Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions - Beyond the Abstract

The 5-year cancer-specific survival rate of patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy (RC) is approximately 50%. Although RC remains the gold standard local definitive therapy, it is associated with significant morbidity and/or mortality.

Historically, patients unfit for RC were treated with bladder-sparing trimodality therapy (TMT). In the contemporary era, younger and fitter patients are now opting for TMT. Accumulating evidence suggests similar overall survival (OS) rates and potentially improved quality of life (QOL) in patients treated with TMT versus RC, however careful patient selection is critical. In this context, TMT is discussed.1

TMT consists of maximal TURBT followed by chemoradiotherapy with long-term surveillance to enable timely salvage therapy (Figures 1 and 2). Concurrent systemic therapy with radiotherapy improves locoregional disease control. Cisplatin, 5-fluorouracin plus mitomycin, and carbogen plus nicotinamide are supported by high-level evidence. Low dose gemcitabine also has supporting Phase II data, and is very well tolerated in this setting.

Trimodality therapy for MIBC
Fig 1
. Trimodality therapy for MIBC

The role of neoadjuvant chemotherapy (NAC) in the setting of TMT is not fully established. The Phase III BA06 30894 trial2 and ABC meta-analysis3 highlighted the potential benefit of NAC regardless of whether patients received RC or bladder-sparing radiotherapy. However, results from the RTOG 89-03 Phase III trial which aimed to evaluate the role of CMV (cisplatin, methotrexate and vinblastine) NAC prior to TMT were disappointing.4 Notably, this trial were not adequately powered (only 123 patients randomized), and arguably did not deliver sufficient NAC (two cycles and poorly tolerated) to show benefit. Therefore, the absence of benefit from this study cannot be interpreted as lack of benefit. NAC improves OS by eliminating micrometastatic disease and achieving complete response. It also helps to test the disease biology which is important for patient selection for TMT. Newer TMT trials are now increasingly incorporating NAC (NCT02145390, NCT02861196, NCT02710734). At our institution, NAC is routinely offered for patients with MIBC, and if a good response is observed, then TMT will be discussed for eligible patients in a multidisciplinary clinic (Figure 2). This approach seems to have good tolerability and encouraging outcomes.5


Trimodality Therapy at Princess Margaret Cancer Center
Fig. 2. Trimodality Therapy at Princess Margaret Cancer Center

Radiotherapy in TMT remains non-standardized. Whether split course versus continuous radiotherapy and additional pelvic nodal versus bladder-only radiation is the best approach remains unknown. Many ongoing trials are evaluating the potential benefit of intensity-modulated radiotherapy (IMRT) and adaptive radiotherapy with fiducial markers such as injected lipiodol (NCT02447549, NCT03125226, NCT03409029, NCT00350688). Other topics warranting further research include blue light cystoscopy, novel systemic therapy delivery techniques, combination strategies with targeted therapies and immunotherapy and biomarkers.
In conclusion, bladder sparing TMT for MIBC has gained increasing momentum and is now endorsed by major cancer organizations as an accepted alternative to RC in appropriately selected patients. TMT protocols are not yet standardized. Future research on the use of neoadjuvant chemotherapy, blue light cystoscopy, optimal radiotherapy delivery techniques, and radio-sensitizing agents, as well as predictive biomarkers, may further improve outcomes.

Written by: Di Maria Jiang, MD, Medical Oncologist, Princess Margaret Cancer Centre, Toroto, Canada, Twitter: @DiMariaJiang; Srikala Sridhar, MD, MSc, FRCPC, Clinician Investigator, Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, Canda, Twitter: @kalasri3

References:

1. Jiang, Di Maria, Peter Chung, Girish S. Kulkarni, and Srikala S. Sridhar. "Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions." Current Oncology Reports 22, no. 2 (2020): 14.
2. of Trialists, International Collaboration. "International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial." Journal of Clinical Oncology 29, no. 16 (2011): 2171.
3. Vale, C. "for the Advanced Bladder Cancer (ABC) Overview Collaboration (2003) Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis." Lancet 361: 1927-1934.
4. Shipley, W. U., K. A. Winter, D. S. Kaufman, W. R. Lee, N. M. Heney, W. R. Tester, B. J. Donnelly et al. "Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03." Journal of Clinical Oncology 16, no. 11 (1998): 3576-3583.
5. Jiang, Haiyan, Peter WM Chung, Alexandre R. Zlotta, Neil Eric Fleshner, Robert G. Bristow, Alejandro Berlin, Girish S. Kulkarni, Nimira S. Alimohamed, Gregory Lo, and Srikala S. Sridhar. "Neoadjuvant chemotherapy before bladder-sparing chemoradiotherapy in patients with nonmetastatic muscle-invasive bladder cancer." Clinical genitourinary cancer 17, no. 1 (2019): 38-45.

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