PURPOSE: Reliable assessment of clinical complete response (cCR) is essential to facilitate bladder-sparing treatment approaches in patients with muscle-invasive bladder cancer (MIBC) undergoing neoadjuvant systemic therapy, yet there is no agreement on the choice of diagnostic modalities for its assessment. We aimed to summarize strategies for assessing cCR in MIBC to facilitate development of bladder-preservation strategies. METHODS: In this prospectively registered systematic review (CRD420251088678), we searched MEDLINE, Embase, and Web of Science in July 2025 for studies reporting on cCR in MIBC patients undergoing neoadjuvant therapy prior to definitive local therapy or bladder preservation strategies. Risk-of-bias (RoB) was assessed using ROBINS-I tool. RESULTS: Out of 1696 individual records, 41 studies comprising 3588 patients were included in this systematic review. Majority of studies used cisplatin-based neoadjuvant therapies (n = 2941, 23 studies), with eight studies including perioperative immunotherapy (n = 647). For cCR evaluation, 12 studies (n = 1064) used only medical imaging (including CT, MRI, or FDG-PET/CT), three studies (n = 231) performed re-TURBT, one study (n = 56) used cystoscopy, and the remaining 25 studies (n = 2237) assessed cCR through combinations of medical imaging and clinical evaluation. Reported cCR rates ranged from 4.2% to 45% for CT, 15% to 78% for MRI, 76% for FDG-PET/CT, 25% to 46% for TURBT, 50% for cystoscopy, and 7.4% to 87% in studies combining medical imaging with local clinical evaluation. Most studies were rated as having moderate RoB concerns, while one preliminary report was classified as having serious RoB due to limited sample size. CONCLUSION: We found substantial heterogeneity in cCR assessment modalities, limiting comparability across bladder-sparing studies and highlighting the need for standardization. Data on patients receiving neoadjuvant chemo-immunotherapy remain scarce, and none incorporated urinary tumor DNA in cCR definitions. Serial MRI, with or without invasive assessment, appears promising for selecting candidates for bladder preservation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00345-025-06146-7.

Collegium Medicum Faculty of Medicine WSB University Dąbrowa Górnicza Poland

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

Department of Urology 2nd Health Cluster Riyadh Ministry of Health Riyadh KSA Saudi Arabia

Department of Urology Città della Salute e della Scienza University of Torino School of Medicine Torino Italy

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

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

Department of Urology Jikei University School of Medicine Tokyo Japan

Department of Urology Prince Saud Bin Jalawi Hospital Al Ahsa Health Cluster Al Ahsa KSA Saudi Arabia

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

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

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

S H Ho Urology Centre Department of Surgery The Chinese University of Hong Kong Hong Kong China

Zobrazit více v PubMed

van der Heijden AG, Bruins HM, Carrion A, Cathomas R, Compérat E, Dimitropoulos K, Efstathiou JA, Fietkau R, Kailavasan M, Lorch A et al (2025) European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2025 guidelines. Eur Urol 87(5):582–600 PubMed DOI

Holzbeierlein J, Bixler BR, Buckley DI, Chang SS, Holmes RS, James AC, Kirkby E, McKiernan JM, Schuckman A (2024) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/SUO guideline (2017; amended 2020, 2024). J Urol 212(1):3–10 PubMed DOI

Powles T, Catto JWF, Galsky MD, Al-Ahmadie H, Meeks JJ, Nishiyama H, Vu TQ, Antonuzzo L, Wiechno P, Atduev V et al (2024) Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med 391(19):1773–1786 PubMed DOI

Matsukawa A, Cormio A, Miszczyk M, Parizi MK, Fazekas T, Tsuboi I, Mancon S, Schulz RJ, Litterio G, Laukhtina E et al (2025) Impact of immune checkpoint inhibitors as neoadjuvant therapy for Muscle-invasive bladder cancer: A systematic Review, Meta-analysis, and network Meta-analysis. Eur Urol Oncol PubMed

Yanagisawa T, Matsukawa A, Teoh JY, Mori K, Kawada T, Katayama S, Rajwa P, Quhal F, Pradere B, Moschini M et al (2025) Advancements in systemic therapy for muscle-invasive bladder cancer: a systematic review from the beginning to the latest updates. Bladder Cancer 11(2):23523735251335122 PubMed DOI PMC

Milenkovic U, Akand M, Moris L, Demaegd L, Muilwijk T, Bekhuis Y, Laenen A, Van Cleynenbreugel B, Everaerts W, Van Poppel H et al (2019) Impact of neoadjuvant chemotherapy on short-term complications and survival following radical cystectomy. World J Urol 37(9):1857–1866 PubMed DOI

Hoeh B, Flammia RS, Hohenhorst L, Sorce G, Chierigo F, Panunzio A, Tian Z, Saad F, Gallucci M, Briganti A et al (2022) Effect of neoadjuvant chemotherapy on complications, in-hospital mortality, length of stay and total hospital costs in bladder cancer patients undergoing radical cystectomy. Cancers (Basel). 10.3390/cancers14051222 PubMed DOI PMC

Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullén A, Nilsson S, Malmström PU (2012) Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol 61(6):1229–1238 PubMed DOI

Masson-Lecomte A, Grisay G, Damme JV, Achard V, Mertens LS, Boellaard TN, D’Haese D, Fournier B, Govaerts AS, Huddart R et al (2025) Challenges in defining clinical complete response to systemic therapy in muscle-invasive bladder cancer: insights from the EORTC STARBURST project. Eur Urol Oncol 8(3):603–607 PubMed DOI

Laukhtina E, Moschini M, Teoh JY, Shariat SF (2024) Bladder sparing options for muscle-invasive bladder cancer. Curr Opin Urol 34(6):471–476 PubMed DOI

Laukhtina E, Moschini M, Teoh JY, Shariat SF (2025) Perioperative platform for muscle-invasive bladder cancer trials: designs and endpoints. Curr Opin Urol 35(1):35–40 PubMed DOI

Winoker JS, Liaw CW, Galsky MD, Wiklund P, Mehrazin R (2020) Clinical complete response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: a call for standardized assessments and definitions. Eur Urol Focus 6(4):627–629 PubMed DOI

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10(1):89 PubMed DOI PMC

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E et al (2017) AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358:j4008 PubMed DOI PMC

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919 PubMed DOI PMC

Asad D, Styrke J, Hagsheno M, Johansson M, Huge Y, Svensson J, Pelander S, Lauer J, Netterling H, Aljabery F et al (2022) A prospective multicenter study of visual response-evaluation by cystoscopy in patients undergoing neoadjuvant chemotherapy for muscle invasive urinary bladder cancer. Scand J Urol 56(1):20–26 PubMed DOI

Mehr JP, Bates JN, Lerner SP (2023) Is there a benefit of restaging transurethral resection of bladder tumor prior to radical cystectomy with or without neoadjuvant chemotherapy? Bladder Cancer 9(1):41–48 PubMed DOI PMC

Abdelrahman I, Aboulkassem H, Elazab A, Abdallah AY, Ismail Y, Taher M (2023) Evaluation of short-term outcomes of neoadjuvant chemotherapy followed by radical cystectomy in muscle-invasive bladder cancer: a single Egyptian institution experience. J Egypt Natl Canc Inst 35(1):13 PubMed DOI

Fukui T, Matsui Y, Umeoka S, Inoue T, Kamba T, Togashi K, Ogawa O, Kobayashi T (2016) Predictive value of radiological response rate for pathological response to neoadjuvant chemotherapy and post-cystectomy survival of bladder urothelial cancer. Jpn J Clin Oncol 46(6):560–567 PubMed DOI

Mertens LS, Meijer RP, Kerst JM, Bergman AM, van Tinteren H, van Rhijn BW, Horenblas S (2012) Carboplatin based induction chemotherapy for nonorgan confined bladder cancer–a reasonable alternative for cisplatin unfit patients? J Urol 188(4):1108–1113 PubMed DOI

Mogos H, Eriksson E, Styrke J, Sherif A (2020) Computerized tomography before the final treatment cycle of neoadjuvant chemotherapy or induction chemotherapy in muscle-invasive urinary bladder cancer, cannot predict pathoanatomical outcomes and does not reflect prognosis-results of a single centre retrospective prognostic study. Transl Androl Urol 9(3):1062–1072 PubMed DOI PMC

Zhang H, Li J, Zhang Q, Liu Y, Liang X, Zhang Z (2025) Comparison of neoadjuvant chemotherapy and combined chemotherapy with immunotherapy for muscle-invasive bladder cancer: a propensity score-matched analysis. Am J Transl Res 17(1):125–143 PubMed DOI PMC

Alam SM, Martin A, McLeay MT 2nd, Smith H, Golshani M, Thompson J, Sardiu M, Best S, Taylor JA (2023) 3rd: predictive value of computed tomography following neoadjuvant chemotherapy for muscle invasive bladder cancer. Bladder Cancer 9(2):167–174 PubMed DOI PMC

Fitoussi O, Roche JB, Riviere J, Wallerand H, Poulain JE, Gordien P, Galland S, Henriques B, Dupin C, Vincent M et al (2023) Accuracy of FDG-PET/CT for response evaluation of muscle-invasive bladder cancer following neoadjuvant or induction chemotherapy. Urol Int 107(3):239–245 PubMed DOI

Elkarta A, Awadalla A, El-hefnawy A, Mosbah A, Abolenein H, Shokeir A (2024) Predictors of response following neoadjuvant cisplatin-based chemotherapy for muscle invasive urothelial bladder cancer using molecular profile: a prospective clinical study. Clin Genitourin Cancer 22(2):38-46e31 PubMed DOI

Brembilla G, Basile G, Cosenza M, Giganti F, Del Prete A, Russo T, Pennella R, Lavalle S, Raggi D, Mercinelli C et al (2024) Neoadjuvant chemotherapy VI-RADS scores for assessing muscle-invasive bladder cancer response to neoadjuvant immunotherapy with multiparametric MRI. Radiology. 10.1148/radiol.233020 PubMed DOI

De Maeseneer D, De Visschere P, Van den Broecke M, Delbare F, Villeirs G, Verbeke S, Fonteyne V, Van Praet C, Decaestecker K, Decruyenaere A et al (2024) Retrospective analysis of multiparametric MRI in predicting complete pathologic response of neo-adjuvant chemotherapy in bladder cancer. BMC Med Imaging 24(1):268 PubMed DOI PMC

Necchi A, Bandini M, Calareso G, Raggi D, Pederzoli F, Farè E, Colecchia M, Marandino L, Bianchi M, Gallina A et al (2020) Multiparametric magnetic resonance imaging as a noninvasive assessment of tumor response to neoadjuvant pembrolizumab in muscle-invasive bladder cancer: preliminary findings from the PURE-01 study. Eur Urol 77(5):636–643 PubMed DOI

Pecoraro M, Del Giudice F, Magliocca F, Simone G, Flammia S, Leonardo C, Messina E, De Berardinis E, Cortesi E, Panebianco V (2022) Vesical imaging-reporting and data system (VI-RADS) for assessment of response to systemic therapy for bladder cancer: preliminary report. Abdom Radiol 47(2):763–770 PubMed DOI

Becker REN, Meyer AR, Brant A, Reese AC, Biles MJ, Harris KT, Netto G, Matoso A, Hoffman-Censits J, Hahn NM et al (2021) Clinical restaging and tumor sequencing are inaccurate indicators of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 79(3):364–371 PubMed DOI

Kim H, Jeong BC, Hong J, Kwon GY, Kim CK, Park W, Pyo H, Song W, Sung HH, Hong JY et al (2023) Neoadjuvant nivolumab plus gemcitabine/cisplatin chemotherapy in muscle-invasive urothelial carcinoma of the bladder. Cancer Res Treat 55(2):636–642 PubMed DOI PMC

Reese AC, Ball MW, Gandhi N, Gorin MA, Netto GJ, Bivalacqua TJ, Schoenberg MP (2014) The utility of an extensive postchemotherapy staging evaluation in patients receiving neoadjuvant chemotherapy for bladder cancer. Urology 84(2):358–363 PubMed DOI PMC

Piao C, Liu D, Liu Z, Shan L (2024) Markers in identifying pathological complete response status in muscle invasive bladder cancer patients who achieved clinical complete response after neoadjuvant chemotherapy. Clin Genitourin Cancer 22(6):102211 PubMed DOI

Scattoni V, Da Pozzo L, Nava L, Broglia L, Galli L, Torelli T, Campo B, Maffezzini M, Rigatti P (1995) Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer. Eur Urol 28(2):102–107 PubMed DOI

deVere White RW, Lara PN Jr., Goldman B, Tangen CM, Smith DC, Wood DP Jr., Hussain MH, Crawford ED (2009) A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest oncology group trial (S0219). J Urol 181(6):2476–2480 discussion 2480 – 2471 PubMed DOI PMC

Sternberg CN, Pansadoro V, Calabrò F, Schnetzer S, Giannarelli D, Emiliozzi P, De Paula F, Scarpone P, De Carli P, Pizzo M et al (2003) Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 97(7):1644–1652 PubMed DOI

Herr HW, Bajorin DF, Scher HI (1998) Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 16(4):1298–1301 PubMed DOI

Splinter TA, Pavone-Macaluso M, Jacqmin D, Roberts JT, Carpentier P, de Pauw M, Sahmoud T (1996) Genitourinary group phase II study of chemotherapy in stage T3-4 N0-X M0 transitional cell cancer of the bladder: prognostic factor analysis. Eur J Cancer 32a(7):1129–1134 PubMed DOI

Sternberg CN, Arena MG, Calabresi F, De Carli P, Platania A, Zeuli M, Giannarelli D, Cancrini A, Pansadoro V (1993) Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for infiltrating transitional cell carcinoma of the bladder. Cancer 72(6):1975–1982 PubMed DOI

Onishi T, Sekito S, Shibahara T, Yabana T (2021) Impact of noninvasive down-staging after transurethral resection of bladder tumor plus systemic chemotherapy on bladder-sparing strategy in patients with muscle-invasive bladder cancer. Urol Oncol 39(2):132.e131-132.e136 PubMed DOI

Yap SA, Pugashetti N, Chandrasekar T, Dall’Era MA, Evans CP, Lara PN, deVere White RW (2018) The promise and disappointment of neoadjuvant chemotherapy and transurethral resection for muscle invasive bladder cancer: updated results and long-term followup. Urol Pract 5(4):305–310 PubMed DOI

Agrawal C, Bansal S, Biswas M, Gupta M, Nautiyal V, Ahmed M (2021) Bladder preservation with neoadjuvant chemotherapy followed by concurrent chemoradiation for the treatment of muscle-invasive carcinoma of the bladder: a single-center experience. South Asian J Cancer 9(3):121–125 PubMed PMC

Herr HW (2008) Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 54(1):126–132 PubMed DOI

Dracham CB, Kumar N, Kumar S, Elangovan A, Yadav BS, Mavuduru RS, Lal A, Gupta PK, Kapoor R (2022) A phase II study of neoadjuvant chemotherapy followed by organ preservation in patients with muscle-invasive bladder cancer. Asian J Urol 9(3):318–328 PubMed DOI PMC

Meyer A, Ghandour R, Bergman A, Castaneda C, Wosnitzer M, Hruby G, Benson M, McKiernan J (2014) The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol 192(3):696–701 PubMed DOI

Chang PH, Chen HY, Chang YS, Su PJ, Huang WK, Lin CF, Hsieh JC, Wu CT (2024) Effect of clinical complete remission following neoadjuvant pembrolizumab or chemotherapy in bladder-preservation strategy in patients with muscle-invasive bladder cancer declining definitive local therapy. Cancers (Basel). 10.3390/cancers16050894 PubMed DOI PMC

Cho SW, Lim SH, Kwon GY, Kim CK, Park W, Pyo H, Chung JH, Song W, Sung HH, Jeong BC et al (2024) Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of the bladder: post hoc analysis of two prospective studies. Cancer Res Treat 56(3):893–897 PubMed DOI PMC

Galsky MD, Daneshmand S, Izadmehr S, Gonzalez-Kozlova E, Chan KG, Lewis S, Achkar BE, Dorff TB, Cetnar JP, Neil BO et al (2023) Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial. Nat Med 29(11):2825–2834 PubMed DOI PMC

Hafeez S, Horwich A, Omar O, Mohammed K, Thompson A, Kumar P, Khoo V, Van As N, Eeles R, Dearnaley D et al (2015) Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder. Br J Cancer 112(10):1626–1635 PubMed DOI PMC

Han B, Liang S, Jing Y, Cui D, An X, Zou Q, Wei H, Xia S (2014) Organ preservation for muscle-invasive bladder cancer by preoperative intra-arterial chemotherapy and transurethral resection. Med Oncol 31(4):912 PubMed DOI

Hatcher PA, Hahn RG, Richardson RL, Zincke H (1994) Neoadjuvant chemotherapy for invasive bladder carcinoma: disease outcome and bladder preservation and relationship to local tumor response. Eur Urol 25(3):209–215 PubMed DOI

Liang S, Zou Q, Han B, Jing Y, Cui D, An X, Gao Y, Hu J, Xia S (2015) Intra-arterial chemotherapy for muscle-invasive bladder cancer following transurethral resection. Urol Int 94(4):406–411 PubMed DOI

Luo C, Luo S, Wusimanjiang W, Wang Z, Liu P, Wang B, Yuan D, Lin H, Xu A, Deng N et al (2024) Bladder-sparing treatment using Tislelizumab combined with gemcitabine/cisplatin in selected patients with muscle-invasive bladder cancer: a real-world study. Clin Transl Oncol 26(7):1759–1767 PubMed DOI

Mazza P, Moran GW, Li G, Robins DJ, Matulay JT, Herr HW, Decastro GJ, McKiernan JM, Anderson CB (2018) Conservative management following complete clinical response to neoadjuvant chemotherapy of muscle invasive bladder cancer: contemporary outcomes of a multi-institutional cohort study. J Urol 200(5):1005–1013 PubMed DOI PMC

Mofid B, Razzaghdoust A, Ghajari M, Basiri A, Fattahi MR, Houshyari M, Jafari A, Taghizadeh-Hesary F (2022) Oncological outcomes of neoadjuvant gemcitabine plus carboplatin versus gemcitabine plus cisplatin in locally advanced bladder cancer: a retrospective analysis. Urol J 19(5):371–378 PubMed

Sung HH, Kim H, Kim R, Kim CK, Kwon GY, Park W, Song W, Jeong BC, Park SH (2022) Neoadjuvant chemotherapy with gemcitabine and cisplatin followed by selective bladder preservation chemoradiotherapy in muscle-invasive urothelial carcinoma of bladder. Investig Clin Urol 63(2):168–174 PubMed DOI PMC

Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, Schoenberg MP, Lerner SP, Sagalowsky AI, Lotan Y (2007) Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol 51(1):137–149 discussion 149–151 PubMed DOI

Linscott JA, Miyagi H, Murthy PB, Yao S, Grass GD, Vosoughi A, Xu H, Wang X, Yu X, Yu A et al (2024) From detection to cure - Emerging roles for urinary tumor DNA (utDNA) in bladder cancer. Curr Oncol Rep 26(8):945–958 PubMed DOI

Chauhan PS, Chen K, Babbra RK, Feng W, Pejovic N, Nallicheri A, Harris PK, Dienstbach K, Atkocius A, Maguire L et al (2021) Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: a cohort study. PLoS Med 18(8):e1003732 PubMed DOI PMC

Lindskrog SV, Strandgaard T, Nordentoft I, Galsky MD, Powles T, Agerbæk M, Jensen JB, Alix-Panabières C, Dyrskjøt L (2025) Circulating tumour DNA and circulating tumour cells in bladder cancer - from discovery to clinical implementation. Nat Rev Urol. 10.1038/s41585-025-01023-9 PubMed DOI

Jeong IG, Yun SC, Ha HK, Kang SG, Lee S, Park S, Sung HH, Kim SI, Hwang EC, Moon KC et al (2025) Urinary DNA methylation test for bladder cancer diagnosis. JAMA Oncol 11(3):293–299 PubMed DOI PMC

Powles T, Kann AG, Castellano D, Gross-Goupil M, Nishiyama H, Bracarda S, Bjerggaard Jensen J, Makaroff L, Jiang S, Ku JH et al (2025) ctDNA-Guided adjuvant Atezolizumab in Muscle-Invasive bladder cancer. N Engl J Med PubMed

Patel KM, van der Vos KE, Smith CG, Mouliere F, Tsui D, Morris J, Chandrananda D, Marass F, van den Broek D, Neal DE et al (2017) Association of plasma and urinary mutant DNA with clinical outcomes in muscle invasive bladder cancer. Sci Rep 7(1):5554 PubMed DOI PMC

Christensen E, Birkenkamp-Demtröder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, Wu HT, Knudsen M, Lamy P, Lindskrog SV et al (2019) Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 37(18):1547–1557 PubMed DOI