      P = 0.67
      7.8 mo

      P = 0.36
      18.0 mo

      P = 0.98
      Neutropenia (13.6%), anemia (10.2%), thrombocytopenia (8.5%)
      Bellmunt et al. 1997
      • Bellmunt J.
      • Ribas A.
      • Eres N.
      • Albanell J.
      • Almanza C.
      • Bermejo B.
      • et al.
      Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.
      MVACUrothelial TCC

      KPS ≥ 60
      2418 mo

      (6–60)
      52% (30–73)NR16 mo

      (range, 3–24+ )
      Granulocytopenic fever (18%), anemia (3.7%), thrombocytopenia (3.7%)
      MCAVI2339% (20–62)

      P = 0.3
      9 mo (range, 2–17)

      P = 0.03
      Granulocytopenic fever (3.2%), anemia (3.2%), thrombocytopenia (3.2%)
      Bellmunt et al. 2012
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      Paclitaxel + cisplatin + gemcitabine (21 d)Stage IV locally advanced or metastatic urothelial TCC

      WHO PS 0–1
      3124.6 y

      (max. 6.8)
      55.5%

      P = 0.0031
      8.3 mo

      P = 0.113
      15.8 mo (13.6–17.5)

      P = 0.075
      Neutropenia (64.2%), WBC count (51.3%), thrombocytopenia (34.4%), hemoglobin (22.5%)
      Gemcitabine + cisplatin (28 d)31443.6%7.6 mo12.7 mo (11.0–14.4)Thrombocytopenia (52.1%), neutropenia (50.5%), WBC count (38.7%), hemoglobin (25.6%)
      Bellmunt et al 2017
      • Bellmunt J.
      • Eigl B.J.
      • Senkus E.
      • Loriot Y.
      • Twardowski P.
      • Castellano D.
      • et al.
      Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.
      Gemcitabine + cisplatin + apatorsen 600 mgMetastatic or locally advanced UC

      KPS ≥ 70%
      58NR57%7.5 mo (6.0–9.9)

      P = 0.20
      15.3 mo (10.7–23.2)

      P = 0.25
      Neutropenia (48.3%), anemia (41.4%), hyperuricemia (31.0%), thrombocytopenia (29.3%), leukopenia (29.3%), lymphopenia (25.9%)
      Gemcitabine + cisplatin + apatorsen 1000 mg6050%7.5 mo (4.9–8.9)

      P = 0.37
      15.6 mo (11.5–19.2)

      P = 0.32
      Neutropenia (56.7%), anemia (46.7%), leukopenia (41.7%), thrombocytopenia (36.7%), hyperuricemia (33.3%), lymphopenia (31.7%)
      Gemcitabine + cisplatin + placebo6161%6.2 mo (4.9–8.0)15.0 mo (11.7–19.4)Hyperuricemia (44.3%), neutropenia (42.6%), anemia (37.7%), leukopenia (27.9%), lymphopenia (26.2%), thrombocytopenia (21.3%)
      Culine et al. 2011
      • Culine S.
      • Flechon A.
      • Guillot A.
      • Le Moulec S.
      • Pouessel D.
      • Rolland F.
      • et al.
      Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01).
      Gemcitabine + oxaliplatinAdvanced TCC of the urothelium

      (cisplatin ineligible)
      2221 mo27% (11–50)3.4 mo8.1 mo (3.7–10.7)Neutropenia (31.8%), anemia (13.5%), thrombopenia (22.7%)
      Gemcitabine2243% (22–66)3.8 mo5.4 mo (3.3–13.4)Neutropenia (61.9%), anemia (42.9%), thrombopenia (19.0%)
      Culine et al 2017
      • Culine S.
      • Flechon A.
      • Gravis G.
      • Roubaud G.
      • Loriot Y.
      • Joly F.
      • et al.
      Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
      DD-MVAC + G-CSFLocally advanced or metastatic bladder or upper urinary tract TCC3327 mo70%6.8 mo20.2 moHematologic (54.5%), infection/febrile neutropenia (24.2%)
      DD-MVAC + panitumumab + G-CSF6348%5.7 mo12.5 moHematologic (49.2%), infection/febrile neutropenia (25.4%)
      De Santis et al. 2012
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • Kerst J.M.
      • Leahy M.
      • Maroto P.
      • 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.
      Gemcitabine + carboplatinAdvanced urothelial cancer

      (cisplatin ineligible)
      1194.5 y

      (max. 7.8)
      41.2%5.8 mo9.3 moNeutropenia (52.5%), leukopenia (44.9%), thrombocytopenia (48.3%)
      MCAVI11930.3%

      P = 0.08
      4.2 mo

      P = 0.78
      8.1 mo

      P = 0.64
      Neutropenia (63.5%), leukopenia (46.6%), thrombocytopenia (19.4%)
      De Santis et al. 2016
      • De Santis M.
      • Wiechno P.J.
      • Bellmunt J.
      • Lucas C.
      • Su W.C.
      • Albiges L.
      • 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).
      Vinflunine + gemcitabineLocally advanced or metastatic UC (TCC predominant);

      ECOG PS 0–1, cisplatin ineligible
      3425.9 mo

      44.1%5.9 mo (4.2-9.4)14.0 mo (8.3-20.1)Neutropenia (38.2%), anemia (26.5%), thrombocytopenia (5.9%)
      Vinflunine + carboplatin3528.6%6.1 mo (4.6-10.4)12.8 mo (9.5-17.7)

      P = 0.86
      Neutropenia (65.7%), anemia (25.7%), thrombocytopenia (20.0%)
      De Wit et al. 1991
      • de Wit R.
      • Tesselaar M.
      • Kok T.C.
      • Seynaeve C.
      • Rodenburg C.J.
      • Verweij J.
      • et al.
      Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.
      CarboplatinMetastatic or unresectable urothelial TCC;

      WHO PS 0–2
      15NR0%NRNRThrombocytopenia (33.3%), leukocytopenia (20.0%)
      Iproplatin3217% (4–31)Thrombocytopenia (34.4%), leukocytopenia (3.1%)
      Dogliotti et al. 2007
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      Gemcitabine + cisplatin (21 d)Locally advanced or metastatic urothelial TCC; Zubrod PS 0–2557.2 mo65.9% (49.4–79.9)NR12.8 moNeutropenia (34.6%), thrombocytopenia (30.9%), anemia (20.0%), leukopenia (16.4%)
      Gemcitabine + carboplatin556.9 mo56.4% (39.6–72.2)9.8 moNeutropenia (45.4%), thrombocytopenia (38.2%), anemia (25.4%), leukopenia (29.1%)
      Dreicer et al. 2004
      • Dreicer R.
      • Manola J.
      • Roth B.J.
      • See W.A.
      • Kuross S.
      • Edelman M.J.
      • et al.
      Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
      MVACAdvanced or metastatic urothelial TCC;

      ECOG PS 0–2
      4332.5 mo35.9%(21.2–52.8)

      P = 0.63
      8.7 mo

      P = 0.24
      15.4 mo

      P = 0.65
      Neutropenia (67.4%), anemia (37.2%), thrombocytopenia (20.9%)
      Carboplatin + paclitaxel4130.8% (15.0–44.9)5.2 mo13.8 moNeutropenia (29.3%), anemia (4.9%), thrombocytopenia (9.8%)
      Haggag et al. 2014
      • Haggag R.
      • Farag K.
      • Abu-Taleb F.
      • Shamaa S.
      • Zekri A.R.
      • Elbolkainy T.
      • et al.
      Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update.
      Low-dose gemcitabine + cisplatin (21 d)Unresectable, recurrent, and/or metastatic urinary bladder cancer on top of bilharzial cystitis;

      ECOG PS  0-2
      609.5 mo41.7%NR12 mo (3.8–20.2)



      1-year OS: 49.9%
      Anemia (15.0%), neutropenia (10.0%), thrombocytopenia (15.0%)
      Standard-dose gemcitabine + cisplatin (21 d)6033.3%

      P = 0.37
      16 mo (6.5–25.5)

      1-year OS: 54.7%

      P = 0.8
      Anemia (23.3%), neutropenia (16.7%), thrombocytopenia (6.7%)
      Hussain et al. 2014
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      Gemcitabine + cisplatin (28 d)Metastatic or locally advanced/unresectable UC; ECOG PS  0-228NR57.1% (37–76)

      8.5 mo (5.7–10.4)

      17.4 mo (12.8–NYR)

      Neutropenia (42.8%), thrombocytopenia (39.3%), leukopenia (21.5%), anemia (10.7%)
      Gemcitabine + cisplatin + cetuximab (28 d)5961.4% (48–74)

      P = 0.81
      7.6 mo (6.1–8.7)

      P = 0.47
      14.3 mo (11.6–22.2)

      P = 0.43
      Neutropenia (40.7%), thrombocytopenia (25.5%), leukopenia (30.5%), anemia (8.5%)
      Krege et al. 2014
      • Krege S.
      • Rexer H.
      • vom Dorp F.
      • de Geeter P.
      • Klotz T.
      • Retz M.
      • et al.
      Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).
      Gemcitabine + cisplatin + sorafenib (21 d)Locally advanced or metastatic TCC of the bladder or upper urinary tract; ECOG PS 0–14018 mo52.5% (36.1–68.5)

      P = 0.67
      6.2 mo (3.2–9.5)

      P = 0.69
      11.2 mo (6.3–18.4)

      P = 0.66
      Leukopenia (12.2%), thrombocytopenia (12.2%), anemia (9.8%), pancytopenia (4.9%)
      Gemcitabine + cisplatin + placebo (21 d)4946.9% (32.5–61.7)6.0 (4.0-7.0)10.4 mo (8.4–14.9)Leukopenia (12.2%), thrombocytopenia (12.2%), anemia (14.3%), pancytopenia (8.2%)
      Kuroda et al. 1998
      • Kuroda M.
      • Kotake T.
      • Akaza H.
      • Hinotsu S.
      • Kakizoe T.
      Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group.
      Standard MECT3b, T4, or metastatic UC; WHO PS 0–224NR54%NRNRLeukopenia 38.9%, thrombocytopenia (12.5%), anemia (23.6%)
      Intensified MEC +

      G-CSF
      2475%Leukopenia (25.0%), thrombocytopenia (46.9%), anemia (17.2%)
      MVAC2442%Leukopenia (44.8%), thrombocytopenia (13.4%), anemia (16.4%)
      Logothetis et al. 1990
      • Logothetis C.J.
      • Dexeus F.H.
      • Finn L.
      • Sella A.
      • Amato R.J.
      • Ayala A.G.
      • et al.
      A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
      MVACMetastatic UC (pure TCC and mixed histologic types)55NR65% (52–77)

      P < 0.05
      NR11.2 mo

      (range, 1.2–37.4+)

      P < 0.001
      Leukopenic fever (14%) [frequency of toxicity courses]
      CISCA5546% (32–62)8.3 mo

      (range, 1.6–33.9+)
      Leukopenic fever (5%) [frequency of toxicity courses]
      Logothetis et al. 1995
      • Logothetis C.J.
      • Finn L.D.
      • Smith T.
      • Kilbourn R.G.
      • Ellerhorst J.A.
      • Zukiwski A.A.
      • et al.
      Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
      Escalated MVACMetastatic or locally advanced, unresectable UC;

      ECOG PS  0-3
      23NRNRNRNRAfter 3 courses: leukopenic fever (0%), infection (15%); median (nadir): platelets, 28; hemoglobin level, 8.1
      Escalated MVAC + GM-CSF25After 3 courses: leukopenic fever (9%), infection (41%); median (nadir): platelets, 10; hemoglobin level, 7.8
      Lorusso et al. 2005
      • Lorusso V.
      • Crucitta E.
      • Silvestris N.
      • Rosati G.
      • Manzione L.
      • De Lena M.
      • et al.
      Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
      Paclitaxel + gemcitabine + cisplatin (21 d)Metastatic or unresectable TCC of urinary tract;

      ECOG PS 0-2
      42NR43% (23–63)NR14.1 mo (range 0.5–19.6)Leukopenia (49%), thrombocytopenia (36%), anemia (20%)
      Gemcitabine + cisplatin (28 d)4344% (28–60)11.3 mo (range 0.5–16.6)Leukopenia (35%), thrombocytopenia (21%), anemia (24%)
      McCaffrey et al. 1997
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • Sadan S.
      • Heineman M.
      • Hirsch J.
      • et al.
      Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
      Gallium nitrate + fluorouracilUrothelial TCC;

      KPS 60%–80%
      1735 mo

      (2–51)
      12% (1.4–36.4)NR19 moAnemia (58.8%), neutropenia (0%), thrombocytopenia (0%)
      Dose-intensified MVAC + G-CSF1794% (71.3–99.8)17 moAnemia (70.6%), neutropenia (82.4%), thrombocytopenia (23.5%)
      Mead et al. 1998
      • Mead G.M.
      • Russell M.
      • Clark P.
      • Harland S.J.
      • Harper P.G.
      • Cowan R.
      • et al.
      A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.
      Methotrexate + vinblastineUnresectable, advanced or metastatic TCC106NR19%3 mo4.5 mo

      1-yr OS rate: 16%
      Neutropemic fever (1.9%), leukopenia (0%), thrombocytopenia (0%)
      Cisplatin + methotrexate + vinblastine10846%5.5 mo

      P = 0.0001
      7 mo

      1-yr OS rate: 29%

      P = 0.0065
      Neutropemic fever (10.2%), leukopenia (4.6%), thrombocytopenia (4.6%)
      Miller et al. 2016
      • Miller K.
      • Morant R.
      • Stenzl A.
      • Zuna I.
      • Wirth M.
      A phase II study of the Central European Society of anticancer-drug research (CESAR) group: results of an open-label study of gemcitabine plus cisplatin with or without concomitant or sequential gefitinib in patients with advanced or metastatic transitional cell carcinoma of the urothelium.
      Gemcitabine + cisplatin + gefitinib 250 mg QD, followed by gefitinib maintenance (21 d)Advanced or metastatic urothelial TCC;

      WHO PS 0–1
      35NR58.6%NR13.3 mo (10.5–19.2)Leukopenia (60.0%), anemia (28.6%), neutropenia (37.1%), pancytopenia (22.9%)
      Gemcitabine + cisplatin followed by gefitinib 250 mg QD (21 d)3753.3%8.5 mo (7.0–14.5)Leukopenia (54.1%), anemia (48.6%), neutropenia (18.9%), pancytopenia (18.9%)
      Gemcitabine + cisplatin followed by observation (21 d)3342.8%15.9 mo (10.9–31.3)Leukopenia (78.8%), anemia (30.3%), neutropenia (24.2%), pancytopenia (6.1%)
      Oudard et al. 2015
      • Oudard S.
      • Culine S.
      • Vano Y.
      • Goldwasser F.
      • Theodore C.
      • Nguyen T.
      • et al.
      Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
      Gemcitabine + cisplatin/carboplatin (21 d)Advanced or metastatic UC overexpressing Her2; ECOG PS 0-229NR65.5%

      10.2 mo (4.3–13.4)

      15.7 mo (12.2–23.6)

      Neutropenia (75.9%), thrombocytopenia (48.3%), anemia (41.4%)
      Gemcitabine + cisplatin/carboplatin + trastuzumab (21 d)3253.2%

      P = 0.39
      8.2 mo (4.6–10.6)

      P = 0.69
      14.1 mo (9.3–28.0)

      P = 0.68
      Neutropenia (67.7%), thrombocytopenia (38.7%), anemia (38.3%)
      Petrioli et al. 1996
      • Petrioli R.
      • Frediani B.
      • Manganelli A.
      • Barbanti G.
      • De Capua B.
      • De Lauretis A.
      • et al.
      Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients.
      MVECRecurrent or metastatic bladder cancer;

      ECOG PS  0-3
      2921

      (12–31)
      71.4%NR13 mo

      (range, 4–31+)
      During cycle 6 (grade 2–4): leukopenia (37%), thrombocytopenia (21%), anemia (25%)
      MVECa2840.7%9.5 mo

      (range, 3–27+)
      During cycle 6 (grade 2–4): leukopenia (58%), thrombocytopenia (26%), anemia (10%)
      Pizzocaro et al. 1991
      • Pizzocaro G.
      • Milani A.
      • Piva L.
      • Faustini M.
      • Spino E.
      Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer.
      MVACMetastatic TCC of the urinary tract14NR71.4%NRNRLeukopenia (14.3%), thrombocytopenia (14.3%), anemia (7.1%)
      Methotrexate + cisplatin1450.0%Leukopenia (7.1%), thrombocytopenia (7.1%), anemia (7.1%)
      Saxman et al. 1997
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      CisplatinMetastatic UC

      KPS ≥ 60%
      1226 yr (minimum)12% (7–19)

      4.3 mo8.2 mo

      Decreased platelets (1.6%) and leukocytes (0.8%)
      MVAC13339% (30–48)10.0 mo12.5 mo

      P = 0.00015
      Decreased platelets (4.8%) and leukocytes (19%)
      Siefker-Radtke et al. 2002
      • Siefker-Radtke A.O.
      • Millikan R.E.
      • Tu S.M.
      • Moore Jr., D.F.
      • Smith T.L.
      • Williams D.
      • et al.
      Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.
      MVACUnresectable, locally advanced or metastatic UC866059%NR12.5 moAnemia (23.3%), febrile neutropenia (19.8%), thrombocytopenia (7.0%)
      FAP836142%12.5 moAnemia (10.8%), febrile neutropenia (4.8%), thrombocytopenia (2.4%)
      Sternberg et al. 2006
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      MVACLocally advanced or metastatic TCC of the urinary tract;

      WHO PS 0–2
      1297.3 y58% (48–67)

      P = 0.06
      8.1 mo (7.0–9.9)

      P = 0.017
      14.9 mo

      5-yr OS rate: 13.5%
      Whole blood cell (62.0%), platelets (17.1%), neutropenic fever (25.6%)
      HD-MVAC + G-CSF13472%

      P = 0.016
      9.5 mo (7.6–12.2)

      P = 0.017
      15.1 mo

      5-yr OS rate: 21.8%

      P = 0.042
      Whole blood cell (20.1%), platelets (20.9%), neutropenic fever (9.7%)
      Sternberg et al. 2013
      • Sternberg C.N.
      • Skoneczna I.A.
      • Castellano D.
      • Theodore C.
      • Blais N.
      • Voog E.
      • et al.
      Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB).
      Larotaxel + cisplatinLocally advanced or metastatic urothelial or bladder TCC;

      ECOG PS 0–2
      166NR31% (22–41)5.6 mo (4.1–6.2)13.7 mo (11.2–17.1)

      P = 0.33
      Neutropenia (34.0%), leukopenia (16.0%), anemia (7.4%), thrombocytopenia (1.9%)
      Gemcitabine + cisplatin (28 d)17143% (33–52)7.6 mo (6.6–9.1)14.3 mo (10.5–NYR)Neutropenia (60.2%), leukopenia (42.2%), anemia (21.7%), thrombocytopenia (45.2%)
      Trump et al. 1990
      • Trump D.L.
      • Elson P.
      • Madajewicz S.
      • Dickman S.H.
      • Hahn R.G.
      • Harris J.E.
      • et al.
      Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
      CarboplatinMetastatic urothelial TCC;

      ECOG PS 0–3
      32NR14% (3–35)NR5.0 mo

      P = 0.76
      Severe or life-threatening myelosuppression-primarily thrombocytopenia (31%)
      Iproplatin (CHIP)3216% (5–36)4.3 moSevere or life-threatening myelosuppression-primarily thrombocytopenia (34%)
      von der Maase et al. 2005
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      MVACLocally advanced or metastatic urothelial TCC; KPS ≥ 702025 y45.7%

      P = 0.51
      8.3 mo (7.3–9.7)

      P = 0.63
      15.2 mo (13.2–17.3)

      P = 0.66

      5-yr OS rate: 13.0%
      Neutropenia (82%), thrombocytopenia (57%), anemia (27%)
      Gemcitabine + cisplatin (28 d)20349.4%7.7 mo (6.8–8.8)14 mo (12.3–15.5)

      5-yr OS rate: 15.3%
      Neutropenia (71%), thrombocytopenia (21%), anemia (18%)
      Where reported, P values indicate between-group differences.
      ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHIP, cis-dichloro-trans-dihyroxy-bis-isopropylamine platinum IV; CI, confidence interval; d, days; DD, dose dense; DVT, deep vein thrombosis; ECOG, Eastern Cooperative Oncology Group; FAP, fluorouracil, interferon–alpha-2b, and cisplatin; G-CSF, granulocyte–colony stimulating factor; HD, high dose; ITT, intent-to-treat (population); KPS, Karnofsky performance status; max, maximum; MCAVI, methotrexate, carboplatin, and vinblastine; MEC, methotrexate, epirubicin, and cisplatin; mo, months; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; MVEC, methotrexate, vinblastine, epirubicin, and cisplatin; MVECa, methotrexate, vinblastine, epirubicin, and carboplatin; NR, not reported; NYR, not yet reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; QD, once daily; TCC, transitional cell carcinoma; UC, urothelial carcinoma; WHO, World Health Organization; wk, weeks; y, years.
      a P = 0.017 for MVAC versus docetaxel + cisplatin; however, P = 0.100 when all randomized patients were analyzed and non-assessable patients were considered non-responders.
      Efficacy data from studies of approved and experimental first-line treatments for UC are summarized in Table 2. In brief, median overall survival (OS) ranged from 4.3 months with iproplatin [
      • Trump D.L.
      • Elson P.
      • Madajewicz S.
      • Dickman S.H.
      • Hahn R.G.
      • Harris J.E.
      • et al.
      Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
      ] to 20.2 months with dose-dense MVAC [
      • Culine S.
      • Flechon A.
      • Gravis G.
      • Roubaud G.
      • Loriot Y.
      • Joly F.
      • et al.
      Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
      ]. For standard of care regimens, gemcitabine plus cisplatin has shown improved OS versus gemcitabine plus carboplatin, although this difference did not reach statistical significance (median OS of 12.8 vs 9.8 months, respectively) [
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      ]. When MVAC was compared with gemcitabine plus cisplatin in a randomized phase III trial, no significant differences in any efficacy endpoint were observed [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ,
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ]. ORR was 49.4% with gemcitabine plus cisplatin and 45.7% with MVAC [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ]. Follow-up analyses from this study showed a median OS of 14.0 months with gemcitabine plus cisplatin and 15.2 months with MVAC, and 5-year OS rates of 13.0% and 15.3%, respectively [
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ]. Median PFS was 7.7 months with gemcitabine plus cisplatin and 8.3 months with MVAC.
      In most trials of MVAC chemotherapy, patients had longer OS (range, 12.1–20.2 months) [
      • Culine S.
      • Flechon A.
      • Gravis G.
      • Roubaud G.
      • Loriot Y.
      • Joly F.
      • et al.
      Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
      ,
      • Logothetis C.J.
      • Dexeus F.H.
      • Finn L.
      • Sella A.
      • Amato R.J.
      • Ayala A.G.
      • et al.
      A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
      ] than those who received other chemotherapies, such as methotrexate, carboplatin, and vinblastine (MCAVI) or docetaxel plus cisplatin (8.2–19 months) [
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ,
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      ,
      • Bellmunt J.
      • Ribas A.
      • Eres N.
      • Albanell J.
      • Almanza C.
      • Bermejo B.
      • et al.
      Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.
      ,
      • Bamias A.
      • Aravantinos G.
      • Deliveliotis C.
      • Bafaloukos D.
      • Kalofonos C.
      • Xiros N.
      • et al.
      Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
      ]. In a phase III study that compared MVAC with supportive granulocyte-colony stimulating factor (G-CSF) to docetaxel plus cisplatin with G-CSF, median OS was 14.2 months for patients in the MVAC arm and 9.3 months for those in the docetaxel plus cisplatin arm (P = 0.026) [
      • Bamias A.
      • Aravantinos G.
      • Deliveliotis C.
      • Bafaloukos D.
      • Kalofonos C.
      • Xiros N.
      • et al.
      Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
      ]. Similar trends were seen for PFS – MVAC chemotherapy was associated with longer PFS (range, 8.1–10 months) compared with other chemotherapies (4.3–7.8 months). However, a phase III study by the EORTC showed improved survival outcomes with high-dose MVAC plus G-CSF versus standard MVAC [
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      ]; PFS was 9.5 months with high-dose MVAC plus G-CSF versus 8.1 months for standard MVAC (P = 0.017), with a 5-year OS rate of 21.8% versus 13.5% (P = 0.042), respectively [
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      ].
      Two randomized studies investigated the addition of paclitaxel to gemcitabine plus cisplatin compared with gemcitabine plus cisplatin [
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      ,
      • Lorusso V.
      • Crucitta E.
      • Silvestris N.
      • Rosati G.
      • Manzione L.
      • De Lena M.
      • et al.
      Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
      ]. Both trials administered the paclitaxel regimen every 21 days and gemcitabine plus cisplatin every 28 days. In the phase III EORTC Intergroup Study 30987 [
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      ], median OS was 15.8 months with paclitaxel and gemcitabine plus cisplatin versus 12.7 months with gemcitabine plus cisplatin (P = 0.075). In the eligible patient population, a significant improvement in OS by 3.2 months was observed with the addition of paclitaxel (P = 0.03). Median PFS was 8.3 months with paclitaxel and gemcitabine plus cisplatin versus 7.6 months with gemcitabine plus cisplatin, although this did not reach statistical significance. However, ORR was significantly higher with paclitaxel and gemcitabine plus cisplatin compared with gemcitabine plus cisplatin (55.5% vs 43.6%; P = 0.031).
      Several studies have evaluated combinations of targeted agents with chemotherapy. One trial assessed gemcitabine plus cisplatin concomitant with or followed by gefitinib (sequential treatment), an inhibitor of epidermal growth factor receptor (EGFR), 250 mg once daily [
      • Miller K.
      • Morant R.
      • Stenzl A.
      • Zuna I.
      • Wirth M.
      A phase II study of the Central European Society of anticancer-drug research (CESAR) group: results of an open-label study of gemcitabine plus cisplatin with or without concomitant or sequential gefitinib in patients with advanced or metastatic transitional cell carcinoma of the urothelium.
      ]. Treatment without gefitinib led to an OS of 15.9 months, whereas gefitinib resulted in a median OS of 13.3 months for concomitant treatment and 8.5 months for sequential treatment. OS, PFS, and ORR were similar for gemcitabine plus cisplatin in combination with sorafenib (a multi-kinase inhibitor) [
      • Krege S.
      • Rexer H.
      • vom Dorp F.
      • de Geeter P.
      • Klotz T.
      • Retz M.
      • et al.
      Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).
      ], trastuzumab (anti–HER2 antibody) [
      • Oudard S.
      • Culine S.
      • Vano Y.
      • Goldwasser F.
      • Theodore C.
      • Nguyen T.
      • et al.
      Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
      ], and cetuximab (anti-EGFR antibody) [
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      ], compared with gemcitabine plus cisplatin alone or plus placebo.

      First-line therapy with IO agents

      Evidence to support the initial regulatory approvals of IO agents as first-line treatments for advanced UC were based on the results of multicenter, single-arm, phase II studies with objective response or ORR as the primary endpoints (Table 3). In the IMvigor210 study of cisplatin-ineligible patients, atezolizumab treatment resulted in an ORR of 23%, with median PFS of 2.7 months and median OS of 15.9 months [
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      ]. An ORR of 28% was reported for IC membrane positivity of PD-L1 ≥ 5% and 21% for IC membrane positivity of PD-L1 < 1%. In an updated analysis at a median follow-up of > 2 years, ORR was 24% and median OS was 16.3 months with 1- and 2-year OS rates of 58% and 41%, respectively [
      • Balar A.V.
      • Dreicer R.
      • Loriot Y.
      • Perez-Gracia J.L.
      • Hoffman-Censits J.H.
      • Petrylak D.
      • et al.
      Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): long-term efficacy from phase 2 study IMvigor210.
      ]. In the KEYNOTE-052 study of cisplatin-ineligible patients treated pembrolizumab, an ORR of 24% was reported [
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Vuky J.
      • Powles T.
      • 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.
      ]. A follow-up analysis showed a confirmed ORR of 29% and median OS of 11.5 months [
      • Vuky J.
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Bellmunt J.
      • et al.
      Updated efficacy and safety of KEYNOTE-052: a single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
      ]. However, in patients with a CPS ≥ 10 for PD-L1 expression, the ORR was 47% and median OS was 18.5 months.
      Table 3Clinical trial results of first-line IO therapy for advanced UC.
      Study [Ref]InterventionPopulationN

      (All/PD-L1 high)
      Follow-up (median)ResponsePFS

      (median)
      OS

      (median)
      OS rate
      All patientsPD-L1 high
      Phase II (IMvigor210)
      PD-L1 assessed using the VENTANA SP142 assay: IC PD-L1 staining ≥ 5% as a proportion of the total TC and IC area.


      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      Atezolizumab monotherapyCisplatin-ineligible119/3217.2 mo23%28%2.7 mo15.9 mo1-yr: 57%
      Phase II (IMvigor210)

      • Balar A.V.
      • Dreicer R.
      • Loriot Y.
      • Perez-Gracia J.L.
      • Hoffman-Censits J.H.
      • Petrylak D.
      • et al.
      Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): long-term efficacy from phase 2 study IMvigor210.
      Atezolizumab monotherapyCisplatin-ineligible119/3229 mo24%16.3 mo1-yr: 58%

      2-yr: 41%
      Phase II (KEYNOTE-052)
      PD-L1 assessed using the pharmDx 22C assay: CPS ≥ 10.


      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Vuky J.
      • Powles T.
      • 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.
      Pembrolizumab monotherapyCisplatin-ineligible370/1105 mo24%38%2 mo
      Phase II (KEYNOTE-052)
      PD-L1 assessed using the pharmDx 22C assay: CPS ≥ 10.


      • Vuky J.
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Bellmunt J.
      • et al.
      Updated efficacy and safety of KEYNOTE-052: a single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
      Pembrolizumab monotherapyCisplatin-ineligible370/11011.5 mo29%47%2.3 mo11.5 mo1-yr: 48%
      Phase II

      • Galsky M.D.
      • Wang H.
      • Hahn N.M.
      • Twardowski P.
      • Pal S.K.
      • Albany C.
      • et al.
      Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes.
      GC followed by GC + ipilimumabCisplatin-eligible3639%7.9 mo13.9 mo1-yr: 61%

      2-yr: 31%
      Phase III (IMvigor130)
      PD-L1 assessed using the VENTANA SP142 assay: IC PD-L1 staining ≥ 5% as a proportion of the total TC and IC area.


      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      Atezolizumab + CTCisplatin-eligible, cisplatin-ineligible451/10811.8 mo47%8.2 mo16.0 mo
      Atezolizumab360/8823%39%15.7 mo
      Placebo + CT400/9144%44%6.3 mo13.4 mo
      Phase III (JAVELIN Bladder 100)
      PD-L1 assessed using the VENTANA SP263 assay: TC PD-L1 staining ≥ 25%, or ≥ 25% or 100% of ICs if the percentage of ICs was > 1% or ≤ 1%, respectively.

      Powles T, Park SH, Voog E, Caserta C, B.P. V, Gurney H. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:Abst LBA1. DOI: 10.1200/JCO.2020.38.18_suppl.LBA1.

      Avelumab + BSCCisplatin-eligible, cisplatin-ineligible3509.7%13.8%3.7 mo21.4 mo
      From randomization (after chemotherapy).
      1-yr: 71%
      BSC alone3501.4%1.2%2.0 mo14.3 mo
      From randomization (after chemotherapy).
      1-yr: 58%
      BSC, best supportive care; GC, gemcitabine plus cisplatin; CT, platinum-based chemotherapy; mo, months; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
      a PD-L1 assessed using the VENTANA SP142 assay: IC PD-L1 staining ≥ 5% as a proportion of the total TC and IC area.
      b PD-L1 assessed using the pharmDx 22C assay: CPS ≥ 10.
      c PD-L1 assessed using the VENTANA SP263 assay: TC PD-L1 staining ≥ 25%, or ≥ 25% or 100% of ICs if the percentage of ICs was > 1% or ≤ 1%, respectively.
      d From randomization (after chemotherapy).
      As platinum-based chemotherapy has been the standard of care for the first-line treatment of advanced UC for almost two decades, the efficacy of IO agents in combination with chemotherapy is of interest. One of the earliest studies to evaluate such a combination was a multicenter, single-arm, phase II study in 36 chemotherapy-naive patients [
      • Galsky M.D.
      • Wang H.
      • Hahn N.M.
      • Twardowski P.
      • Pal S.K.
      • Albany C.
      • et al.
      Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes.
      ]. In this study, gemcitabine plus cisplatin followed by ipilimumab in combination with gemcitabine plus cisplatin yielded an ORR of 69% and a 1-year OS rate of 61%. Median PFS was 7.9 months. More recently, the results of the phase III IMvigor130 study were reported, which evaluated atezolizumab with or without platinum-based chemotherapy in untreated, cisplatin-eligible and cisplatin-ineligible patients with advanced UC [
      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      ]. This study demonstrated a significant improvement in PFS with atezolizumab plus platinum-based chemotherapy versus chemotherapy alone (median PFS of 8.2 vs 6.3 months). Subgroup analyses showed that longer PFS was observed among both cisplatin-eligible and cisplatin-ineligible patients. Median OS was 16.0 months with atezolizumab plus platinum-based chemotherapy versus 13.4 months with chemotherapy alone, but this difference did not reach statistical significance. In contrast, it was reported on June 9, 2020 that the KEYNOTE-361 study did not meet either of its co-primary endpoints, as pembrolizumab plus platinum-based chemotherapy did not yield a statistically significant improvement in PFS or OS versus chemotherapy in patients with untreated advanced UC [

      Merck/MSD. Merck provides update on phase 3 KEYNOTE-361 trial evaluating KEYTRUDA® (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma [press release]. 2020. https://investors.merck.com/news/press-release-details/2020/Merck-Provides-Update-on-Phase-3-KEYNOTE-361-Trial-Evaluating-KEYTRUDA-pembrolizumab-as-Monotherapy-and-in-Combination-with-Chemotherapy-in-Patients-with-Advanced-or-Metastatic-Urothelial-Carcinoma/default.aspx. accessed June 10, 2020.

      ].
      Data are emerging from ongoing phase III studies evaluating different regimens for untreated advanced UC, such as IO plus IO combinations as potential non-chemotherapy treatment options or IO agents as maintenance therapy. Although results have yet to be published, it was revealed that the DANUBE trial did not meet the primary endpoints of improved OS with durvalumab versus standard of care chemotherapy in patients with high tumor PD-L1 expression (≥ 25% of tumor or tumor-associated immune cells staining positive for PD-L1) nor with durvalumab plus tremelimumab versus standard of care chemotherapy in all randomized patients [

      AstraZeneca. Update on phase III DANUBE trial for imfinzi and tremelimumab in unresectable, stage IV bladder cancer [press release] March 6, 2020. 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html. accessed June 15, 2020.

      ]. In the JAVELIN Bladder 100 trial, patients with untreated advanced UC who achieved an objective response or stable disease with platinum-based chemotherapy were randomized to maintenance avelumab plus best supportive care or best supportive care [

      Powles T, Park SH, Voog E, Caserta C, B.P. V, Gurney H. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:Abst LBA1. DOI: 10.1200/JCO.2020.38.18_suppl.LBA1.

      ]. From the date of randomization (after chemotherapy), median OS was 21.4 months for avelumab versus 14.3 for best supportive care. Longer OS with avelumab was observed in both patients who had received gemcitabine plus cisplatin and in those who had received gemcitabine plus carboplatin.

      Safety of first-line treatments for advanced UC

      While the survival outcomes with gemcitabine plus cisplatin are similar to those of MVAC in advanced UC [
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ], the former has an overall better safety profile and thus higher benefit-risk ratio compared with MVAC (Table 2) [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ]. Common adverse events (AEs) with gemcitabine plus cisplatin include anemia, diarrhea, thrombocytopenia, and neutropenia. When compared with MVAC, patients treated with gemcitabine plus cisplatin have higher rates of grade 3–4 anemia (27% vs 18%) and grade 3–4 thrombocytopenia (57% vs 21%) [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ]. However, higher rates of grade 3–4 AEs reported for MVAC compared with gemcitabine plus cisplatin include neutropenia (82% vs 71%), alopecia (55% vs 11%), mucositis (22% vs 1%), infection (15% vs 3%), diarrhea (8% vs 3%), and pulmonary (6% vs 3%) [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ]. The frequency of severe toxicities is also higher in patients treated with MVAC compared with gemcitabine plus carboplatin, with grade 4 AEs in 33% and 15% of patients, respectively [
      • Dreicer R.
      • Manola J.
      • Roth B.J.
      • See W.A.
      • Kuross S.
      • Edelman M.J.
      • et al.
      Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
      ]. As expected, the addition of G-CSF to MVAC results in considerably lower frequencies of toxicities than reported for MVAC without G-CSF [
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      ].
      In the phase III study of advanced UC in which dose-dense gemcitabine plus cisplatin (over 14 days) was compared with dose-dense MVAC, the former was shown to have better tolerability [
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ]. Grade 3–4 AEs were reported in 50% of patients in the dose-dense MVAC group and in 44% of patients in the dose-dense gemcitabine plus cisplatin group, with discontinuations due to toxicity of 13% and 3%, respectively. Neutropenic infections, in particular, occurred less frequently in the gemcitabine plus cisplatin group than in the MVAC group (0% vs 8%). Conversely, studies that have compared MVAC with other experimental regimens have shown a more favorable safety profile with MVAC. In one such study, non-hematologic AEs of at least grade 3 were reported in 48% of patients who received MVAC compared with 71% of patients who received fluorouracil plus interferon–alpha-2b and cisplatin [
      • Siefker-Radtke A.O.
      • Millikan R.E.
      • Tu S.M.
      • Moore Jr., D.F.
      • Smith T.L.
      • Williams D.
      • et al.
      Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.
      ].
      For IO agents, the safety profile observed across studies of advanced UC was generally consistent with that reported in other tumor types. In the IMvigor210 study, treatment-related AEs of any grade and of grade 3–4 occurred in 66% and 16% of patients treated with atezolizumab, respectively, the most common being fatigue, diarrhea, and pruritus [
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      ]. Among 119 treated patients, one death was due to study drug toxicity. In the CheckMate-052 study, treatment-related AEs of any grade and of grade 3–4 occurred in 68% and 20% of patients treated with pembrolizumab, respectively, the most common being fatigue and pruritus [
      • Vuky J.
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Bellmunt J.
      • et al.
      Updated efficacy and safety of KEYNOTE-052: a single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
      ]. One death among 370 treated patients was related to study drug toxicity. As expected, the rate of AEs was higher in the IMvigor130 trial. AEs (any causality) were reported in > 99% of patients in the atezolizumab plus platinum-based chemotherapy group and in 99% of patients in the chemotherapy group, with grade 3–4 AEs in 85% and 86% of patients, respectively [
      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      ]. Treatment-related AEs of any grade and of grade 3–4 were reported in 96% and 81% of patients, respectively, in both groups. AEs leading to treatment discontinuation occurred in 34% of patients in both groups. Deaths related to study drug toxicity were reported in 6% of patients in the atezolizumab plus platinum-based chemotherapy group and in 5% of patients in the chemotherapy group. In the JAVELIN Bladder 100 trial, the rate of treatment-emergent AEs (any causality) of any grade and of grade 3–4 were similar to that reported for atezolizumab monotherapy in IMvigor130 (98% vs 93% and 47% vs 42%) [
      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      ,

      Powles T, Park SH, Voog E, Caserta C, B.P. V, Gurney H. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:Abst LBA1. DOI: 10.1200/JCO.2020.38.18_suppl.LBA1.

      ], suggesting that prior chemotherapy does not meaningfully impact the safety profile of an IO agent used as first-line maintenance therapy.

      HRQoL assessments

      Among nine clinical trials that reported HRQoL results in ten publications (Fig. 1B), three were RCTs of first-line chemotherapy. In the phase III that compared gemcitabine plus cisplatin and MVAC, HRQoL was assessed (using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire –Core 30 [EORTC QLQ-C30]) in 165 of 203 (81%) patients in the gemcitabine plus cisplatin arm and in 161 of 202 patients (80%) in the MVAC arm, with on-study compliance in 87.2% and 84.4% of patients, respectively [
      • von der Maase H.
      • Hansen S.W.
      • Roberts J.T.
      • Dogliotti L.
      • Oliver T.
      • Moore M.J.
      • 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.
      ]. HRQoL was similar in both groups, with improvements from baseline in median scores for emotional functioning and pain. However, fewer patients in the gemcitabine plus cisplatin arm reported a ≥ 10-point worsening of fatigue from baseline compared with the MVAC arm (44% and 49%, respectively). The authors noted that the better safety and tolerability of gemcitabine plus cisplatin compared with MVAC was not reflected in the HRQoL results; this might be partially due to the use of generic HRQoL questionnaires as opposed to disease- or treatment-specific instruments and, therefore, may not have addressed the presence of any toxicities (such as mucositis and neutropenic sepsis) that are of a particular concern in the treatment of UC with MVAC. Another explanation could be that patients who discontinued therapy because of toxicity may not have completed a questionnaire at that cycle. In a separate analysis of data from this trial, certain HRQoL parameters (such as high physical functioning, low role functioning, and no anorexia), were found to be predictive of longer survival in univariate models [
      • Roychowdhury D.F.
      • Hayden A.
      • Liepa A.M.
      Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.
      ].

      Assessment of study bias and gaps in evidence

      We used the criteria of the Centre for Reviews and Dissemination, University of York, [
      • Centre for Reviews and Dissemination
      Systematic reviews: CRD's guidance for undertaking reviews in health care.
      ] to assess the quality of the included RCTs. The assessment included selection bias, performance bias, attrition bias, crossover effects, and detection bias (ie, whether a precise definition of outcome assessment was provided and use of valid and reliable methods to assess outcomes). Overall risk of bias was determined to be low in five studies [
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • Kerst J.M.
      • Leahy M.
      • Maroto P.
      • 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.
      ,
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ,
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      ,
      • Lorusso V.
      • Crucitta E.
      • Silvestris N.
      • Rosati G.
      • Manzione L.
      • De Lena M.
      • et al.
      Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
      ,
      • De Santis M.
      • Wiechno P.J.
      • Bellmunt J.
      • Lucas C.
      • Su W.C.
      • Albiges L.
      • 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).
      ], moderate in two studies [
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Vuky J.
      • Powles T.
      • 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.
      ,
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ], high in seven studies [
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      ,
      • Bamias A.
      • Aravantinos G.
      • Deliveliotis C.
      • Bafaloukos D.
      • Kalofonos C.
      • Xiros N.
      • et al.
      Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
      ,
      • Miller K.
      • Morant R.
      • Stenzl A.
      • Zuna I.
      • Wirth M.
      A phase II study of the Central European Society of anticancer-drug research (CESAR) group: results of an open-label study of gemcitabine plus cisplatin with or without concomitant or sequential gefitinib in patients with advanced or metastatic transitional cell carcinoma of the urothelium.
      ,
      • Krege S.
      • Rexer H.
      • vom Dorp F.
      • de Geeter P.
      • Klotz T.
      • Retz M.
      • et al.
      Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).
      ,
      • Culine S.
      • Flechon A.
      • Guillot A.
      • Le Moulec S.
      • Pouessel D.
      • Rolland F.
      • et al.
      Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01).
      ,
      • Mead G.M.
      • Russell M.
      • Clark P.
      • Harland S.J.
      • Harper P.G.
      • Cowan R.
      • et al.
      A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.
      ,
      • Sternberg C.N.
      • Skoneczna I.A.
      • Castellano D.
      • Theodore C.
      • Blais N.
      • Voog E.
      • et al.
      Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB).
      ], and very high in sixteen studies [
      • Haggag R.
      • Farag K.
      • Abu-Taleb F.
      • Shamaa S.
      • Zekri A.R.
      • Elbolkainy T.
      • et al.
      Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update.
      ,
      • Trump D.L.
      • Elson P.
      • Madajewicz S.
      • Dickman S.H.
      • Hahn R.G.
      • Harris J.E.
      • et al.
      Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
      ,
      • Logothetis C.J.
      • Dexeus F.H.
      • Finn L.
      • Sella A.
      • Amato R.J.
      • Ayala A.G.
      • et al.
      A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
      ,
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      ,
      • Bellmunt J.
      • Ribas A.
      • Eres N.
      • Albanell J.
      • Almanza C.
      • Bermejo B.
      • et al.
      Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.
      ,
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      ,
      • Oudard S.
      • Culine S.
      • Vano Y.
      • Goldwasser F.
      • Theodore C.
      • Nguyen T.
      • et al.
      Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
      ,
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      ,
      • Dreicer R.
      • Manola J.
      • Roth B.J.
      • See W.A.
      • Kuross S.
      • Edelman M.J.
      • et al.
      Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
      ,
      • Siefker-Radtke A.O.
      • Millikan R.E.
      • Tu S.M.
      • Moore Jr., D.F.
      • Smith T.L.
      • Williams D.
      • et al.
      Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.
      ,
      • de Wit R.
      • Tesselaar M.
      • Kok T.C.
      • Seynaeve C.
      • Rodenburg C.J.
      • Verweij J.
      • et al.
      Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.
      ,
      • Kuroda M.
      • Kotake T.
      • Akaza H.
      • Hinotsu S.
      • Kakizoe T.
      Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group.
      ,
      • Logothetis C.J.
      • Finn L.D.
      • Smith T.
      • Kilbourn R.G.
      • Ellerhorst J.A.
      • Zukiwski A.A.
      • et al.
      Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
      ,
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • Sadan S.
      • Heineman M.
      • Hirsch J.
      • et al.
      Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
      ,
      • Petrioli R.
      • Frediani B.
      • Manganelli A.
      • Barbanti G.
      • De Capua B.
      • De Lauretis A.
      • et al.
      Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients.
      ,
      • Pizzocaro G.
      • Milani A.
      • Piva L.
      • Faustini M.
      • Spino E.
      Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer.
      ]. The results of one study were published as a meeting abstract and therefore its quality was not assessed based on a lack of reported information [
      • Culine S.
      • Flechon A.
      • Gravis G.
      • Roubaud G.
      • Loriot Y.
      • Joly F.
      • et al.
      Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
      ].
      Among the RCTs that investigated the efficacy and safety of chemotherapy in advanced UC, 16 reported an appropriate method of randomization and five reported adequate allocation concealment. In 21 studies, patient baseline characteristics across treatment arms were comparable [
      • De Santis M.
      • Bellmunt J.
      • Mead G.
      • Kerst J.M.
      • Leahy M.
      • Maroto P.
      • 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.
      ,
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      ,
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ,
      • Haggag R.
      • Farag K.
      • Abu-Taleb F.
      • Shamaa S.
      • Zekri A.R.
      • Elbolkainy T.
      • et al.
      Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update.
      ,
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ,
      • Logothetis C.J.
      • Dexeus F.H.
      • Finn L.
      • Sella A.
      • Amato R.J.
      • Ayala A.G.
      • et al.
      A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
      ,
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      ,
      • Bellmunt J.
      • Ribas A.
      • Eres N.
      • Albanell J.
      • Almanza C.
      • Bermejo B.
      • et al.
      Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.
      ,
      • Bamias A.
      • Aravantinos G.
      • Deliveliotis C.
      • Bafaloukos D.
      • Kalofonos C.
      • Xiros N.
      • et al.
      Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
      ,
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • Theodore C.
      • Fossa S.D.
      • van Oosterom A.T.
      • 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.
      ,
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      ,
      • Lorusso V.
      • Crucitta E.
      • Silvestris N.
      • Rosati G.
      • Manzione L.
      • De Lena M.
      • et al.
      Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
      ,
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      ,
      • Dreicer R.
      • Manola J.
      • Roth B.J.
      • See W.A.
      • Kuross S.
      • Edelman M.J.
      • et al.
      Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
      ,
      • Siefker-Radtke A.O.
      • Millikan R.E.
      • Tu S.M.
      • Moore Jr., D.F.
      • Smith T.L.
      • Williams D.
      • et al.
      Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.
      ,
      • De Santis M.
      • Wiechno P.J.
      • Bellmunt J.
      • Lucas C.
      • Su W.C.
      • Albiges L.
      • 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).
      ,
      • Culine S.
      • Flechon A.
      • Guillot A.
      • Le Moulec S.
      • Pouessel D.
      • Rolland F.
      • et al.
      Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01).
      ,
      • Mead G.M.
      • Russell M.
      • Clark P.
      • Harland S.J.
      • Harper P.G.
      • Cowan R.
      • et al.
      A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.
      ,
      • Kuroda M.
      • Kotake T.
      • Akaza H.
      • Hinotsu S.
      • Kakizoe T.
      Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group.
      ,
      • Logothetis C.J.
      • Finn L.D.
      • Smith T.
      • Kilbourn R.G.
      • Ellerhorst J.A.
      • Zukiwski A.A.
      • et al.
      Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
      ,
      • Petrioli R.
      • Frediani B.
      • Manganelli A.
      • Barbanti G.
      • De Capua B.
      • De Lauretis A.
      • et al.
      Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients.
      ]. One study did not report baseline characteristics of the patients [
      • Pizzocaro G.
      • Milani A.
      • Piva L.
      • Faustini M.
      • Spino E.
      Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer.
      ]. Seven studies used open-label designs [
      • Dogliotti L.
      • Carteni G.
      • Siena S.
      • Bertetto O.
      • Martoni A.
      • Bono A.
      • et al.
      Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
      ,
      • Bamias A.
      • Dafni U.
      • Karadimou A.
      • Timotheadou E.
      • Aravantinos G.
      • Psyrri A.
      • et al.
      Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
      ,
      • von der Maase H.
      • Sengelov L.
      • Roberts J.T.
      • Ricci S.
      • Dogliotti L.
      • Oliver T.
      • 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.
      ,
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • Skoneczna I.
      • De Santis M.
      • Daugaard G.
      • 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.
      ,
      • Lorusso V.
      • Crucitta E.
      • Silvestris N.
      • Rosati G.
      • Manzione L.
      • De Lena M.
      • et al.
      Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
      ,
      • Oudard S.
      • Culine S.
      • Vano Y.
      • Goldwasser F.
      • Theodore C.
      • Nguyen T.
      • et al.
      Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
      ,
      • De Santis M.
      • Wiechno P.J.
      • Bellmunt J.
      • Lucas C.
      • Su W.C.
      • Albiges L.
      • 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).
      ], and six had a crossover design [
      • Trump D.L.
      • Elson P.
      • Madajewicz S.
      • Dickman S.H.
      • Hahn R.G.
      • Harris J.E.
      • et al.
      Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
      ,
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      ,
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      ,
      • de Wit R.
      • Tesselaar M.
      • Kok T.C.
      • Seynaeve C.
      • Rodenburg C.J.
      • Verweij J.
      • et al.
      Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.
      ,
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • Sadan S.
      • Heineman M.
      • Hirsch J.
      • et al.
      Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
      ,
      • Pizzocaro G.
      • Milani A.
      • Piva L.
      • Faustini M.
      • Spino E.
      Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer.
      ], which may have impacted survival outcomes in four cases [
      • Trump D.L.
      • Elson P.
      • Madajewicz S.
      • Dickman S.H.
      • Hahn R.G.
      • Harris J.E.
      • et al.
      Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
      ,
      • Saxman S.B.
      • Propert K.J.
      • Einhorn L.H.
      • Crawford E.D.
      • Tannock I.
      • Raghavan D.
      • et al.
      Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
      ,
      • Hussain M.
      • Daignault S.
      • Agarwal N.
      • Grivas P.D.
      • Siefker-Radtke A.O.
      • Puzanov I.
      • et al.
      A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
      ,
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • Sadan S.
      • Heineman M.
      • Hirsch J.
      • et al.
      Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
      ]. All trials used Response Evaluation Criteria In Solid Tumors or World Health Organization (WHO) criteria to assess ORRs and National Cancer Institute or WHO criteria to grade AEs, and most included precise definitions of survival outcomes.

      Discussion

      Platinum-based combination chemotherapy has remained the standard of care for the first-line treatment of advanced UC for two decades. Most treatment guidelines recommend gemcitabine plus cisplatin or MVAC for cisplatin-eligible patients. However, given that the efficacy of these two regimens is similar, gemcitabine plus cisplatin is most commonly used due to a better overall safety profile compared with MVAC. Some guidelines (EAU) also recommend paclitaxel in combination with gemcitabine plus cisplatin for eligible patients, whereas other guidelines (NCCN) do not recommend this regimen based on the risk–benefit profile. Patients unfit to receive cisplatin, often due to impaired renal function, can be treated with carboplatin-based regimens which are less nephrotoxic [
      • Yafi F.A.
      • North S.
      • Kassouf W.
      First- and second-line therapy for metastatic urothelial carcinoma of the bladder.
      ]. Although survival outcomes with gemcitabine plus carboplatin are worse than with gemcitabine plus cisplatin, patients unfit for cisplatin typically have prognostic factors that are associated with poor survival outcomes.
      In accordance with treatment guidelines, most RCTs used cisplatin-based therapies as comparators (MVAC and gemcitabine plus cisplatin). Among the studies that assessed guideline-recommended treatments, dose-dense MVAC was associated with the longest OS and highest ORR [
      • Culine S.
      • Flechon A.
      • Gravis G.
      • Roubaud G.
      • Loriot Y.
      • Joly F.
      • et al.
      Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
      ,
      • Oudard S.
      • Culine S.
      • Vano Y.
      • Goldwasser F.
      • Theodore C.
      • Nguyen T.
      • et al.
      Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
      ,
      • McCaffrey J.A.
      • Hilton S.
      • Mazumdar M.
      • Sadan S.
      • Heineman M.
      • Hirsch J.
      • et al.
      Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
      ]. In contrast, gemcitabine monotherapy was associated with a median OS of only 5.4 months and median PFS of 3.8 months, and carboplatin plus paclitaxel with an ORR of only 31% [
      • Dreicer R.
      • Manola J.
      • Roth B.J.
      • See W.A.
      • Kuross S.
      • Edelman M.J.
      • et al.
      Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
      ,
      • Culine S.
      • Flechon A.
      • Guillot A.
      • Le Moulec S.
      • Pouessel D.
      • Rolland F.
      • et al.
      Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01).
      ]. Notably, these studies evaluated small numbers of patients, and thus the results should be interpreted with caution. Collectively, a number of different chemotherapeutic regimens have been evaluated over the past three decades, including variations of dose and schedule for platinum-containing regimens, platinum-free doublets, novel combinations with three or more agents, and sequential regimens. However, no chemotherapeutic regimen has been shown to improve upon standard of care chemotherapy as toxicities outweighed the benefits, and thus treatment options for patients with advanced UC, particularly for cisplatin-eligible patients, had reached a plateau.
      The treatment landscape for advanced UC changed in 2017 and 2018 when the US FDA and EMA, respectively, approved atezolizumab and pembrolizumab for cisplatin-ineligible patients. These approvals ushered in a new era for the treatment of advanced UC as they offered the first non-chemotherapeutic options for patients. Based on survival outcomes of patients with low tumor PD-L1 expression who received atezolizumab or pembrolizumab monotherapy compared with platinum-based chemotherapy, the use of these IO agents was subsequently restricted to cisplatin-ineligible patients with high tumor PD-L1 expression. In a meta-analysis of studies of IO agents in advanced UC, PD-L1 expression was found to be predictive of response [
      • Ghate K.
      • Amir E.
      • Kuksis M.
      • Hernandez-Barajas D.
      • Rodriguez-Romo L.
      • Booth C.M.
      • et al.
      PD-L1 expression and clinical outcomes in patients with advanced urothelial carcinoma treated with checkpoint inhibitors: a meta-analysis.
      ]. In the phase II study of atezolizumab, patients with IC PD-L1 expression ≥ 5% had an ORR of 28%, compared with an ORR of 21% for those with IC PD-L1 expression <1% [
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      ]. Pembrolizumab yielded an ORR of 47% for patients with PD-L1 CPS ≥ 10, compared with an ORR of 29% ORR for the full population [
      • Vuky J.
      • Balar A.V.
      • Castellano D.
      • O'Donnell P.H.
      • Grivas P.
      • Bellmunt J.
      • et al.
      Updated efficacy and safety of KEYNOTE-052: a single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
      ]. It remains unclear if long-term survival outcomes with these agents are associated with PD-L1 expression.
      The phase II study of ipilimumab and gemcitabine plus cisplatin provided evidence for the feasibility of combining an IO agent with standard of care chemotherapy [
      • Galsky M.D.
      • Wang H.
      • Hahn N.M.
      • Twardowski P.
      • Pal S.K.
      • Albany C.
      • et al.
      Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes.
      ]. Results from IMvigor130 were the first to be reported for a phase III study that evaluated the combination of an IO agent and platinum-based chemotherapy as a first-line treatment for advanced UC, and the first RCT to evaluate an IO agent in both cisplatin-eligible and cisplatin-ineligible patients [
      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      ]. This study demonstrated a significant improvement in PFS of 1.9 months with atezolizumab plus platinum-based chemotherapy versus chemotherapy alone. Subgroup analyses suggested longer PFS in both cisplatin-eligible and cisplatin-ineligible patients. At the interim analysis, median OS was 15.7 months for atezolizumab monotherapy, consistent with that initially reported from the IMvigor210 study in cisplatin-ineligible patients (median OS of 15.9 months) [
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • Powles T.
      • Petrylak D.P.
      • Bellmunt J.
      • 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.
      ]. Data also suggest that, with atezolizumab monotherapy, patients with high tumor PD-L1 expression may have higher ORR as well as longer OS compared with the overall population and those with low PD-L1 expression. In contrast to the IMvigor130 trial [
      • Galsky M.D.
      • Arija J.A.A.
      • Bamias A.
      • Davis I.D.
      • De Santis M.
      • Kikuchi E.
      • et al.
      Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
      ], the KEYNOTE-361 study of pembrolizumab plus platinum-based chemotherapy did not significantly improve PFS or OS versus chemotherapy alone [

      Merck/MSD. Merck provides update on phase 3 KEYNOTE-361 trial evaluating KEYTRUDA® (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma [press release]. 2020. https://investors.merck.com/news/press-release-details/2020/Merck-Provides-Update-on-Phase-3-KEYNOTE-361-Trial-Evaluating-KEYTRUDA-pembrolizumab-as-Monotherapy-and-in-Combination-with-Chemotherapy-in-Patients-with-Advanced-or-Metastatic-Urothelial-Carcinoma/default.aspx. accessed June 10, 2020.

      ].
      The recently reported results from the JAVELIN Bladder 100 study [

      Powles T, Park SH, Voog E, Caserta C, B.P. V, Gurney H. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:Abst LBA1. DOI: 10.1200/JCO.2020.38.18_suppl.LBA1.

      ] showed a median OS of 21.4 months with avelumab, which was assessed from the time chemotherapy was stopped and maintenance therapy was initiated. Thus, considering the 3.5 months when patients received induction platinum-based chemotherapy, the actual median OS may be closer to 25 months. Importantly, a significant improvement in OS was observed in a biomarker unselected population. However, median OS had not been reached in patients with high tumor PD-L1 expression, suggesting that PD-L1-positive patients may derive an even greater survival benefit. Although this is the first study to demonstrate a significant improvement in OS with an IO agent as a first-line therapy for advanced UC, a remaining unmet need is a non-chemotherapy option for cisplatin-eligible patients. The anti–PD-L1 agent, durvalumab, was approved for the second-line treatment of UC based on the results of a phase I/II study that showed increased antitumor activity in patients with tumors expressing high PD-L1 levels [
      • Powles T.
      • O'Donnell P.H.
      • Massard C.
      • Arkenau H.T.
      • Friedlander T.W.
      • Hoimes C.J.
      • et al.
      Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study.
      ]. In an exploratory analysis of response and PD-L1 expression, a scoring algorithm was identified with a combined assessment of PD-L1 staining in TCs and ICs (PD-L1 defined as “high” for ≥ 25% staining in either TCs or ICs). The DANUBE trial, evaluating durvalumab with or without tremelimumab as a first-line treatment for advanced UC (ClinicalTrials.gov, NCT02516241) [

      US National Library of Medicine, ClinicalTrials.gov. Study of MEDI4736 (durvalumab) with or without tremelimumab versus standard of care chemotherapy in urothelial cancer. 2015. https://clinicaltrials.gov/ct2/show/NCT02516241. [accessed January 8, 2020].

      ], did not meet either of its primary endpoints. Secondary and exploratory analyses of data from DANUBE and KEYNOTE-361 may provide insight into the efficacy of durvalumab, with and without tremelimumab, and pembrolizumab in untreated, metastatic UC.
      Most of the trials included in this report did not specifically address the impact of treatment tolerability on HRQoL, an important outcome measure for both patients and physicians. Similar to the evidence for clinical efficacy and safety of chemotherapeutic regimens, the HRQoL studies support an unmet need for additional treatment options among patients with metastatic UC. Future studies are needed to provide additional HRQoL-related data on first-line treatments, particularly for IO agents. In designing future studies, we recommend that investigators select the instruments that will best elucidate the effects of tolerability, such as Functional Assessment of Cancer Therapy — Bladder Cancer, which was designed to evaluate patient-reported outcomes associated with bladder cancer therapy [
      • Degboe A.
      • Ivanescu C.
      • Rohay J.M.
      • Turner R.R.
      • Cella D.
      Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients.
      ].
      Some countries, such as Scotland, have indicated that additional cost and evidence of clinical efficacy are required to justify the cost of IO agents relative to their benefits [

      Scottish Medicines Consortium. Advising on new medicines for Scotland. 2019. http://www.scottishmedicines.org.uk/. [accessed November 11, 2019].

      ]. The request for cost-benefit evidence, and the recent inclusion of these agents in ESMO and EAU treatment guidelines, highlight the need for additional evidence to support their use in patients with high PD-L1 tumor expression, particularly those who are ineligible for platinum-based therapy. IO agents have the potential to improve outcomes and HRQoL for patients with metastatic UC, particularly those with tumors that express PD-L1, but longer-term outcomes must support and validate the evidence reported thus far. In addition, there is a lack of consistency among IO clinical trials with regard to the assessment of PD-L1 expression, as there are different cutoffs, scoring algorithms, and companion assays used [
      • Zajac M.
      • Scott M.
      • Ratcliffe M.
      • Scorer P.
      • Barker C.
      • Al-Masri H.
      • et al.
      Concordance among four commercially available, validated programmed cell death ligand-1 assays in urothelial carcinoma.
      ,
      • Powles T.
      • Walker J.
      • Williams J.A.
      • Bellmunt J.
      The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma.
      ]. Therefore, explanation of benefits of one IO therapy compared to another using indirect comparisons becomes challenging as the PD-L1 algorithm acts as an effect modifier.

      Limitations

      One limitation of the SLRs is the availability of data specifically related to the first-line treatment of advanced UC. Many publications addressed subsequent treatment lines, did not specify treatment line, or grouped the results of first-line treatment with those of subsequent therapies. Among the trials identified in the SLRs, many were assessed to have moderate (n = 2), high (n = 7), or very high (n = 16) risk of bias. Only five RCTs were categorized as low risk. Lack of detail in the publications (eg, unclear randomization or statistical methods) was primarily responsible for these classifications, although open-label and crossover study designs also contributed.
      As with any literature review, it is possible that some studies may not have been captured by the search terms, or that relevant studies may have been excluded if their abstracts did not clearly describe the patient population, methodology, and/or results. To minimize these possibilities, efforts were made to manually review bibliographies and use thorough search strings in multiple databases, and where necessary, the abstract lists of conferences were manually searched. Results were independently reviewed in duplicate or triplicate to avoid the omission of any potentially relevant publications. For IO agents, different study designs, patient populations, and inconsistent outcomes across trials, along with variations in the assays, scoring algorithms, and cutoffs used to measure PD-L1, has rendered the interpretation of data a challenge at present [
      • Powles T.
      • Walker J.
      • Williams J.A.
      • Bellmunt J.
      The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma.
      ].

      Conclusions

      Global guidelines for the first-line treatment of advanced UC continue to evolve with emerging data on IO agents. Clinical evidence indicates poor long-term outcomes and tolerability profiles with current standard of care options, emphasizing the need for new treatments that yield prolonged survival, with improved benefit-risk profiles. Our SLRs demonstrate a paucity of information related to HRQoL assessments of first-line treatments for advanced UC. Future studies are needed to fill these gaps, particularly given the recent approvals of IO agents for cisplatin-ineligible populations and the potential for newly approved therapies in cisplatin-eligible patients. In addition, cost-effectiveness analyses and assessments of HRQoL data will support the treatment decisions of physicians and patients and influence treatment guideline recommendations.

      Funding

      Funding for this work was provided by AstraZeneca.

      CRediT authorship contribution statement

      Maria Koufopoulou: Conceptualization, Data curation, Formal analysis, Methodology. Paulo A.P. Miranda: Writing - review & editing, Validation. Paulina Kazmierska: Formal analysis, Methodology. Sohan Deshpande: Data curation, Methodology, Formal analysis, Validation. Priyanka Gaitonde: Conceptualization, Supervision, Validation, Funding acquisition, Writing - review & editing. : .

      Declaration of Competing Interest

      PM and PG are employees of AstraZeneca, which funded this work. MK, PK, and SD are employees of Evidera.

      Acknowledgements

      Medical writing support, which was in accordance with Good Publication Practice guidelines, was provided by Ward A. Pedersen of Parexel and was funded by AstraZeneca . Editorial assistance was provided by Patricia Goodfriend of Parexel and was funded by AstraZeneca.

      Appendix A.

      Table A1Search terms for the systematic literature review.
      Search strategy for Embase (via Embase.com).
      Search CriteriaSearch Terms
      Clinical Outcomes
      Patient population
      1'urinary bladder neoplasms'/exp OR 'urethral neoplasm':ab,ti
      2'carcinoma, transitional cell'/exp/mj OR cancer*:ab,ti OR carcinoma*:ab,ti OR adenoma*:ab,ti OR adenocarcinoma*:ab,ti OR squamous:ab,ti OR neoplasm*:ab,ti OR tumor*:ab,ti OR malignan*:ab,ti
      3Bladder:ab,ti OR urethra*:ab,ti OR ureter*:ab,ti OR urotheli*:ab,ti OR calice*:ab,ti
      4#2 AND #3
      5#1 OR #4
      Treatment line
      6‘first line’:ab,ti OR first-line:ab,ti OR ‘front line’:ab,ti OR front-line:ab,ti OR ‘1st line’:ab,ti OR 1st-line:ab,ti OR ‘induction therapy’:ab,ti OR ‘primary therapy’:ab,ti OR ‘primary treatment’:ab,ti OR ((primary:ab,ti OR initial:ab,ti OR induction:ab,ti OR naïve:ab,ti) AND (therapy:ab,ti OR treatment:ab,ti)) OR (front:ab,ti AND line:ab,ti) OR (induction:ab,ti AND therapy:ab,ti) OR (first:ab,ti AND line:ab,ti) OR untreated:ab,ti OR un-treated:ab,ti OR ‘treatment naïve’:ab,ti OR treatment-naïve:ab,ti
      7Unresectable:ab,ti OR ‘stage four’:ab,ti OR ‘stage 4′:ab,ti OR ‘stage IV’:ab,ti OR ‘stage iv’:ab,ti OR ‘late stage’:ab,ti OR ‘late-stage’:ab,ti OR advance*:ab,ti OR inoperable:ab,ti OR metastasi*:ab,ti OR metastatic:ab,ti
      8#6 OR #7
      Study design
      9'clinical trial'/exp OR 'clinical trial' OR random* OR placebo:ab,ti OR 'clinical article'/de OR 'clinical trial'/de OR 'controlled clinical trial'/de OR 'controlled study'/de OR 'major clinical study'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de AND [article]/lim
      10[controlled clinical trial]/lim OR [randomized controlled trial]/lim OR [article in press]/lim
      11#9 OR #10
      Publication types
      12Letter:it OR editorial:it OR [conference abstract]/lim OR [conference paper]/lim OR [conference review]/lim OR [editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR [short survey]/lim OR 'case report'/de OR 'retrospective study'/de
      13Review:it NOT (systematic OR meta AND analy* OR (indirect OR mixed AND 'treatment comparison'))
      14#12 OR #13
      Studies of interest
      15(#5 AND #8 AND #11) NOT #14
      Other limits
      16#15 AND [humans]/lim AND ([adult]/lim OR [aged]/lim OR [very elderly]/lim)
      17#16 NOT ('animal experiment'/de OR 'cancer cell culture'/de OR 'human cell'/de OR 'human tissue'/de OR 'in vitro study'/de OR 'nonhuman'/de)
      18#17 AND [english]/lim AND [abstracts]/lim AND [1990–2018]/py
      19#18 NOT ('surgery'/lnk OR ‘radiotherapy’/lnk)
      HRQoL/PROs/Utilities Outcomes
      Patient population
      1'urinary bladder neoplasms'/exp OR 'urethral neoplasm':ab,ti
      2'carcinoma, transitional cell'/exp/mj OR cancer*:ab,ti OR carcinoma*:ab,ti OR adenoma*:ab,ti OR adenocarcinoma*:ab,ti OR squamous:ab,ti OR neoplasm*:ab,ti OR tumor*:ab,ti OR malignan*:ab,ti
      3Bladder:ab,ti OR urethra*:ab,ti OR ureter*:ab,ti OR urotheli*:ab,ti OR calice*:ab,ti
      4#2 AND #3
      5#1 OR #4
      Outcomes
      6'eq-5d':ab,ti OR eq5d:ab,ti OR euroqol:ab,ti OR 'euro qol':ab,ti
      7utility:ab,ti OR utilities:ab,ti
      8sf16:ab,ti OR 'sf 16′:ab,ti OR 'short form 16′:ab,ti OR 'shortform 16′:ab,ti OR 'sf sixteen':ab,ti OR sfsixteen:ab,ti OR 'shortform sixteen':ab,ti OR 'short form sixteen':ab,ti OR sf12:ab,ti OR 'sf 12′:ab,ti OR 'short form 12′:ab,ti OR 'shortform 12′:ab,ti OR 'sf twelve':ab,ti OR sftwelve:ab,ti OR 'shortform twelve':ab,ti OR 'short form twelve':ab,ti OR sf36:ab,ti OR 'sf 36′:ab,ti OR 'short form 36′:ab,ti OR 'shortform 36′:ab,ti OR 'sf thirtysix':ab,ti OR 'sf thirty six':ab,ti OR 'shortform thirtysix':ab,ti OR 'shortform thirty six':ab,ti OR 'short form thirtysix':ab,ti OR 'short form thirty six':ab,ti OR fact:ab,ti OR 'functional assessment of cancer therapy':ab,ti OR eortc:ab,ti OR qlq:ab,ti OR utility:ab,ti OR utilities:ab,ti OR BCI:ab,ti OR ‘bladder cancer index’:ab,ti OR ‘EORTC QLQ-BLM30′:ab,ti OR FACT-BI:ab,ti OR FACT-VCI:ab,ti
      9'patient reported':ab,ti OR 'patient-reported':ab,ti OR 'patients reported':ab,ti
      10'self report*':ab,ti OR 'functional status':ab,ti OR 'health status':ab,ti OR 'physical function':ab,ti OR 'time trade off':ab,ti OR 'time tradeoff':ab,ti OR tto:ab,ti
      11disab*:ab,ti OR satisfa*:ab,ti
      12questionnaire:ab,ti OR satisfaction:ab,ti OR sexual:ab,ti OR sleep:ab,ti OR 'sickness impact profile':ab,ti
      13burden:ab,ti AND (patient:ab,ti OR carer:ab,ti OR caregiver:ab,ti)
      14'quality of life' OR 'health related quality of life':ab,ti OR hrqol:ab,ti OR hqol:ab,ti OR 'hr qol':ab,ti OR qol:ab,ti
      15'medical leave':ab,ti OR (work:ab,ti AND disability:ab,ti) OR absenteeism:ab,ti OR 'sick leave':ab,ti OR 'sick day':ab,ti
      16#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
      Publication types
      17Letter:it OR editorial:it OR [conference abstract]/lim OR [conference paper]/lim OR [conference review]/lim OR [editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR [short survey]/lim OR 'case report'/de
      18Review:it NOT (systematic OR meta AND analy* OR (indirect OR mixed AND 'treatment comparison'))
      19#17 OR #18
      Studies of interest
      20#5 AND #16 NOT #19
      Other limits
      21#20 AND [humans]/lim AND ([adult]/lim OR [aged]/lim OR [very elderly]/lim)
      22#21 NOT ('animal experiment'/de OR 'cancer cell culture'/de OR 'human cell'/de OR 'human tissue'/de OR 'in vitro study'/de OR 'nonhuman'/de)
      23#22 AND [english]/lim AND [abstracts]/lim AND [1990–2016]/py
      24#23 NOT ('surgery'/lnk OR ‘radiotherapy’/lnk)
      a Search strategy for Embase (via Embase.com).
      Table A2Inclusion criteria for systematic literature reviews.
      Inclusion CriteriaExclusion Criteria
      DomainFirst-line Clinical OutcomesHRQoL/PROs/UtilitiesAll Searches
      PopulationAdults with unresectable stage IV UC who received first-line chemotherapy
      • Any population other than unresectable stage IV UC treated with first-line chemotherapy, including grouped outcomes for both first- and subsequent-line systemic treatments
      • Studies in which line of therapy was unclear
      Intervention/ ComparatorsaChemotherapeutic/systemic agents (approved or under investigation) for the treatment of stage IV and locally advanced and/or metastatic (stage IV) UC as monotherapy or combination therapy
      • Studies related to surgery, radiotherapy, radioimmunotherapy, “watch and wait”/no treatment, prophylactic or palliative care alone, or BCG vaccine
      • Intravesical or oral administration
      OutcomesEfficacy
      • OS, PFS
      • TTP, TTF
      • Duration of response
      • Disease control rate
      • Overall response
      • Progression
      Safety: Overall, severe, and grade 3–4 AEs
      • HRQoL/PROs evaluated with disease-specific or generic questionnaires
      • Symptoms
      • Functional impairment, activity limitations
      • Utilities/disutilities
      • Caregiver burden
      • In vitro, animal, fetal
      • Molecular, genetic
      • Pathology
      • Pharmacokinetics/pharmacodynamics
      Study DesignsPhase II and III RCTs
      • Phase II and III RCTs
      • Prospective interventional studies
      • Real-world observational studies
      • Narrative or non-systematic reviews
      • Case studies/reports
      • Editorials
      • Study protocols
      Time Period
      • Literature databases (1990–2018*)
      • SLRs/meta-analyses (2014–2018)
      Publication outside of the specified time windows
      CountryNoneNone
      LanguageEnglishNon-English
      Sample Size>25 patientsNoneN/A
      AE, adverse event; BCG, bacillus Calmette-Guérin; HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcome; RCT, randomized control trial; SLR, systematic literature review; TTF, time to treatment failure; TTP, time to progression; UC, urothelial carcinoma.

      References

        • Wong M.C.S.
        • Fung F.D.H.
        • Leung C.
        • Cheung W.W.L.
        • Goggins W.B.
        • Ng C.F.
        The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection.
        Sci Rep. 2018; 8: 1129https://doi.org/10.1038/s41598-018-19199-z
        • Lavaud P.
        • Hamilou Z.
        • Loriot Y.
        • Massard C.
        Durvalumab in urothelial cancers.
        Expert Rev Anticancer Ther. 2018; 18: 311-318
        • Bukhari N.
        • Al-Shamsi H.O.
        • Azam F.
        Update on the treatment of metastatic urothelial carcinoma.
        ScientificWorldJournal. 2018; 2018: 5682078https://doi.org/10.1155/2018/5682078
        • James N.D.
        • Hussain S.A.
        • Hall E.
        • Jenkins P.
        • Tremlett J.
        • Rawlings C.
        • et al.
        Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.
        N Engl J Med. 2012; 366: 1477-1488
        • Bellmunt J.
        • Petrylak D.P.
        New therapeutic challenges in advanced bladder cancer.
        Semin Oncol. 2012; 39: 598-607
      1. National Institutes of Health/National Cancer Institute. Surveillance Epidemiology and End Results (SEER) program, Cancer Stat Facts: Bladder Cancer. 2018. https://seer.cancer.gov/statfacts/html/urinb.html [accessed November 11, 2019].

      2. Bellmunt J. Treatment of metastatic urothelial cancer of the bladder and urinary tract. 2019. https://www.uptodate.com/contents/treatment-of-metastatic-urothelial-cancer-of-the-bladder-and-urinary-tract. [accessed September 21, 2019].

        • De Santis M.
        • Bellmunt J.
        • Mead G.
        • Kerst J.M.
        • Leahy M.
        • Maroto P.
        • 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. 2012; 30: 191-199
        • Dogliotti L.
        • Carteni G.
        • Siena S.
        • Bertetto O.
        • Martoni A.
        • Bono A.
        • et al.
        Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial.
        Eur Urol. 2007; 52: 134-141
        • Balar A.V.
        • Galsky M.D.
        • Rosenberg J.E.
        • Powles T.
        • Petrylak D.P.
        • Bellmunt J.
        • 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. 2017; 389: 67-76
        • Balar A.V.
        • Castellano D.
        • O'Donnell P.H.
        • Grivas P.
        • Vuky J.
        • Powles T.
        • 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. 2017; 18: 1483-1492
        • Ghate K.
        • Amir E.
        • Kuksis M.
        • Hernandez-Barajas D.
        • Rodriguez-Romo L.
        • Booth C.M.
        • et al.
        PD-L1 expression and clinical outcomes in patients with advanced urothelial carcinoma treated with checkpoint inhibitors: a meta-analysis.
        Cancer Treat Rev. 2019; 76: 51-56
        • Downs S.H.
        • Black N.
        The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
        J Epidemiol Community Health. 1998; 52: 377-384
      3. Alberta Health Services. Muscle invasive and locally advanced/metastatic bladder cancer clinical practice guideline GU-002 version 5. 2013. http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-gu002-bladder.pdf. [accessed November 11, 2019].

        • Bellmunt J.
        • Orsola A.
        • Leow J.J.
        • Wiegel T.
        • De Santis M.
        • Horwich A.
        • et al.
        Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2014; 25 (iii40-8)https://doi.org/10.1093/annonc/mdu223
      4. European Association of Urology (EAU). Muscle-invasive and metastatic bladder cancer. Summary of changes. 2020. 2020. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=summary-of-changes. [accessed June 15, 2020].

        • Milowsky M.I.
        • Rumble R.B.
        • Booth C.M.
        • Gilligan T.
        • Eapen L.J.
        • Hauke R.J.
        • et al.
        Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology guideline): American Society of Clinical Oncology clinical practice guideline endorsement.
        J Clin Oncol. 2016; 34: 1945-1952
      5. National Institute for Health and Care Excellence. Bladder cancer: diagnosis and management, NICE guideline. 2015. https://www.nice.org.uk/guidance/ng2. [accessed November 11, 2019].

      6. Princess Margaret Cancer Centre. Princess Margaret Cancer Centre clinical practice guidelines. 2012. http://www.uhn.ca/PrincessMargaret/Health_Professionals/Programs_Departments/Genitourinary_GU/Documents/CPG_GU_Urothelial.pdf. [accessed November 11, 2019].

      7. European Society for Medical Oncology (ESMO). eUpdate - bladder cancer treatment recommendations 2019. https://www.esmo.org/guidelines/genitourinary-cancers/bladder-cancer/eupdate-bladder-cancer-treatment-recommendations3. [accessed June 15, 2020].

        • Flaig T.W.
        • Spiess P.E.
        • Agarwal N.
        • Bangs R.
        • Boorjian S.A.
        • Buyyounouski M.K.
        • et al.
        Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.
        J Natl Compr Canc Netw. 2020; 18: 329-354
        • Bamias A.
        • Dafni U.
        • Karadimou A.
        • Timotheadou E.
        • Aravantinos G.
        • Psyrri A.
        • et al.
        Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).
        Ann Oncol. 2013; 24: 1011-1017
        • Haggag R.
        • Farag K.
        • Abu-Taleb F.
        • Shamaa S.
        • Zekri A.R.
        • Elbolkainy T.
        • et al.
        Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update.
        Med Oncol. 2014; 31: 811
        • Trump D.L.
        • Elson P.
        • Madajewicz S.
        • Dickman S.H.
        • Hahn R.G.
        • Harris J.E.
        • et al.
        Randomized phase II evaluation of carboplatin and CHIP in advanced transitional cell carcinoma of the urothelium. The Eastern Cooperative Oncology Group.
        J Urol. 1990; 144: 1119-1122
        • Culine S.
        • Flechon A.
        • Gravis G.
        • Roubaud G.
        • Loriot Y.
        • Joly F.
        • et al.
        Results of the GETUG-AFU 19 trial: a randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
        J Clin Oncol. 2017; 35: 307
        • von der Maase H.
        • Hansen S.W.
        • Roberts J.T.
        • Dogliotti L.
        • Oliver T.
        • Moore M.J.
        • 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. 2000; 18: 3068-3077
        • von der Maase H.
        • Sengelov L.
        • Roberts J.T.
        • Ricci S.
        • Dogliotti L.
        • Oliver T.
        • 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. 2005; 23: 4602-4608
        • Logothetis C.J.
        • Dexeus F.H.
        • Finn L.
        • Sella A.
        • Amato R.J.
        • Ayala A.G.
        • et al.
        A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.
        J Clin Oncol. 1990; 8: 1050-1055
        • Saxman S.B.
        • Propert K.J.
        • Einhorn L.H.
        • Crawford E.D.
        • Tannock I.
        • Raghavan D.
        • et al.
        Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
        J Clin Oncol. 1997; 15: 2564-2569
        • Bellmunt J.
        • Ribas A.
        • Eres N.
        • Albanell J.
        • Almanza C.
        • Bermejo B.
        • et al.
        Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma.
        Cancer. 1997; 80: 1966-1972
        • Bamias A.
        • Aravantinos G.
        • Deliveliotis C.
        • Bafaloukos D.
        • Kalofonos C.
        • Xiros N.
        • et al.
        Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.
        J Clin Oncol. 2004; 22: 220-228
        • Sternberg C.N.
        • de Mulder P.
        • Schornagel J.H.
        • Theodore C.
        • Fossa S.D.
        • van Oosterom A.T.
        • 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. 2006; 42: 50-54
        • Bellmunt J.
        • von der Maase H.
        • Mead G.M.
        • Skoneczna I.
        • De Santis M.
        • Daugaard G.
        • 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. 2012; 30: 1107-1113
        • Lorusso V.
        • Crucitta E.
        • Silvestris N.
        • Rosati G.
        • Manzione L.
        • De Lena M.
        • et al.
        Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.
        Oncol Rep. 2005; 13: 283-287
        • Miller K.
        • Morant R.
        • Stenzl A.
        • Zuna I.
        • Wirth M.
        A phase II study of the Central European Society of anticancer-drug research (CESAR) group: results of an open-label study of gemcitabine plus cisplatin with or without concomitant or sequential gefitinib in patients with advanced or metastatic transitional cell carcinoma of the urothelium.
        Urol Int. 2016; 96: 5-13
        • Krege S.
        • Rexer H.
        • vom Dorp F.
        • de Geeter P.
        • Klotz T.
        • Retz M.
        • et al.
        Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).
        BJU Int. 2014; 113: 429-436
        • Oudard S.
        • Culine S.
        • Vano Y.
        • Goldwasser F.
        • Theodore C.
        • Nguyen T.
        • et al.
        Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
        Eur J Cancer. 2015; 51: 45-54
        • Hussain M.
        • Daignault S.
        • Agarwal N.
        • Grivas P.D.
        • Siefker-Radtke A.O.
        • Puzanov I.
        • et al.
        A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.
        Cancer. 2014; 120: 2684-2693
        • Balar A.V.
        • Dreicer R.
        • Loriot Y.
        • Perez-Gracia J.L.
        • Hoffman-Censits J.H.
        • Petrylak D.
        • et al.
        Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): long-term efficacy from phase 2 study IMvigor210.
        J Clin Oncol. 2018; 36 (abstract 4523)
        • Vuky J.
        • Balar A.V.
        • Castellano D.
        • O'Donnell P.H.
        • Grivas P.
        • Bellmunt J.
        • et al.
        Updated efficacy and safety of KEYNOTE-052: a single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
        J Clin Oncol. 2018; 36 (abstract 4524)
        • Galsky M.D.
        • Wang H.
        • Hahn N.M.
        • Twardowski P.
        • Pal S.K.
        • Albany C.
        • et al.
        Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes.
        Eur Urol. 2018; 73: 751-759
        • Galsky M.D.
        • Arija J.A.A.
        • Bamias A.
        • Davis I.D.
        • De Santis M.
        • Kikuchi E.
        • et al.
        Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.
        Lancet. 2020; 395: 1547-1557
      8. Merck/MSD. Merck provides update on phase 3 KEYNOTE-361 trial evaluating KEYTRUDA® (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma [press release]. 2020. https://investors.merck.com/news/press-release-details/2020/Merck-Provides-Update-on-Phase-3-KEYNOTE-361-Trial-Evaluating-KEYTRUDA-pembrolizumab-as-Monotherapy-and-in-Combination-with-Chemotherapy-in-Patients-with-Advanced-or-Metastatic-Urothelial-Carcinoma/default.aspx. accessed June 10, 2020.

      9. AstraZeneca. Update on phase III DANUBE trial for imfinzi and tremelimumab in unresectable, stage IV bladder cancer [press release] March 6, 2020. 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html. accessed June 15, 2020.

      10. Powles T, Park SH, Voog E, Caserta C, B.P. V, Gurney H. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:Abst LBA1. DOI: 10.1200/JCO.2020.38.18_suppl.LBA1.

        • Dreicer R.
        • Manola J.
        • Roth B.J.
        • See W.A.
        • Kuross S.
        • Edelman M.J.
        • et al.
        Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium.
        Cancer. 2004; 100: 1639-1645
        • Siefker-Radtke A.O.
        • Millikan R.E.
        • Tu S.M.
        • Moore Jr., D.F.
        • Smith T.L.
        • Williams D.
        • et al.
        Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.
        J Clin Oncol. 2002; 20: 1361-1367
        • Roychowdhury D.F.
        • Hayden A.
        • Liepa A.M.
        Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.
        J Clin Oncol. 2003; 21: 673-678
        • Centre for Reviews and Dissemination
        Systematic reviews: CRD's guidance for undertaking reviews in health care.
        3rd ed. York Publishing Services, Ltd, York, UK2008
        • De Santis M.
        • Wiechno P.J.
        • Bellmunt J.
        • Lucas C.
        • Su W.C.
        • Albiges L.
        • 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. 2016; 27: 449-454
        • Culine S.
        • Flechon A.
        • Guillot A.
        • Le Moulec S.
        • Pouessel D.
        • Rolland F.
        • et al.
        Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01).
        Eur Urol. 2011; 60: 1251-1257
        • Mead G.M.
        • Russell M.
        • Clark P.
        • Harland S.J.
        • Harper P.G.
        • Cowan R.
        • et al.
        A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.
        Br J Cancer. 1998; 78: 1067-1075
        • Sternberg C.N.
        • Skoneczna I.A.
        • Castellano D.
        • Theodore C.
        • Blais N.
        • Voog E.
        • et al.
        Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB).
        Oncology. 2013; 85: 208-215
        • de Wit R.
        • Tesselaar M.
        • Kok T.C.
        • Seynaeve C.
        • Rodenburg C.J.
        • Verweij J.
        • et al.
        Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.
        Eur J Cancer. 1991; 27: 1383-1385
        • Kuroda M.
        • Kotake T.
        • Akaza H.
        • Hinotsu S.
        • Kakizoe T.
        Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group.
        Jpn J Clin Oncol. 1998; 28: 497-501
        • Logothetis C.J.
        • Finn L.D.
        • Smith T.
        • Kilbourn R.G.
        • Ellerhorst J.A.
        • Zukiwski A.A.
        • et al.
        Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
        J Clin Oncol. 1995; 13: 2272-2277
        • McCaffrey J.A.
        • Hilton S.
        • Mazumdar M.
        • Sadan S.
        • Heineman M.
        • Hirsch J.
        • et al.
        Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
        J Clin Oncol. 1997; 15: 2449-2455
        • Petrioli R.
        • Frediani B.
        • Manganelli A.
        • Barbanti G.
        • De Capua B.
        • De Lauretis A.
        • et al.
        Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients.
        A randomized phase II study. Cancer. 1996; 77: 344-351
        • Pizzocaro G.
        • Milani A.
        • Piva L.
        • Faustini M.
        • Spino E.
        Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer.
        A randomized study. Eur Urol. 1991; 20: 89-92
        • Yafi F.A.
        • North S.
        • Kassouf W.
        First- and second-line therapy for metastatic urothelial carcinoma of the bladder.
        Curr Oncol. 2011; 18: e25-e34
        • Powles T.
        • O'Donnell P.H.
        • Massard C.
        • Arkenau H.T.
        • Friedlander T.W.
        • Hoimes C.J.
        • et al.
        Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study.
        JAMA Oncol. 2017; 3: e172411
      11. US National Library of Medicine, ClinicalTrials.gov. Study of MEDI4736 (durvalumab) with or without tremelimumab versus standard of care chemotherapy in urothelial cancer. 2015. https://clinicaltrials.gov/ct2/show/NCT02516241. [accessed January 8, 2020].

        • Degboe A.
        • Ivanescu C.
        • Rohay J.M.
        • Turner R.R.
        • Cella D.
        Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients.
        Support Care Cancer. 2019; 27: 4189-4198
      12. Scottish Medicines Consortium. Advising on new medicines for Scotland. 2019. http://www.scottishmedicines.org.uk/. [accessed November 11, 2019].

        • Zajac M.
        • Scott M.
        • Ratcliffe M.
        • Scorer P.
        • Barker C.
        • Al-Masri H.
        • et al.
        Concordance among four commercially available, validated programmed cell death ligand-1 assays in urothelial carcinoma.
        Diagn Pathol. 2019; 14: 99
        • Powles T.
        • Walker J.
        • Williams J.A.
        • Bellmunt J.
        The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma.
        Cancer Treat Rev. 2020; 82101925https://doi.org/10.1016/j.ctrv.2019.101925
        • Bellmunt J.
        • Eigl B.J.
        • Senkus E.
        • Loriot Y.
        • Twardowski P.
        • Castellano D.
        • et al.
        Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.
        Ann Oncol. 2017; 28: 2481-2488