Data from Moschini and colleagues suggest that whether T2 disease is de novo or progressive is prognostically important.1 Among 768 patients undergoing radical cystectomy at a single institution, 475 (61.8%) patients had primary and 293 (38.2%) patients had progressive muscle invasive bladder cancer. The 10-year recurrence free survival, cancer-specific mortality, and overall mortality rates for primary versus progressive status were 43% versus 36% (p = 0.01), 43% versus 37% (p = 0.01), and 35% versus 28% (p = 0.03), respectively: 
On multivariable Cox regression analyses, progressive status remained significantly associated with a higher rate of recurrence (HR 1.47, 95% CI 1.12-1.79), cancer-specific mortality (HR 1.42, 95% CI 1.07-1.89) and overall mortality (HR1.42, 95% CI 1.13-1.65).1
What’s clinically difficult in high-risk non-muscle-invasive bladder cancer is that 50% of patients undergoing TURBT plus intravesical therapy have long-term recurrence-free survival, however 20% will progress to muscle-invasive bladder cancer. On the other hand, radical cystectomy is associated with a 70-80% cancer-specific survival rate at 5 years, but is a morbid operation. With regards to performing radical cystectomy for NMIBC, the 2016 AUA/SUO guideline makes the following statements:
- For initial high-grade T1: radical cystectomy should be considered for high-grade T1 on repeat resection or T1 with CIS, LVI
- For variant histology: due to the high rate of upstaging associated with variant histology, clinicians should consider offering initial radical cystectomy
- Recurrent high-grade T1/Ta: radical cystectomy should be considered when recurrence is within one year of two induction BCG regimens or one induction and one maintenance BCG regimen
Dr. Shuckman notes that it is important to try and identify patients that are the most likely to progress to muscle-invasive disease. The EORTC calculator is available to assist with these decisions, noting that predictors of disease progression include T stage, high-grade disease, and CIS. The AUA guidelines delineate high-risk disease as being (i) high-grade T1, (ii) any recurrent, high-grade Ta, (iii) high-grade Ta (>3 cm or multifocal), (iv) any CIS, (v) any BCG failure in high-grade cases, (vi) any variant histology, (vii) any LVI, and (viii) any high-grade prostatic urethral involvement.
Correct staging of T1 disease is crucial, thus it is important to perform a re-TUR in patients with initial T1 disease. The USC experience for upstaging at radical cystectomy based on cT1 at last TUR versus patients with muscle in the last TUR is as follows:
Variant histology is also an important prognostic factor with regards to timing of radical cystectomy. In a study by Gofrit et al.2 100 patients diagnosed with variant histology were compared to 140 patients with conventional high-grade urothelial carcinoma. Among these 100 patients 41 had Ta/T1 and underwent BCG, whereas 59 patients were referred for radical cystectomy. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade urothelial carcinoma, including 5-year recurrence-free survival (63.5% versus 71.5%, p = 0.05), 5-year progression (≥T2)-free survival (60% versus 82.5%, p = 0.002), 5-year disease-specific survival (73% versus 92.5%, p = 0.0004), and overall survival (66% versus 89.5%, p = 0.05). Patients with micropapillary disease are at significantly increased risk of upstaging. Of patients undergoing upfront radical cystectomy, patients with micropapillary disease are at ~20% increased risk of upstaging to T2-T4 and ~20% increased risk of upstaging to N+ disease compared to those with non-micropapillary disease.
There are several ongoing trials for BCG-refractory NMIBC with CIS, although currently there are only two FDA approved agents (valrubicin and pembrolizumab):
To conclude this presentation Dr. Schuckman provided her recommendations as to who should undergo up front radical cystectomy, including patients with:
- High-grade T1 disease on re-TUR
- High-grade T1 with CIS
- Variant histology
- Multiple predictors of progression on nomograms
- Unresectable volume of disease
- Intractable hematuria
- Prostatic urethral involvement
Presented by: Anne K. Schuckman, MD, Assistant Professor, Director, LAC+USC Urologic Oncology, Keck Hospital of USC, USC Norris Cancer Hospital, Los Angeles, California
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
References:
- Moschini M, Sharma V, Dell’oglio P, et al. Comparing long-term outcomes of primary and progressive carcinoma invading bladder muscle after radical cystectomy. BJU Int. 2016 Apr;117(4):604-610.
- Gofrit ON, Yutkin V, Shapiro A, et al. The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer. Front Oncol. 2016 Mar 15;6:43.