BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph-node dissection is the standard treatment for cT2-4a cN0 cM0 muscle-invasive bladder cancer (MIBC). Despite the significant improvement of primary-tumor downstaging with NAC, up to 50% of patients are eventually found to have advanced residual disease (pT3-T4 and/or histopathologically confirmed nodal metastases (pN+)) at RC. Currently, there is no established standard of care in such cases. The aim of this systematic review and meta-analysis was to assess differences in survival rates between patients with pT3-T4 and/or pN+ MIBC who received NAC and surgery followed by adjuvant chemotherapy (AC), and patients without AC. MATERIALS AND METHODS: A systematic search was conducted in accordance with the PRISMA statement using the Medline, Embase, and Cochrane Library databases. The last search was performed on 12 November 2020. The primary end point was overall survival (OS) and the secondary end point was disease-specific survival (DSS). RESULTS: We identified 2124 articles, of which 6 were selected for qualitative and quantitative analyses. Of a total of 3096 participants in the included articles, 2355 (76.1%) were in the surveillance group and 741 (23.9%) received AC. The use of AC was associated with significantly better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.94; p = 0.002) and DSS (HR 0.56, 95% CI 0.32-0.99; p = 0.05). Contrary to the main analysis, in the subgroup analysis including only patients with pN+, AC was not significantly associated with better OS compared to the surveillance group (HR 0.89, 95% CI 0.58-1.35; p = 0.58). CONCLUSIONS: The administration of AC in patients with MIBC and pT3-T4 residual disease after NAC might have a positive impact on OS and DSS. However, this may not apply to N+ patients.

2nd Department of Urology Centre of Postgraduate Medical Education 01 813 Warsaw Poland

Department of Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori 20133 Milan Italy

Department of Oncology and Urology University Hospital of Tours 37000 Tours France

Department of Pharmacology and Toxicology Faculty of Veterinary Medicine Wroclaw University of Environmental and Life Sciences 50 375 Wrocław Poland

Department of Urology 2nd Faculty of Medicine and Hospital Motol Charles University 15006 Prague Czech Republic

Department of Urology and Oncologic Urology Wrocław Medical University 50 556 Wroclaw Poland

Department of Urology Institute Mutualiste Montsouris Université Paris Descartes 75014 Paris France

Department of Urology Medical University of Vienna 1090 Vienna Austria

Department of Urology University of Texas Southwestern Medical Center Dallas TX 75390 USA

Departments of Urology Weill Cornell Medical College New York NY 10065 USA

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman 11942 Jordan

Division of Urology Department of Surgical Sciences San Giovanni Battista Hospital University of Studies of Torino 10124 Turin Italy

European Association of Urology Research Foundation 6803 AA Arnhem The Netherlands

Fundació Puigvert Department of Urology Autonomous University of Barcelona 08025 Barcelona Spain

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University 119146 Moscow Russia

Klinik für Urologie Luzerner Kantonsspital 6004 Lucerne Switzerland

S H Ho Urology Centre Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong

Unit of Urology Urological Research Institute IRCCS Ospedale San Raffaele 20132 Milan Italy

Zobrazit více v PubMed

Witjes J.A., Lebret T., Compérat E.M., Cowan N.C., De Santis M., Bruins H.M., Hernández V., Espinós E.L., Dunn J., Rouanne M., et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur. Urol. 2017;71:462–475. doi: 10.1016/j.eururo.2016.06.020. PubMed DOI

Yin M., Joshi M., Meijer R.P., Glantz M., Holder S., Harvey H.A., Kaag M., Van De Putte E.E.F., Horenblas S., Drabick J.J. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncol. 2016;21:708–715. doi: 10.1634/theoncologist.2015-0440. PubMed DOI PMC

Manoharan M., Katkoori D., Kishore T.A., Kava B., Singal R., Soloway M.S. Outcome after radical cystectomy in patients with clinical T2 bladder cancer in whom neoadjuvant chemotherapy has failed. BJU Int. 2009;104:1646–1649. doi: 10.1111/j.1464-410X.2009.08626.x. PubMed DOI

Mertens L.S., Meijer R.P., Meinhardt W., Van Der Poel H.G., Bex A., Kerst J.M., Van Der Heijden M.S., Bergman A.M., Horenblas S., Van Rhijn B.W.G. Occult lymph node metastases in patients with carcinoma invading bladder muscle: Incidence after neoadjuvant chemotherapy and cystectomy vs after cystectomy alone. BJU Int. 2014;114:67–74. doi: 10.1111/bju.12447. PubMed DOI

Galsky M.D., Stensland K.D., Moshier E., Sfakianos J.P., McBride R.B., Tsao C.-K., Casey M., Boffetta P., Oh W.K., Mazumdar M., et al. Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer. J. Clin. Oncol. 2016;34:825–832. doi: 10.1200/JCO.2015.64.1076. PubMed DOI

Leow J.J., Martin-Doyle W., Rajagopal P.S., Patel C.G., Anderson E.M., Rothman A.T., Cote R.J., Urun Y., Chang S.L., Choueiri T.K., et al. Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials. Eur. Urol. 2014;66:42–54. doi: 10.1016/j.eururo.2013.08.033. PubMed DOI

Moher D., Liberati A., Tetzlaff J., Altman D.G., Prisma Group Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000097. PubMed DOI PMC

Higgins J.P.T., Thomas J., Chandler J., Cumpston M., Li T., Page M.J., Welch V.A., editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020) John Wiley & Sons; Chichester, UK: 2020. [(accessed on 1 November 2020)]. Available online: www.training.cochrane.org/handbook.

Wells G., Shea B., O’connell D., Peterson J., Welch V., Losos M., Tugwell P. The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. The Ottawa Hospital Research Institute Clinical Epidemiology Program. [(accessed on 1 November 2020)];2012 Available online: http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf.

Kassouf W., Agarwal P.K., Grossman H.B., Leibovici D., Munsell M.F., Siefker-Radtke A., Pisters L.L., Swanson D.A., Dinney C.P., Kamat A.M. Outcome of Patients with Bladder Cancer With pN+ Disease After Preoperative Chemotherapy and Radical Cystectomy. Urology. 2009;73:147–152. doi: 10.1016/j.urology.2008.07.035. PubMed DOI PMC

Chanza N.M., Werner L., Plimack E., Yu E.Y., Alva A.S., Crabb S.J., Powles T., Rosenberg J.E., Baniel J., Vaishampayan U.N., et al. Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers. Eur. Urol. Oncol. 2020;3:671–679. doi: 10.1016/j.euo.2018.12.013. PubMed DOI PMC

Parker W.P., Habermann E.B., Day C.N., Zaid H.B., Frank I., Thompson R.H., Tollefson M.K., Boorjian S.A., Pagliaro L., Karnes R.J. Adverse Pathology After Neoadjuvant Chemotherapy and Radical Cystectomy: The Role of Adjuvant Chemotherapy. Clin. Genitourin. Cancer. 2018;16:64–71. doi: 10.1016/j.clgc.2017.07.010. PubMed DOI

Seisen T., Jamzadeh A., Leow J.J., Rouprêt M., Cole A.P., Lipsitz S.R., Kibel A.S., Nguyen P.L., Sun M., Menon M., et al. Adjuvant Chemotherapy vs Observation for Patients with Adverse Pathologic Features at Radical Cystectomy Previously Treated with Neoadjuvant Chemotherapy. JAMA Oncol. 2018;4:225–229. doi: 10.1001/jamaoncol.2017.2374. PubMed DOI PMC

Sui W., Lim E.A., DeCastro G.J., McKiernan J.M., Anderson C.B. Use of Adjuvant Chemotherapy in Patients with Advanced Bladder Cancer after Neoadjuvant Chemotherapy. Bl. Cancer. 2017;3:181–189. doi: 10.3233/BLC-170107. PubMed DOI PMC

Zargar-Shoshtari K., Kongnyuy M., Sharma P., Fishman M.N., Gilbert S.M., Poch M.A., Pow-Sang J.M., Spiess P.E., Zhang J., Sexton W.J. Clinical role of additional adjuvant chemotherapy in patients with locally advanced urothelial carcinoma following neoadjuvant chemotherapy and cystectomy. World J. Urol. 2016;34:1567–1573. doi: 10.1007/s00345-016-1825-3. PubMed DOI

Harshman L.C., Werner L., Wong Y.-N., Yu E.Y., Alva A.S., Crabb S.J., Powles T., Rosenberg J.E., Baniel J., Vaishampayan U.N., et al. Adjuvant chemotherapy for residual disease after neoadjuvant chemotherapy for muscle invasive urothelial cancer (MIUC) J. Clin. Oncol. 2015;33:4524. doi: 10.1200/jco.2015.33.15_suppl.4524. DOI

Millikan R., Dinney C., Swanson D., Sweeney P., Ro J.Y., Smith T.L., Williams D., Logothetis C. Integrated Therapy for Locally Advanced Bladder Cancer: Final Report of a Randomized Trial of Cystectomy Plus Adjuvant M-VAC Versus Cystectomy with Both Preoperative and Postoperative M-VAC. J. Clin. Oncol. 2001;19:4005–4013. doi: 10.1200/JCO.2001.19.20.4005. PubMed DOI

Apolo A.B., Infante J.R., Balmanoukian A., Patel M.R., Wang D., Kelly K., Mega A.E., Britten C.D., Ravaud A., Mita A.C., et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients with Refractory Metastatic Urothelial Carcinoma: Results from a Multicenter, Phase Ib Study. J. Clin. Oncol. 2017;35:2117–2124. doi: 10.1200/JCO.2016.71.6795. PubMed DOI PMC

Zhang Y., Wang Y., Song B., Li H. Patients’ self-report anxiety, depression and quality of life and their predictive factors in muscle invasive bladder cancer patients receiving adjuvant chemotherapy. Psychol. Health Med. 2019;25:190–200. doi: 10.1080/13548506.2019.1687912. PubMed DOI