PURPOSE: The present systematic review and network meta-analysis (NMA) compared the current different neoadjuvant chemotherapy (NAC) regimes for bladder cancer patients to rank them. METHODS: We used the Bayesian approach in NMA of six different therapy regimens cisplatin, cisplatin/doxorubicin, (gemcitabine/cisplatin) GC, cisplatin/methotrexate, methotrexate, cisplatin, and vinblastine (MCV) and (MVAC) compared to locoregional treatment. RESULTS: Fifteen studies comprised 4276 patients who met the eligibility criteria. Six different regimes were not significantly associated with a lower likelihood of overall mortality rate compared to local treatment alone. In progression-free survival (PFS) rates, cisplatin, GC, cisplatin/methotrexate, MCV and MVAC were not significantly associated with a higher likelihood of PFS rate compared to locoregional treatment alone. In local control outcome, MCV, MVAC, GC and cisplatin/methotrexate were not significantly associated with a higher likelihood of local control rate versus locoregional treatment alone. Nevertheless, based on the analyses of the treatment ranking according to SUCRA, it was highly likely that MVAC with high certainty of results appeared as the most effective approach in terms of mortality, PFS and local control rates. GC and cisplatin/doxorubicin with low certainty of results was found to be the best second options. CONCLUSION: No significant differences were observed in mortality, progression-free survival and local control rates before and after adjusting the type of definitive treatment in any of the six study arms. However, MVAC was found to be the most effective regimen with high certainty, while cisplatin alone and cisplatin/methotrexate should not be recommended as a neoadjuvant chemotherapy regime.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Center Montreal Canada

Department of Family Medicine King Khalid University Abha Saudi Arabia

Department of Radiology King Khalid University Abha Saudi Arabia

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Aseer Central Hospital Abha Saudi Arabia

Department of Urology Comprehensive Cancer Center Vienna General Hospital Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology King Faisal Medical City Abha Saudi Arabia

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Salzburg Paracelsus Medical University Salzburg Salzburg Austria

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

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

Division of Urology Department of Surgery King Khalid University Abha Saudi Arabia

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

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

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Men's Health and Reproductive Health Research Center Shahid Beheshti University of Medical Sciences Tehran Iran

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

The National Center for Diabetes Endocrinology and Genetics The University of Jordan Amman Jordan

World J Urol. 2023 Oct;41(10):2875-2876. doi: 10.1007/s00345-023-04575-w. PubMed

Zobrazit více v PubMed

Ghoneim MA, El-Mekresh MM, Mokhtar AA, Gomha MA, El-Baz MA, El-Attar IA. A predictive model of survival after radical cystectomy for carcinoma of the bladder. BJU Int. 2000;85(7):811–816. doi: 10.1111/j.1464-410x.2000.00618.x. PubMed DOI

Witjes JA, Compérat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014;65(4):778–792. doi: 10.1016/j.eururo.2013.11.046. PubMed DOI

North SJCUAJ. Why consider neoadjuvant chemotherapy for muscle-invasive transitional cell carcinoma of the bladder? Can Urol Assoc J. 2008;2(3):222. doi: 10.5489/cuaj.602. PubMed DOI PMC

Sternberg CN. Perioperative chemotherapy in muscle-invasive bladder cancer to enhance survival and/or as a strategy for bladder preservation. Semin Oncol. 2007;34(2):122–128. doi: 10.1053/j.seminoncol.2006.12.006. PubMed DOI

Vale CL. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–205. doi: 10.1016/j.eururo.2005.04.006. PubMed DOI

Winquist E, Kirchner TS, Segal R, Chin J, Lukka H. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol. 2004;171(2 Pt 1):561–569. doi: 10.1097/01.ju.0000090967.08622.33. PubMed DOI

Vale C. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet (London, England) 2003;361(9373):1927–1934. doi: 10.1016/s0140-6736(03)13580-5. PubMed DOI

Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP, Lotan Y, Meeks JJ, Michalski JM, Morgan TM, Quale DZ, Rosenberg JE, Zietman AL, Holzbeierlein JM. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552–559. doi: 10.1016/j.juro.2017.04.086. PubMed DOI PMC

Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G, Hernández V, Linares Espinós E, Lorch A, Neuzillet Y, Rouanne M, Thalmann GN, Veskimäe E, Ribal MJ, van der Heijden AG. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2021;79(1):82–104. doi: 10.1016/j.eururo.2020.03.055. PubMed DOI

Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171–2177. doi: 10.1200/jco.2010.32.3139. PubMed DOI PMC

Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catalá-López F, Gøtzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–784. doi: 10.7326/m14-2385. PubMed DOI

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed) 2011;343:d5928. doi: 10.1136/bmj.d5928. PubMed DOI PMC

van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012;3(4):285–299. doi: 10.1002/jrsm.1054. PubMed DOI

Owen RK, Bradbury N, Xin Y, Cooper N, Sutton A. MetaInsight: An interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta. Res Synth Methods. 2019;10(4):569–581. doi: 10.1002/jrsm.1373. PubMed DOI PMC

Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol. 1995;153(3 Pt 2):964–973. doi: 10.1016/S0022-5347(01)67614-6. PubMed DOI

Wallace DMA, Raghavan D, Kelly KA, SAndeman TF, Conn IG, Teriana N, Dunn J, Boulas J, Latief T, Neo-adjuvant (Pre-emptive) Cisplatin Therapy in Invasive Transitional Cell Carcinoma of the Bladder. Br J Urol. 1991;67(6):608–615. doi: 10.1111/j.1464-410X.1991.tb15225.X. PubMed DOI

Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MKB, International Collaboration of T, Medical Research Council Advanced Bladder Cancer Working P, European Organisation for R, Treatment of Cancer Genito-Urinary Tract Cancer G, Australian Bladder Cancer Study G, National Cancer Institute of Canada Clinical Trials G, Finnbladder, Norwegian Bladder Cancer Study G, Club Urologico Espanol de Tratamiento Oncologico G International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171–2177. doi: 10.1200/JCO.2010.32.3139. PubMed DOI PMC

Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89–03. J Clin Oncol. 1998;16(11):3576–3583. doi: 10.1200/jco.1998.16.11.3576. PubMed DOI

Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP, Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–866. doi: 10.1056/NEJMoa022148. PubMed DOI

Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014;25(6):1192–1198. doi: 10.1093/annonc/mdu126. PubMed DOI

Bassi P, Pappagallo GL, Sperandio P, Monfardini S, Pagano F, Cosciani S, Lembo A, Anselmo G, Signorelli G, Lavelli DJ. Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: results of a multicenter phase III trial. J Urol. 1999;161(4S):264. doi: 10.1097/00005392-199904020-00060. DOI

Sengeløv L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sørensen B. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol (Stockholm, Sweden) 2002;41(5):447–456. doi: 10.1080/028418602320405041. PubMed DOI

Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, Malmström PU. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer—nordic cystectomy trial 2. Scand J Urol Nephrol. 2002;36(6):419–425. doi: 10.1080/003655902762467567. PubMed DOI

Rintala E, Hannisdahl E, Fosså SD, Hellsten S, Sander S. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scan J Urol Nephrol. 1993;27(3):355–362. doi: 10.3109/00365599309180447. PubMed DOI

Khaled HM, Shafik HE, Zabhloul MS, Ghoneim M, Saber RA, Manie M, Enein HA, Megeed HA, Mansur O, Sherbini ME, Mahran TZ, Kalawee ME, Badran A, Ramadan SM. Gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive transitional and squamous cell carcinoma of the bladder: effect on survival and bladder preservation. Clin Genitourin Cancer. 2014;12(5):e233–240. doi: 10.1016/j.clgc.2014.04.002. PubMed DOI

Osman MA, Gabr AM, Elkady MS. Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer. Arch Ital Urol. 2014;86(4):278–283. doi: 10.4081/aiua.2014.4.278. PubMed DOI

Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022;40(18):2013–2022. doi: 10.1200/jco.21.02051. PubMed DOI

Vale CL. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data: advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–206. doi: 10.1016/j.eururo.2005.04.006. PubMed DOI

von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. 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(17):3068–3077. doi: 10.1200/jco.2000.18.17.3068. PubMed DOI

Dash A, Pettus JAT, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471–2477. doi: 10.1002/cncr.23848. PubMed DOI PMC

Chung DY, Kang DH, Kim JW, Ha JS, Kim DK, Cho KS. Comparison of oncologic outcomes of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) with gemcitabine and cisplatin (GC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer: systematic review and meta-analysis. Cancers. 2021;13(11):2770. doi: 10.3390/cancers13112770. PubMed DOI PMC

Mir MC, Marchioni M, Zargar H, Zargar-Shoshtari K, Fairey AS, Mertens LS, Dinney CP, Krabbe LM, Cookson MS, Jacobsen NE, Griffin J, Montgomery JS, Vasdev N, Yu EY, Xylinas E, McGrath JS, Kassouf W, Dall'Era MA, Sridhar SS, Aning J, Shariat SF, Wright JL, Thorpe AC, Morgan TM, Holzbeierlein JM, Bivalacqua TJ, North S, Barocas DA, Lotan Y, Grivas P, Stephenson AJ, Shah JB, van Rhijn BW, Spiess PE, Daneshmand D, Black PC. Nomogram predicting bladder cancer–specific mortality after neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer: results of an international consortium. Eur Urol Focus. 2021;7(6):1347–1354. doi: 10.1016/j.euf.2020.07.002. PubMed DOI

Justin P Mehr JNB, Seth P Lerner (2021) Benefit of re-staging transurethral resection of bladder tumor prior to radical cystectomy with or without neoadjuvant chemotherapy. https://suo-abstracts.secure-platform.com/a/gallery/rounds/12/details/1530. Accessed 2 Dec 2022 PubMed PMC

Shsm H, Fahmy UA, Alhakamy NA, Khairul-Asri MG, Fahmy O. Neoadjuvant therapy using checkpoint inhibitors before radical cystectomy for muscle invasive bladder cancer: a systematic review. J Pers Med. 2021;11(11):1195. doi: 10.3390/jpm11111195. PubMed DOI PMC

Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706–1714. doi: 10.1038/s41591-019-0628-7. PubMed DOI

Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol. 2018;36(34):3353–3360. doi: 10.1200/jco.18.01148. PubMed DOI