Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis

Alexandre R Zlotta¹, Leslie K Ballas², Andrzej Niemierko³, Katherine Lajkosz⁴, Cynthia Kuk⁵, Gus Miranda⁶, Michael Drumm³, Andrea Mari⁷, Ethan Thio⁶, Neil E Fleshner⁸, Girish S Kulkarni⁸, Michael A S Jewett⁸, Robert G Bristow⁹, Charles Catton¹⁰, Alejandro Berlin¹⁰, Srikala S Sridhar¹¹, Anne Schuckman¹², Adam S Feldman¹³, Matthew Wszolek¹³, Douglas M Dahl¹³, Richard J Lee¹⁴, Philip J Saylor¹⁴, M Dror Michaelson¹⁴, David T Miyamoto³, Anthony Zietman³, William Shipley³, Peter Chung¹⁰, Siamak Daneshmand¹², Jason A Efstathiou³

Affiliations

¹ Divisions of Urology and Surgical Oncology, Department of Surgery, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, ON, Canada; Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: alexandre.zlotta@sinaihealth.ca.
² Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biostatistics, University Health Network, University of Toronto, Toronto, ON, Canada.
⁵ Divisions of Urology and Surgical Oncology, Department of Surgery, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, ON, Canada; Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁶ Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Unit of Oncologic Minimally-Invasive Urology and Andrology, Department of Experimental and Clinical Medicine, Careggi Hospital, University of Florence, Florence, Italy.
⁸ Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁹ Manchester Cancer Research Centre and University of Manchester, Manchester, UK.
¹⁰ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Medical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada.
¹² Aresty Department of Urology, Kenneth Norris Jr Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ MGH Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 37187202
DOI: 10.1016/S1470-2045(23)00170-5

Multicenter Study

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis

Alexandre R Zlotta et al. Lancet Oncol. 2023 Jun.

. 2023 Jun;24(6):669-681.

doi: 10.1016/S1470-2045(23)00170-5. Epub 2023 May 12.

Authors

Affiliations

¹ Divisions of Urology and Surgical Oncology, Department of Surgery, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, ON, Canada; Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: alexandre.zlotta@sinaihealth.ca.
² Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biostatistics, University Health Network, University of Toronto, Toronto, ON, Canada.
⁵ Divisions of Urology and Surgical Oncology, Department of Surgery, Mount Sinai Hospital, Sinai Health System, University of Toronto, Toronto, ON, Canada; Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁶ Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Unit of Oncologic Minimally-Invasive Urology and Andrology, Department of Experimental and Clinical Medicine, Careggi Hospital, University of Florence, Florence, Italy.
⁸ Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.
⁹ Manchester Cancer Research Centre and University of Manchester, Manchester, UK.
¹⁰ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Medical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada.
¹² Aresty Department of Urology, Kenneth Norris Jr Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ MGH Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 37187202
DOI: 10.1016/S1470-2045(23)00170-5

Abstract

Background: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy.

Methods: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW).

Findings: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11).

Interpretation: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option.

Funding: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

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Conflict of interest statement

Declaration of interests ARZ reports participation on a data safety monitoring board or advisory board for Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase; and consulting fees from Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase. NEF reports grants or contracts from Janssen, Sanofi, Astellas, Nucleix, Bayer, and Progenix; consulting fees from Amgen, Sanofi, Janssen, AbbVie, Astellas, Ferring, and Bayer; stock or stock options in Verity Pharmaceuticals and POINT Biopharma; and is Chief Medical Officer for Verity Pharmaceuticals and Chief Medical Officer for POINT Biopharma. GSK reports grants or contracts from Janssen; and participation on a data safety monitoring board or advisory board for BMS, Pfizer, EMD Serono, Theralase, Verity Pharmaceuticals, Merck, Janssen, AstraZeneca, and Ferring. MASJ reports an honorarium from Pfizer; support for attending meetings or travel from the European Association of Urology; and is the Chair of the Board of Directors of the International Kidney Cancer Coalition. SSS reports grants or contracts from Bayer, Janssen, and Seagen; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai, EMD Serona, Hoffmann-LaRoche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, EMD Serono, Seagen, and Bayer; and support for attending meetings or travel from EMD Serono. MDM reports participation on a data safety monitoring board or advisory board for Merck, Janssen, Eisai, and Exelixis. JAE reports consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Genentech; and participation on a data safety monitoring board or advisory board for Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer, Gilead, and Lantheus. All other authors declare no competing interests.

Comment in

Re: Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis.
Cigliola A, Mercinelli C, Patanè D, Raggi D, Necchi A. Cigliola A, et al. Eur Urol. 2023 Dec;84(6):602-603. doi: 10.1016/j.eururo.2023.06.026. Epub 2023 Jul 12. Eur Urol. 2023. PMID: 37451897 No abstract available.
Radical cystectomy vs trimodality therapy for muscle-invasive bladder cancer: further extensive evaluation needed.
Jena R, Issa R, Perry M. Jena R, et al. Lancet Oncol. 2023 Aug;24(8):e324. doi: 10.1016/S1470-2045(23)00321-2. Lancet Oncol. 2023. PMID: 37541275 No abstract available.
Radical cystectomy vs trimodality therapy for muscle-invasive bladder cancer: further extensive evaluation needed - Authors' reply.
Zlotta AR, Lajkosz K, Efstathiou JA. Zlotta AR, et al. Lancet Oncol. 2023 Aug;24(8):e325-e326. doi: 10.1016/S1470-2045(23)00322-4. Lancet Oncol. 2023. PMID: 37541276 No abstract available.
Re: Alexandre R. Zlotta, Leslie K. Ballas, Anderzej Niemierko, et al. Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis. Lancet Oncol 2023;24:669-81.
Seisen T, Rouprêt M, Blanchard P. Seisen T, et al. Eur Urol. 2024 Jan;85(1):e24. doi: 10.1016/j.eururo.2023.07.019. Epub 2023 Aug 31. Eur Urol. 2024. PMID: 37659960 No abstract available.
Reply to Thomas Seisen, Morgan Rouprêt, and Pierre Blanchard's Letter to the Editor re: Alexandre R. Zlotta, Leslie K. Ballas, Andrzej Niemierko, et al. Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis. Lancet Oncol 2023;24:669-81.
Zlotta AR, Lajkosz K, Efstathiou JA. Zlotta AR, et al. Eur Urol. 2024 Jan;85(1):e25-e26. doi: 10.1016/j.eururo.2023.08.011. Epub 2023 Sep 1. Eur Urol. 2024. PMID: 37661552 No abstract available.

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Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis

Affiliations

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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