ASTRO 2022: Multi-Institutional Matched Comparison of Radical Cystectomy to Trimodality Therapy for Muscle Invasive Bladder Cancer

(UroToday.com) The 2022 ASTRO annual meeting featured a session on bladder and kidney preservation, including a presentation by Dr. Jason Efstathiou discussing a multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle invasive bladder cancer. There is a growing body of evidence for trimodality therapy regarding efficacy and safety, and it is now an accepted option by a number of guidelines in selected patients with muscle invasive bladder cancer. However, prior randomized controlled trials comparing bladder preservation to radical cystectomy for muscle invasive bladder cancer closed early due to lack of accrual (ie. the SPARE trial). Given that no future randomized controlled trials are foreseen, and in the absence of level 1 data, Dr. Efstathiou and colleagues aimed to provide the best evidence possible on outcomes of matched cohorts comparing trimodality therapy (maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to radical cystectomy in order to guide management.

 This retrospective analysis included 703 patients with muscle invasive bladder cancer clinical stage T2-T3/4aN0M0 muscle invasive bladder cancer urothelial carcinoma of the bladder. Specifically, there were 421 radical cystectomy patients and 282 trimodality therapy patients who would have been eligible for both trimodality therapy or radical cystectomy, treated at three tertiary referral academic institutions between 2005-2017. To compare homogeneous cohorts, all patients included in this analysis had solitary tumors <7 cm, no or unilateral hydronephrosis, and no extensive carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement and a caliper of 0.25. Covariates included age, sex, clinical T stage (cT2 vs cT3-4), hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival (OS) was estimated with adjusted Cox models, and cancer-specific survival (CSS), distant failure-free survival, regional failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models. The primary endpoint of interest was metastasis-free survival. The analysis was performed as intent-to-treat.

 The 3:1 matched cohort comprised 1,116 patients (834 radical cystectomy vs 282 trimodality therapy). After matching, age (71.3 vs 71.6 years), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 56%) were similar between radical cystectomy and trimodality therapy cohorts:

At 5 years, there was no difference in metastasis-free survival (73 vs 78%, p = 0.07):

There was also no difference in distant failure-free survival (5-year: 78 vs 82%, p = 0.14):

Finally, there was no difference in regional failure-free survival (5-year: 96 vs 95%, p = 0.33):

However, there was a benefit for trimodality therapy for CSS (5-year: 85% vs 78%, p = 0.02):

Additionally, trimodality also favored OS (5-year: 78% vs 66%, p < 0.001):
 

 Outcomes for radical cystectomy and trimodality therapy were not different among centers. Dr. Efstathiou and colleagues also performed several sensitivity analyses. There was no difference in metastasis-free survival for 128 patients that received neoadjuvant chemotherapy matched 1:1 to 128 trimodality therapy patients (p = 0.56):

Among the radical cystectomy patients, metastasis-free survival by pathological stage with or without hydronephrosis was statistically significant (p = 0.042):

Among trimodality therapy patients, there was no difference in cancer specific survival when stratified by salvage cystectomy status (83% vs 80%, p = 0.70):

Furthermore, among trimodality patients, there was no difference in metastasis free survival by (neo)-or adjuvant chemotherapy status (p = 0.26):

Dr. Efstathiou also highlighted several important findings from their study. Non-muscle invasive bladder cancer recurrence occurred in 57/282 (20.2%) trimodality therapy patients. Salvage cystectomy was performed in 38 patients (13%) treated by trimodality therapy. Final pT stage in the 421 radical cystectomy patients was: pT0 14%, pT1 7%, pT2 29%, pT3/4 42% and N+ 24%. Peri radical cystectomy mortality was 2.1% and median number of nodes removed was 40.

Dr. Efstathiou concluded his presentation discussing a multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle invasive bladder cancer with the following take home messages:

• This large multi-institutional contemporary study provides the best evidence to date, in the absence of randomized trials, supporting trimodality therapy for select patients with muscle invasive bladder cancer
• Oncologic outcomes seem to be equivalent between trimodality therapy and radical cystectomy
• This affirms the position that trimodality therapy should be offered as an effective alternative for these patients
• Several limitations of this study are as follows: it included select muscle-invasive bladder cancer patients only, included only centers performing radiotherapy and radical cystectomies with rigorous follow-up, and the best propensity score matched cohorts cannot replace randomized clinical trials (as there is still the possibility of confounders)

Presented by: Jason A. Efstathiou, MD, DPhil, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Co-Authors: L. K. Ballas², A. Niemierko³, K. Lajkosz⁴, C. Kuk⁵, G. Miranda⁶, M. R. Drumm¹, A. Mari⁷, N. E. Fleshner⁸, G. S. Kulkarni⁹, P. Chung¹⁰, R. G. Bristow¹¹, S. S. Sridhar¹², A. S. Feldman¹³, M. Wszolek¹⁴, R. J. Lee³, A. L. Zietman¹, W. U. Shipley¹, S. Daneshmand¹⁵, and A. Zlotta^5,8; 1Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2Department of Radiation Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 3Massachusetts General Hospital, Boston, MA, 4University of Toronto, Toronto, ON, Canada, 5Sinai Health System, Toronto, ON, Canada, 6USC Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 7University of Florence, Florence, Italy, 8Department of Surgical Oncology, Division of Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 9Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, 10Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 11Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom, 12Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 13Department of Urology, Massachusetts General Hospital, Boston, MA, 14Massachusetts General Hospital, Harvard Medical School, Boston, MA, 15University of Southern California, Keck School of Medicine, Department of Urology, Los Angeles, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.