EAU 2020: Definition of Very High-Risk and Refractory Non-Muscle Invasive Bladder Cancer

(UroToday.com) According to the EAU guidelines, the treatment recommendations for high risk non-muscle invasive bladder cancer (NMIBC) include full dose BCG instillations for 1-3 years or radical cystectomy.

BCG reduces the risk of progression in NMIBC, but 30% of T1G3 will require deferred radical cystectomy. In T1G3, five-year disease-related death after BCG occurs in 11.3% of patients.

Even though BCG is the mainstay in the treatment of high-risk NMIBC, in some patients, it is not effective. It is, therefore, important that we identify these unique patients before or during the BCG treatment, to avoid this ineffective treatment for them and/or replace it with a more effective modality.

The following NMIBC patients have the worst prognosis:
  • T1G3/HG +CIS, multiple or large T1G3/HG tumors
  • T1 or G3/HG + lymphovascular invasion
  • Some forms of variant histopathology of urothelial carcinoma

There have been several calculators that have been formed to try to identify these patients with worse prognosis (figure 1), including the EORTC and CUETO calculators.

Figure 1 - NMIBC worst prognosis patient calculators:


Dr. Marko Babjuk moved on to discuss the various variant histologies of NMIBC.

He began by assessing patients with NMIBC and micropapillary differentiation. In these patients, there is significant heterogeneity of results with five-year cancer-specific survival after radical cystectomy, and TURBT + BCG reported to be 81-100% and 60-85%, respectively.1

In plasmacytoid differentiation, there is generally poor prognosis,2 and in sarcomatoid differentiation, a population-based study demonstrated 18.4 months mean survival, even in patients with  T1 disease.3 In the nested variant, a study demonstrated that out of 30 patients with clinical T1 disease, 54% were upstaged at T or N stages after radical cystectomy was performed.4

Next, Dr. Babjuk discussed additional parameters that could serve as predictive markers. These include lymphovascular invasion showing some potential as a predictor for progression and metastasis with patients with newly diagnosed T1 disease.5 Additionally, deep T1 invasion can serve as a marker, with deeper invasion (>=0.5 mm) being associated with worse disease than shallower invasions. This is highly dependent on the quality of TURBT and specimen.6

Molecular subtypes have also been used for prediction of treatment efficacy and for individualized therapy.7

BCG unresponsive disease is defined as patients with recurrent NMIBC for whom continued BCG is unlikely to provide benefit. For this definition, we need the pathology after BCG was given, the timing of persistence/recurrence after the last instillation, and the amount of BCG given.

BCG refractory disease is defined as T1G3/HG at 3months, or TAG3/HG after three months/ 6 months, and lastly, as CIS at three months.

Adequate BCG treatment is regarded as at least 5/6 BCG induction and 2/3 maintenance doses.

Concluding his talk, Dr. Babjuk stated that we currently have the tools to identify NMIBC patients with a worse prognosis where BCG is unlikely to provide benefit. However, more precise biomarkers are still needed.

Presented by: Marek Babjuk, MD, PhD, Hospital Motol, Prague, Czech Republic

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020


  1. Abufaraj M, Foerster B, Schernhammer E, et al. Micropapillary Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-analysis of Disease Characteristics and Treatment Outcomes. Eur Urol 2019; 75(4): 649-58.
  2. Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. J Urol 2013; 189(5): 1656-61.
  3. Sui W, Matulay JT, Onyeji IC, et al. Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer. World journal of urology 2017; 35(7): 1055-61.
  4. Mally AD, Tin AL, Lee JK, et al. Clinical Outcomes of Patients With T1 Nested Variant of Urothelial Carcinoma Compared to Pure Urothelial Carcinoma of the Bladder. Clinical genitourinary cancer 2017.
  5. Cho KS, Seo HK, Joung JY, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182(6): 2625-30.
  6. Fransen van de Putte EE, Otto W, Hartmann A, et al. Metric substage according to micro and extensive lamina propria invasion improves prognostics in T1 bladder cancer. Urologic oncology 2018; 36(8): 361.e7-.e13.
  7. Patschan O, Sjödahl G, Chebil G, et al. A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma. Eur Urol 2015; 68(5): 824-32; discussion 35-6.
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