EAU 2023: Healthy Patient with Very High Risk NMIBC: What Is Best Treatment? Does Variant Histology Change Your Recommendation?

(UroToday.com) The 2023 EAU annual meeting included a rapid fire session discussing common problems and controversies in bladder cancer, featuring a debate assessing the best treatment for a healthy patient with very high risk NMIBC.

Case Presentation

Dr. Roger Li started with a case presentation of a 72 year old male with gross hematuria and CT imaging showing a 3 cm tumor, no adenopathy, with transurethral resection showing T1 high grade with focal micropapillary features:


Re-TURBT was negative, and muscle was present in the specimen. Dr. Li notes that there have been several studies assessing T1 micropapillary disease, including the case for early cystectomy by Kamat et al.,1 and clinical outcomes of this rare histology entity when managed conservatively by our colleagues from Memorial Sloan Kettering Cancer Center.2

Intravesical Therapy is the Best Option

The position of intravesical therapy is the best option was taken by Dr. Morgan Roupret. Dr. Roupret started his presentation by highlighting that there is certainly a potentially significant risk for high grade NMIBC to recur (38-61%) and to progress (5-17%) to muscle invasive disease. However, highlighting the NMIBC flow chart from the EAU guidelines, Dr. Roupret emphasizes that in cases of high risk NMIBC, a 2nd TURBT followed by induction BCG is still one of the standard of care options:

nmibc flow.jpgAdditionally, even in high risk groups, it is important to assess additional clinical risk factors, such as (i) age > 70 years, (ii) multiple papillary tumors, and (iii) tumor diameter > 3 cm. Dr. Roupret notes that we need to consider the probabilities of progression according to the updated EAU prognostic risk groups at 1 and 5 years with primary Tis patients excluded:3

In this most recent analysis,3 BCG lowered progression risk. There were lower progression rates at 1 year in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%) versus 16.0% for the EAU predicted rates. Additionally, progression rates were also lower at 5 years in the high-risk group-7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates. The rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates. 

Dr. Roupret concluded his portion of the presentation by highlighting the following take-home messages:

  • Patients that are BCG unresponsive: well defined by the FDA and are a very high risk group
  • Trials that are finished/enrolling: immune checkpoint blockade, vaccines, genetic therapy, drug delivery systems, proteins, radiation therapy
  • This is a highly unmet need, but there is a lot in the pipeline

Upfront Radical Cystectomy is Best

The position that upfront radical cystectomy is best was taken by Dr. Laura S. Mertens. She notes that it is important to emphasize that the case presented by Dr. Li is very high risk NMIBC, defined by stage, grade, and additional risk factors such as:

  • Ta HG/G3 and CIS with all 3 risk factors
  • T1 G2 and CIS with at least 2 risk factors
  • T1 HG/G3 and CIS with at least 1 risk factor
  • T1 HG/G3 no CIS with all 3 risk factors

Work from the EAU NMIBC guidelines panel,4 shows that very high risk NMIBC is associated with worse progression, as highlighted in the cumulative incidence curve:

line graph.jpg

Dr. Mertens notes that in very high risk NMIBC patients, the EAU guidelines quite simply state we should be offering radical cystectomy: “Offer radical cystectomy or intravesical full dose BCG instillations for one to 3 years in those who refuse or are unfit for radical cystectomy” (Strength recommendation: strong). This is primarily because intravesical therapy in patients with “highest-risk” features leads to poor oncological outcomes. Additional reasons to consider upfront cystectomy include:

  1. Understaging – this may be T1   muscle invasive disease, or from N0   N+
  2. Progression – >50% at 10 years [4]. BCG reduces progression risk, but needs to be validated in very high risk, however in the high-risk group it is still 10-20%
  3. Poor prognosis – this holds a worse prognosis than de-novo muscle invasive bladder cancer with 3 year disease specific survival rates of 67% vs 37% for very high risk NMIBC
  4. Tumor biology – high rates of DNA damage repair gene alterations and mutational burden
  5. Subtype histology – the median time to progression for micropapillary urothelial carcinoma is 8 months
  6. There are no alternatives – for patients that are BCG unresponsive and are unfit or decline cystectomy, we do not have additional options. In the KEYNOTE-057 trial, patients free from high-grade recurrence at 12 months was only 24.3%.5

Dr. Mertens concluded her presentation of early cystectomy for very high risk NMIBC patients with the following take-home messages:

  • Very high risk NMIBC is a small subset of patients with the highest risk of progression
  • This has a very poor prognosis in the case of disease progression
  • BCG needs to be validated and there are no reasonable alternatives
  • There is a window of opportunity for a potential cure: upfront radical cystectomy

Case Presented by: Roger Li, MD, Moffitt Cancer Center, Tampa, Florida

Debater 1: Morgan Roupret, MD, PhD, Pitié-Salpetriere Hospital, Sorbonne University, Paris, France

Debater 2: Laura S. Mertens, MD, PhD, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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 2023 European Association of Urology (EAU) Annual Meeting, Milan, IT, Fri, Mar 10 – Mon, Mar 13, 2023.


  1. Kamat AA, Gee JR, Dinney CP, et al. The case of early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. J Urol. 2006 Mar;175(3 Pt 1):881-885.
  2. Spaliviero M, Dalbagni G, Bochner BH, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol. 2014 Sep;192(3):702-707.
  3. Lobo N, Hensley PJ, Bree KK, et al. Updated European Association of Urology (EAU) Prognostic Factor Risk Groups Overestimate the Risk of Progression in Patients with Non-muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guerin. Eur Urol Oncol. 2022 Feb;5(1):84-91.
  4. Sylvester RJ, Rodriguez O, Hernandez V, et al. European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel. Eur Urol. 2021 Apr;79(4):480-488.
  5. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicenter, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930.