Impact of Gender on Chemotherapeutic Response and Oncologic Outcomes in Patients Treated With Radical Cystectomy and Perioperative Chemotherapy for Bladder Cancer: A Systematic Review and Meta-Analysis

Published:December 04, 2019DOI:


      Female patients with bladder cancer (BCa) have had more advanced disease than their male counterparts at diagnosis and have experienced worse oncologic outcomes. However, the effect of gender on the chemotherapeutic response and oncologic outcomes after radical cystectomy (RC) and perioperative chemotherapy remains to be elucidated. We performed a systematic literature search to identify eligible studies that had investigated the effect of gender on the chemotherapeutic response and oncologic outcomes after RC and perioperative chemotherapy. We identified 15 studies reported from 2008 to 2019. For the patients who had received neoadjuvant chemotherapy (NAC), female gender was not associated with a complete response (pooled odds ratio [OR], 0.94; 95% confidence interval [CI], 0.69-1.26) nor a complete or partial response (pooled OR, 0.96; 95% CI, 0.73-1.27). In addition, women experienced had less upstaging (pooled OR, 0.3; 95% CI, 0.14-0.68) at RC compared with their male counterparts. Moreover, female patients who had undergone RC and NAC were likely to have better disease recurrence and cancer-specific mortality rates than were the male patients (pooled hazard ratio [HR], 0.66 and 95% CI, 0.44-0.98; and pooled HR, 0.49 and 95% CI, 0.29-0.81, respectively). For the patients who had undergone adjuvant chemotherapy, female gender was not associated with overall mortality (pooled HR, 1.15; 95% CI, 0.7-1.89), disease recurrence (pooled HR, 0.95; 95% CI, 0.74-1.23), or cancer-specific mortality (pooled HR, 1.07; 95% CI, 0.81-1.43). Female patients with BCa seem to benefit more from NAC than do their male counterparts. This potential differential sensitivity of female BCa to cisplatin-based combination chemotherapy might help close the gender gap in BCa, suggesting that gender could be a biomarker to help select the best systemic therapy for patients with advanced BCa.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2019.
        CA Cancer J Clin. 2019; 69: 7-34
        • Fajkovic H.
        • Halpern J.A.
        • Cha E.K.
        • et al.
        Impact of gender on bladder cancer incidence, staging, and prognosis.
        World J Urol. 2011; 29: 457-463
        • Scosyrev E.
        • Noyes K.
        • Feng C.
        • Messing E.
        Sex and racial differences in bladder cancer presentation and mortality in the US.
        Cancer. 2009; 115: 68-74
        • Horstmann M.
        • Witthuhn R.
        • Falk M.
        • Stenzl A.
        Gender-specific differences in bladder cancer: a retrospective analysis.
        Gend Med. 2008; 5: 385-394
        • Palou J.
        • Sylvester R.J.
        • Faba O.R.
        • et al.
        Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin.
        Eur Urol. 2012; 62: 118-125
        • Soave A.
        • Dahlem R.
        • Hansen J.
        • et al.
        Gender-specific outcomes of bladder cancer patients: a stage-specific analysis in a contemporary, homogenous radical cystectomy cohort.
        Eur J Surg Oncol. 2015; 41: 368-377
        • Cumberbatch M.G.
        • Cox A.
        • Teare D.
        • Catto J.W.
        Contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis.
        JAMA Oncol. 2015; 1: 1282-1290
        • Lyratzopoulos G.
        • Abel G.A.
        • McPhail S.
        • Neal R.D.
        • Rubin G.P.
        Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey.
        BMJ Open. 2013; 3
        • Zhang Y.
        Understanding the gender disparity in bladder cancer risk: the impact of sex hormones and liver on bladder susceptibility to carcinogens.
        J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2013; 31: 287-304
        • Grossman H.B.
        • Natale R.B.
        • Tangen C.M.
        • et al.
        Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.
        N Engl J Med. 2003; 349: 859-866
        • Alfred Witjes J.
        • Lebret T.
        • Comperat E.M.
        • et al.
        Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer.
        Eur Urol. 2017; 71: 462-475
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        J Clin Epidemiol. 2009; 62: e1-e34
        • Higgins J.P.
        Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011). Cochrane, 2011.
        (Available at:)
        Date accessed: March 25, 2019
        • Wells G.A.
        • Shea B.
        • O’Connell D.
        • et al.
        The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-analyses.
        Ottawa Hospital Research Institute, Ottawa, ON, Canada2011
        • Muramaki M.
        • Miyake H.
        • Kurahashi T.
        • Takenaka A.
        • Inoue T.A.
        • Fujisawa M.
        Prognostic significance of adjuvant cisplatin-based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer.
        Int J Urol. 2008; 15: 314-318
        • Kassouf W.
        • Agarwal P.K.
        • Grossman H.B.
        • et al.
        Outcome of patients with bladder cancer with pN plus disease after preoperative chemotherapy and radical cystectomy.
        Urology. 2009; 73: 147-152
        • Fajkovic H.
        • Cha E.K.
        • Jeldres C.
        • et al.
        Extranodal extension is a powerful prognostic factor in bladder cancer patients with lymph node metastasis.
        Eur Urol. 2013; 64: 837-845
        • Keck B.
        • Wach S.
        • Stoehr R.
        • et al.
        Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy.
        BMC Cancer. 2013; 13: 71
        • Rink M.
        • Hansen J.
        • Cha E.K.
        • et al.
        Outcomes and prognostic factors in patients with a single lymph node metastasis at time of radical cystectomy.
        BJU Int. 2013; 111: 74-84
        • James A.C.
        • Lee F.C.
        • Izard J.P.
        • et al.
        Role of maximal endoscopic resection before cystectomy for invasive urothelial bladder cancer.
        Clin Genitourin Cancer. 2014; 12: 287-291
        • Kim P.H.
        • Kent M.
        • Zhao P.
        • et al.
        The impact of smoking on pathologic response to neoadjuvant cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer.
        World J Urol. 2014; 32: 453-459
        • Mossanen M.
        • Lee F.
        • Cheng H.
        • et al.
        Nonresponse to neoadjuvant chemotherapy for muscle-invasive urothelial cell carcinoma of the bladder.
        Clin Genitourin Cancer. 2014; 12: 210-213
        • Zargar H.
        • Espiritu P.N.
        • Fairey A.S.
        • et al.
        Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer.
        Eur Urol. 2015; 67: 241-249
        • Zargar-Shoshtari K.
        • Zargar H.
        • Lotan Y.
        • et al.
        A multi-institutional analysis of outcomes of patients with clinically node positive urothelial bladder cancer treated with induction chemotherapy and radical cystectomy.
        J Urol. 2016; 195: 53-59
        • Chappidi M.R.
        • Kates M.
        • Brant A.
        • et al.
        Assessing cancer progression and stable disease after neoadjuvant chemotherapy for organ-confined muscle-invasive bladder cancer.
        Urology. 2017; 102: 148-158
        • Minato A.
        • Fujimoto N.
        • Kubo T.
        Squamous differentiation predicts poor response to cisplatin-based chemotherapy and unfavorable prognosis in urothelial carcinoma of the urinary bladder.
        Clin Genitourin Cancer. 2017; 15: e1063-e1067
        • Okabe K.
        • Shindo T.
        • Maehana T.
        • et al.
        Neoadjuvant chemotherapy with gemcitabine and cisplatin for muscle-invasive bladder cancer: multicenter retrospective study.
        Jpn J Clin Oncol. 2018; 48: 934-941
        • Mansour A.M.
        • Abdelrahim M.
        • Laymon M.
        • et al.
        Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer.
        BMC Urol. 2018; 18: 100
        • Boeri L.
        • Soligo M.
        • Frank I.
        • et al.
        Cigarette smoking is associated with adverse pathological response and increased disease recurrence amongst patients with muscle-invasive bladder cancer treated with cisplatin-based neoadjuvant chemotherapy and radical cystectomy: a single-centre experience.
        BJU Int. 2019; 123: 1011-1019
        • Messer J.C.
        • Shariat S.F.
        • Dinney C.P.
        • et al.
        Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis.
        Urology. 2014; 83: 863-867
        • Dobruch J.
        • Daneshmand S.
        • Fisch M.
        • et al.
        Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes.
        Eur Urol. 2016; 69: 300-310
        • Lucca I.
        • Klatte T.
        • Fajkovic H.
        • de Martino M.
        • Shariat S.F.
        Gender differences in incidence and outcomes of urothelial and kidney cancer.
        Nat Rev Urol. 2015; 12: 585-592
        • Uhlig A.
        • Seif Amir Hosseini A.
        • Simon J.
        • et al.
        Gender specific differences in disease-free, cancer specific and overall survival after radical cystectomy for bladder cancer: a systematic review and meta-analysis.
        J Urol. 2018; 200: 48-60
        • Kluth L.A.
        • Fajkovic H.
        • Xylinas E.
        • et al.
        Female gender is associated with higher risk of disease recurrence in patients with primary T1 high-grade urothelial carcinoma of the bladder.
        World J Urol. 2013; 31: 1029-1036
        • Rose T.L.
        • Deal A.M.
        • Nielsen M.E.
        • Smith A.B.
        • Milowsky M.I.
        Sex disparities in use of chemotherapy and survival in patients with advanced bladder cancer.
        Cancer. 2016; 122: 2012-2020
        • Olszewski A.J.
        • Shrestha R.
        • Castillo J.J.
        Treatment selection and outcomes in early-stage classical Hodgkin lymphoma: analysis of the National Cancer Data Base.
        J Clin Oncol. 2015; 33: 625-633
        • Khanal N.
        • Upadhyay S.
        • Dahal S.
        • Bhatt V.R.
        • Silberstein P.T.
        Systemic therapy in stage IV pancreatic cancer: a population-based analysis using the National Cancer Data Base.
        Ther Adv Med Oncol. 2015; 7: 198-205
        • Paulson E.C.
        • Wirtalla C.
        • Armstrong K.
        • Mahmoud N.N.
        Gender influences treatment and survival in colorectal cancer surgery.
        Dis Colon Rectum. 2009; 52: 1982-1991
        • Duplisea J.J.
        • Mason R.J.
        • Reichard C.A.
        • et al.
        Trends and disparities in the use of neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma.
        Can Urol Assoc J. 2019; 13: 24-28
        • Lucca I.
        • Roupret M.
        • Kluth L.
        • et al.
        Adjuvant cisplatin-based combined chemotherapy for lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC): a retrospective international study of >1500 patients.
        BJU Int. 2015; 115: 722-727
        • Choi W.
        • Porten S.
        • Kim S.
        • et al.
        Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
        Cancer Cell. 2014; 25: 152-165
        • Robertson A.G.
        • Kim J.
        • Al-Ahmadie H.
        • et al.
        Comprehensive molecular characterization of muscle-invasive bladder cancer.
        Cell. 2017; 171: 540-556.e25
        • Seiler R.
        • Ashab H.A.D.
        • Erho N.
        • et al.
        Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy.
        Eur Urol. 2017; 72: 544-554