COUNTERPOINT: Is Immediate Radical Cystectomy Justified When Non–Muscle-Invasive Bladder Cancer First Presents as High-Grade T1 Urothelial Carcinoma on Re-Resection?

Oncology (Williston Park). 30(6):541, 543–544.

Harry W. Herr, MD

Figure. Five-Year Progression-Free Survival Outcomes for NMIBC Treated by Restaging TURBT and BCG Therapy.

Patients with T1 bladder cancer on re-resection achieve the best possible survival benefit by IRC and thorough pelvic lymph node dissection.

Certain patients with re-resected T1 bladder cancers may be treated successfully by bladder-sparing strategies, albeit at the risk of tumor progression and reduced survival. Re-resection of T1 bladder cancers achieves two goals: first, it distinguishes true T1 tumors from cases of understaged muscle-invasive cancer; and second, it identifies patients who require early cystectomy to preserve survival. Patients who have minimally invasive residual cancer on a second transurethral resection of bladder tumor (TURBT) (even if the bladder muscle sample is negative for malignancy) often have more advanced disease at cystectomy, and tumors with extensive invasion of the lamina propria are likely to behave aggressively, portending a worse prognosis. In the first instance, immediate cystectomy is therapeutic; in the second, it is preemptive. The decision to perform an early cystectomy is made based on the diagnostic, therapeutic, prognostic, and predictive information provided by contemporary restaging (repeat) TURBT.[1]

Among 57 patients with re-resected T1 bladder cancer who underwent immediate cystectomy, we found 25% had muscle invasion (T2) and 5% had positive nodes. Among 36 patients undergoing deferred cystectomy (mean duration of deferral, 8 months) after failed intravesical therapy, 31% had higher-stage disease and 19% had positive nodes.[2] Another study involving 60 patients with T1 tumors after a restaging TURBT showed that 28 (47%) had more advanced disease at cystectomy.[3] Patients with clinical T1 tumors upstaged to pathologic T2 at cystectomy have worse survival than patients correctly staged as T2 before cystectomy.[4,5] The reduced survival can be attributed, in part, to a delay in the time to cystectomy due to exploration of nonsurgical treatments.

What is the fate of patients with re-resected T1 bladder cancer who are treated conservatively? The Figure shows progression-free survival outcomes for 1,021 patients with non–muscle-invasive bladder cancer, categorized by tumor stage after second TURBT. These patients were treated using intravesical immunotherapy with bacillus Calmette Guérin (BCG), which forestalled tumor progression in the majority of patients with no residual T1 cancer or with non-T1 disease. Of 142 patients with residual T1 cancer upon re-resection, 78% progressed to muscle invasion (median, 16 months) and one-third later died,[1] including patients who had responded initially to BCG therapy.[6] A recent evaluation of European trials showed that patients with high-grade T1 disease fare poorly on currently recommended BCG maintenance schedules, suggesting that alternative treatments (ie, cystectomy) are urgently required.[7]

Lastly, a meta-analysis of 15,215 patients with T1 grade 3 bladder cancer showed that deep invasion of the lamina propria had the greatest negative impact on progression and survival.[8] The authors recommended early radical cystectomy for such patients. A major fault of this study is the lack of a repeat TURBT; however, re-resected T1 disease likely indicates deep lamina propria invasion, thus identifying patients most likely to benefit from immediate cystectomy. A subsequent prospective study showed that patients with extensive submucosal tumor invasion had a three-fold increase in the rate of tumor progression, despite a second TURBT and intense intravesical therapy.[9]

Although our retrospective studies are unable to prove a survival advantage for immediate cystectomy over bladder-sparing approaches (including deferred cystectomy in patients who did not respond to nonsurgical therapy), a likely explanation is that the worst T1 tumors were selected for immediate cystectomy[2,10]-in the majority of cases, this means any residual minimally invasive high-grade cancer found on a repeat TURBT. In a competing-risk analysis, we showed that this approach saves lives.[11]

Patients with T1 bladder cancer on re-resection who want to achieve the best possible survival benefit are better served by an immediate radical cystectomy and thorough pelvic lymph node dissection, rather than a more conservative therapeutic approach.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Herr HW. Role of repeat resection in non-muscle-invasive bladder cancer. J Natl Compr Canc Netw. 2015;13:1041-6.

2. Sternberg IA, Keren Paz GE, Chen LY, et al. Role of immediate radical cystectomy in the treatment of patients with residual T1 bladder cancer on restaging transurethral resection. BJU Int. 2013;112:54-9.

3. Ark JT, Keegan KA, Barocas DA, et al. Incidence and predictors of understaging in patients with clinical T1 urothelial carcinoma undergoing radical cystectomy. BJU Int. 2014;113:894-9.

4. Guzzo TJ, Magheli A, Bivalacqua TJ, et al. Pathological upstaging during radical cystectomy is associated with worse recurrence-free survival in patients with bacillus Calmette-Guerin-refractory bladder cancer. Urology. 2009;74:1276-80.

5. Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol. 2010;57:300-9.

6. Herr HW, Donat SM, Dalbagni G. Can restaging transurethral resection of T1 bladder cancer select patients for immediate cystectomy? J Urol. 2007;177:75-9.

7. Cambier S, Sylvester RJ, Collette L, et al. EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus Calmette Guérin. Eur Urol. 2016;69:60-9.

8. Martin-Doyle W, Leow JJ, Orsola A, et al. Improving selection criteria for early cystectomy in high-grade T1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol. 2015;33:643-50.

9. Orsola A, Werner L, de Torres I, et al. Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients. Br J Cancer. 2015;112:468-74.

10. Dalbagni G, Vora K, Kaag M, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. Eur Urol. 2009;56:903-10.

11. Raj GV, Herr H, Serio AM, et al. Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol. 2007;177:1283-6.