PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Clinica Luganese Moncucco Lugano Switzerland

Clinica Santa Chiara Locarno Switzerland

Department of Experimental and Clinical Medicine University of Florence Florence Italy

Department of Medical Oncology San Raffaele Scientific Institute Milan Italy

Department of Oncology and Hematology Oncology Università Degli Studi Di Milano Milan Italy

Department of Urologic Sciences University of British Columbia Vancouver Canada

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

Department of Urology and Oncologic Urology Wrocław Medical University Wrocław Poland

Department of Urology Bichat Claude Bernard Hospital Paris University Paris France

Department of Urology CHU Toulouse IUCT Oncopole 31400 Toulouse France

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna General Hospital Vienna Austria

Department of Urology Foundation Instituto Valenciano Oncologia Valencia Spain

Department of Urology IEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan Italy

Department of Urology Luzerner Kantonsspital Spitalstrasse Luzern Switzerland

Department of Urology Netherlands Cancer Institute Antoni Van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology Spedali Civili Hospital University of Brescia Brescia Italy

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

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

Department of Urology Urological Research Institute San Raffaele Scientific Institute Milan Italy

Department of Urology Weill Cornell Medical College New York Presbyterian Hospital New York NY USA

Division of Urology Department of Surgical Sciences AOU Città Della Salute E Della Scienza Di Torino Torino School of Medicine Torino IT Italy

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

Mayo Clinic Urology Rochester MN USA

Swiss Medical Group Clinica Sant'Anna Sorengo Switzerland

Zobrazit více v PubMed

Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G et al (2021) European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: summary of the 2020 Guidelines. Eur Urol 79(1):82–104 DOI

Russell B, Liedberg F, Khan MS, Nair R, Thurairaja R, Malde S et al (2020) A systematic review and meta-analysis of delay in radical cystectomy and the effect on survival in bladder cancer patients. Eur Urol Oncol 3(2):239–249 DOI

Nadal R, Apolo AB (2018) Overview of current and future adjuvant therapy for muscle-invasive urothelial carcinoma. Curr Treat Options Oncol 19(7):36 DOI

Dogan S, Hennig M, Frank T, Struck JP, Cebulla A, Salem J et al (2018) Acceptance of adjuvant and neoadjuvant chemotherapy in muscle-invasive bladder cancer in Germany: a survey of current practice. Urologia Int 101:25–30 DOI

Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G et al (2006) Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer 107(3):506–513 DOI

Einstein DJ, Sonpavde G (2019) Treatment approaches for cisplatin-ineligible patients with invasive bladder cancer. Curr Treat Options Oncol 20(2):12 DOI

Galsky MD, Iasonos A, Mironov S, Scattergood J, Boyle MG, Bajorin DF (2007) Phase II trial of dose-dense doxorubicin plus gemcitabine followed by paclitaxel plus carboplatin in patients with advanced urothelial carcinoma and impaired renal function. Cancer 109(3):549–555 DOI

De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P et al (2012) 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 30(2):191–199 DOI

Balar AV, Apolo AB, Ostrovnaya I, Mironov S, Iasonos A, Trout A et al (2013) Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol 31(6):724–730 DOI

Linardou H, Aravantinos G, Efstathiou E, Kalofonos C, Anagnostopoulos A, Deliveliotis C et al (2004) Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: phase II study of the Hellenic Co-operative Oncology Group. Urology 64(3):479–484 DOI

Bellmunt J, de Wit R, Albanell J, Baselga J (2001) A feasibility study of carboplatin with fixed dose of gemcitabine in “unfit” patients with advanced bladder cancer. Eur J Cancer 37(17):2212–2215 DOI

Bamias A, Lainakis G, Kastritis E, Antoniou N, Alivizatos G, Koureas A et al (2007) Biweekly carboplatin/gemcitabine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: report of efficacy, quality of life and geriatric assessment. Oncology 73(5–6):290–297 DOI

Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G (2002) Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer 95(5):1022–1027 DOI

De Santis M, Wiechno PJ, Bellmunt J, Lucas C, Su W-C, Albiges L et al (2016) 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 27(3):449–454 DOI

Freshwater T, Li H, Valiathan C, Li M, Perini R, Bracco OL et al (2019) Systematic literature review and meta-analysis of response to first-line therapies for advanced/metastatic urothelial cancer patients who are cisplatin ineligible. Am J Clin Oncol 42(10):802–809 DOI

Afferi L, Zamboni S, Karnes RJ, Roghmann F, Sargos P, Montorsi F et al (2020) The impact of treatment modality on survival in patients with clinical node-positive bladder cancer: results from a multicenter collaboration. World J Urol. https://doi.org/10.1007/s00345-020-03205-z PubMed DOI PMC

Vetterlein MW, Seisen T, May M, Nuhn P, Gierth M, Mayr R et al (2018) Effectiveness of adjuvant chemotherapy after radical cystectomy for locally advanced and/or pelvic lymph node-positive muscle-invasive urothelial carcinoma of the bladder: a Propensity Score-Weighted Competing Risks Analysis. Eur Urol Focus 4(2):252–259 DOI

Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M et al (2015) Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol 16(1):76–86 DOI

Zamboni S, Afferi L, Soria F, Aziz A, Abufaraj M, Poyet C et al (2020) Adjuvant chemotherapy is ineffective in patients with bladder cancer and variant histology treated with radical cystectomy with curative intent. World J Urol. https://doi.org/10.1007/s00345-020-03362-1 PubMed DOI PMC

Edge S, Byrd DR, Compton CC, Fritz AG, Greene F, Trotti A (eds.) (2010) AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual [Internet]. 7th ed. New York: Springer-Verlag. Available from: https://www.springer.com/gp/book/9780387884424 . Cited 3 Feb 2021

Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R et al (2012) Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol 23(2):406–410 DOI

Leow JJ, Martin-Doyle W, Rajagopal PS, Patel CG, Anderson EM, Rothman AT et al (2014) Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66(1):42–54 DOI

Galsky MD, Stensland KD, Moshier E, Sfakianos JP, McBride RB, Tsao C-K et al (2016) Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. JCO 34(8):825–832 DOI

Ho GY, Woodward N, Coward JIG (2016) Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. Crit Rev Oncol Hematol 102:37–46 DOI

Grivas P, Plimack ER, Balar AV, Castellano D, O’Donnell PH, Bellmunt J et al (2020) Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer (KEYNOTE-052): outcomes in older patients by age and performance status. Eur Urol Oncol 3(3):351–359 DOI

Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee J-L et al (2021) Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa2035807 PubMed DOI PMC

Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y et al (2021) Adjuvant Nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 384(22):2102–2114 DOI

Hussain SA, Birtle A, Crabb S, Huddart R, Small D, Summerhayes M et al (2018) From clinical trials to real-life clinical practice: the role of immunotherapy with PD-1/PD-L1 inhibitors in advanced urothelial carcinoma. Eur Urol Oncol 1(6):486–500 DOI

Bellmunt J, Hussain M, Gschwend JE, Albers P, Oudard S, Castellano D et al (2021) Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. https://doi.org/10.1016/S1470-2045(21)00004-8 PubMed DOI PMC

Moschini M, Arbelaez E, Cornelius J, Mattei A, Shariat SF, Dell Oglio P et al (2018) Pattern of node metastases in patients treated with radical cystectomy and extended or superextended pelvic lymph node dissection due to bladder cancer. Urol Oncol 36(6):307.e9-307.e14 DOI

Vetterlein MW, Witjes JA, Loriot Y, Giannarini G, Albersen M, Ribal MJ et al (2020) Cutting-edge management of muscle-invasive bladder cancer in 2020 and a glimpse into the future. Eur Urol Oncol 3(6):789–801 DOI

Carboplatin Induction Chemotherapy in Clinically Lymph Node-positive Bladder Cancer