Radical Cystectomy versus Trimodality Therapy for Muscle-Invasive Bladder Cancer: A Multi-Institutional Propensity Score Matched and Weighted Analysis - Beyond the Abstract

Radical cystectomy is widely used in muscle-invasive bladder cancer management, but even with improvements in surgical technique, it remains a major operation with significant morbidity, perioperative mortality, and quality of life-altering changes. Bladder preservation has been evaluated as a treatment for muscle-invasive bladder cancer since the 1980s, in hopes of offering better quality of life and to avoid complications due to surgery while maintaining comparable oncological outcomes.

Bladder preservation with trimodality therapy (TMT) combines maximal endoscopic transurethral resection of the bladder tumour followed by concurrent chemoradiation and is supported by a growing body of evidence demonstrating its efficacy and safety. TMT is now an accepted option by several national and international guidelines for well selected patients with muscle-invasive bladder cancer. However, it is not widely used. TMT is often restricted to patients with significant comorbidities who cannot undergo surgery. One possible reason it is not commonly used is the paucity of rigorous comparative studies with the traditional standard of care, radical cystectomy. Previous randomized controlled trials (RCT) aiming to compare oncological outcomes of bladder preservation to radical cystectomy closed due to poor accrual.

In the absence of RCTs, and as none are foreseen in the future, we conducted a large multi-institutional retrospective study with patients seen at three University Institutions (Massachusetts General Hospital, Boston; Princess Margaret Cancer Centre and Sinai Health System, Toronto; and University of Southern California, Los Angeles) to compare trimodality bladder preservation and radical cystectomy. Two independent statistical methods were used to ensure consistency of the results: propensity score matching (PSM) using logistic regression, and inverse probability treatment weighting (IPTW). We included patients with cT2-T4N0M0, unifocal tumors < 7 cm, with no or unilateral hydronephrosis and no multifocal carcinoma, who would have been eligible for both approaches (TMT or radical cystectomy).

Using the PSM method, TMT patients were matched to radical cystectomy patients using a 3:1 ratio (n=837 radical cystectomy, and n=282 TMT). The IPTW method included a total of 722 patients. These statistical methods are robust and provide valuable insights when RCTs are not available. Patients included in the radical cystectomy group represented 29% of patients operated at the contributing institutions, which highlights that ideal candidates for TMT represent a significant subset of patients with muscle invasive bladder cancer.

Our study demonstrated that there were no statistically significant differences in oncological outcomes such as disease-free survival, metastatic-free survival, and cancer-specific survival in these select patients with muscle-invasive bladder cancer and that oncological outcomes were similar across centres and between treatment groups. However, 13% of TMT treated patients ultimately required a salvage cystectomy (usually due to a muscle invasive recurrence), and another 20% presented with non-muscle invasive recurrences, stressing that TMT patients must be followed cystoscopically lifelong.

Notably, in the radical cystectomy cohort, we observed low surgical positive margin rates (1%), a median of 39 lymph nodes removed, a 5-year cancer-specific survival above 80%, and a peri-operative mortality rate of 2.5%. These results indicate that these findings were not due to suboptimal outcomes in either cohort.

This study offers potentially the best evidence to date to support that bladder-sparing therapy is an acceptable alternative to radical cystectomy in selected patients with muscle invasive bladder cancer. This study exemplifies the need for close collaboration between surgeons, radiation oncologists, and medical oncologists, and demonstrates findings that are clinically relevant with the potential to guide patients and health professionals during the decision-making process.

Hopefully, although the likelihood is low, our results will renew the interest in launching an RCT comparing TMT to cystectomy. Future studies may assess extending eligibility criteria for TMT and further optimizing clinical staging of disease, optimizing the delivery of radiation therapy and systemic therapies (e.g. immunotherapy is being explored) to further improve outcomes, and validating biomarkers to guide bladder preservation therapy and for personalized treatment selection.

Written by: Alexandre Zlotta MD1 & Jason Efstathiou MD2

  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
  2. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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Radical Cystectomy Versus Trimodality Therapy for Muscle-Invasive Bladder Cancer: A Multi-Institutional Propensity Score Matched and Weighted Analysis - Jason Efstathiou & Alexandre Zlotta