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

June 15, 2016

After a thorough repeat TURBT, disease control can be achieved with intravesical BCG and a bladder-sparing approach.

After a thorough repeat TURBT, disease control can be achieved with intravesical BCG and a bladder-sparing approach.

In 2016, there will be an estimated 76,960 new cases of bladder cancer and 16,390 deaths from bladder cancer in the United States.[1] Approximately 70% of all newly diagnosed cases of urothelial carcinoma of the bladder present as tumors that are non–muscle-invasive bladder cancer. As many as 50% to 70% of those tumors will recur, and 10% to 20% will progress to disease that invades the muscularis propria.[2] High-grade lamina propria–invasive urothelial tumors of the bladder are at particularly high risk for recurrence and progression, with a reported disease-specific mortality as high as 34%.[3] Management decisions for patients with these tumor types can be very challenging, and are critical in the care of urothelial carcinoma of the bladder.

It is critical to note that any patient found to have high-grade lamina propria–invasive urothelial carcinoma of the bladder should undergo a repeat cystoscopic transurethral resection of the bladder tumor site to assure that there is no evidence of invasion of the muscularis propria. The rationale for this is the high risk of understaging on the initial transurethral resection of the bladder tumor (TURBT), which can be as high as 64% in patients who did not have invasion of the muscularis propria on the initial resection, but also as high as 30% in patients who did have muscle in the specimen.[4] While there are select cases where immediate radical cystectomy should be considered, the majority of patients presenting with their first non–muscle-invasive bladder cancer as a high-grade T1 urothelial carcinoma on restaging TURBT can be managed with intravesical therapy and a bladder-sparing approach.

The American Urological Association and European Association of Urology guidelines both recommend an induction course of intravesical bacillus Calmette-Guérin (BCG), followed by maintenance therapy for a patient with histologically confirmed T1 bladder cancer, and suggest that radical cystectomy should be considered in the highest-risk patients.[5,6] Several meta-analyses have demonstrated that adjuvant intravesical BCG decreases recurrence and progression of non–muscle-invasive bladder cancer, as compared with TURBT alone or adjuvant intravesical chemotherapy.[7,8] It has also been demonstrated that the addition of maintenance intravesical BCG following the initial 6-week induction course further improves outcomes.[9,10]

Several groups have investigated outcomes after intravesical BCG, specifically in patients with high-grade T1 bladder cancer. Shahin et al[11] reported retrospectively on their outcomes in patients who underwent intravesical BCG alone. They demonstrated recurrence and progression risks of 70% and 33%, respectively, in patients treated with BCG and 75% and 36%, respectively, in those who had TURBT alone. Although the recurrence and progression rates in this cohort are high, it is important to note that only 54% of patients underwent repeat TURBT within 3 months after initial TURBT and no patients had maintenance BCG. This underscores the utility of maintenance BCG and the importance of repeat TURBT in all cases, which has been shown to increase BCG treatment success.[12] Brake et al reported much-improved results, with 86% of patients remaining tumor-free and retaining their bladder after 1 or 2 cycles of BCG and a median follow-up time of 53 months.[13] In this cohort, 98% of patients underwent a repeat TURBT. In a more contemporary series, Novotny et al reported recurrence and progression rates of 25% and 13%, respectively, among patients who underwent BCG treatment for high-grade T1 disease.[14] Cancer-specific mortality at 5 years was under 10%. Canter et al reported on the natural history of high-grade T1 bladder cancer in a study of 222 patients from multiple institutions.[15] In this cohort, repeat TURBT was routine, and 79% of the patients received adjuvant BCG. Progression to muscularis propria–invasive disease was 8.6% at 4 years, and 5.9% of the entire cohort died of bladder cancer. These more contemporary series demonstrate a relatively lower risk of tumor recurrence and progression when repeat TURBT is performed as needed and maintenance BCG is utilized.

The alternative to intravesical BCG for high-grade T1 disease is early radical cystectomy with urinary diversion. In patients who undergo early cystectomy for high-grade T1 disease, disease-specific survival at 5 years has been reported to be 83% to 84%, with a risk of upstaging at cystectomy in 20% to 30% of patients.[16,17] It is also important to note that these patients who underwent early cystectomy did not have repeat TURBT, accounting for the significant risk of upstaging. Had these patients undergone repeat TURBT, it is likely that a significant proportion of patients would have been reclassified as having muscularis propria–invasive disease, thus leading to better survival outcomes for a more pure T1 population undergoing early cystectomy, but also perhaps causing a greater proportion of patients to be overtreated.

In addition to risk of overtreatment with early cystectomy, the potential morbidity and mortality of the surgery should not be underestimated, and must be taken into consideration when approaching these patients, who often have significant comorbidities. Overall 90-day complication rates of radical cystectomy have been reported to be as high as 59% to 64%.[18,19] In addition, it has recently become more apparent that urinary diversion after radical cystectomy can have long-term effects on renal function, particularly in older patients with comorbidities.[20]

Although many patients with high-grade T1 bladder cancer can be spared from radical cystectomy, certainly a small proportion of patients will eventually progress to muscle-invasive disease. For this reason, several groups have attempted to identify those highest-risk patients who would benefit from upfront cystectomy. A recent large, retrospective, multicenter analysis investigated risk factors in patients with high-grade T1 disease, and found that age of 70 or older, tumor size ≥ 3 cm, and concomitant carcinoma in situ were factors associated with the highest risk for progression to invasive disease.[21] A recent meta-analysis confirmed these three features, as well as deep lamina propria invasion and lymphovascular invasion, as significant risk factors for progression and reduced cancer-specific survival.[22] Certainly the presence of these risk factors needs to be weighed against the potential morbidities resulting from radical cystectomy; while their presence may increase the risk of disease, they are not always absolute indications for radical cystectomy.

While select patients may benefit from early cystectomy, current data suggest that after a thorough repeat TURBT, many patients with high-grade T1 bladder cancer will have successful and acceptable disease control with intravesical BCG treatment and a bladder-sparing 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.


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30.

2. Rübben H, Lutzeyer W, Fischer N, et al. Natural history and treatment of low and high risk superficial bladder tumors. J Urol. 1988;139:283-5.

3. Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol. 2010;57:60-70.

4. Dutta SC, Smith JA Jr, Shappell SB, et al. Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol. 2001;166:490-3.

5. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol. 2007;178:2314-30.

6. Babjuk M, Böhle A, Burger M, et al. European Association of Urology. Non-muscle-invasive bladder cancer. http://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. Accessed May 9, 2016.

7. Witjes JA, Hendricksen K. Intravesical pharmacotherapy for non-muscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. Eur Urol. 2008;53:45-52.

8. van Rhijn BW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009;56:430-42.

9. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163:1124-9.

10. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168:1964-70.

11. Shahin O, Thalmann GN, Rentsch C, et al. A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol. 2003;169:96-100.

12. Herr HW. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy. J Urol. 2005;174:2134-7.

13. Brake M, Loertzer H, Horsch R, Keller H. Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology. 2000;55:673-8.

14. Novotny V, Froehner M, Ollig J, et al. Impact of adjuvant intravesical bacillus Calmette-Guérin treatment on patients with high-grade T1 bladder cancer. Urol Int. 2016;96:136-41.

15. Canter DJ, Revenig LM, Smith ZL, et al. Re-examination of the natural history of high-grade T1 bladder cancer using a large contemporary cohort. Int Braz J Urol. 2014;40:172-8.

16. Denzinger S, Fritsche HM, Otto W, et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol. 2008;53:146-52.

17. Hautmann RE, Volkmer BG, Gust K. Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3). World J Urol. 2009;27:347-51.

18. Novara G, Catto JW, Wilson T, et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol. 2015;67:376-401.

19. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol. 2009;55:164-74.

20. Eisenberg MS, Thompson RH, Frank I, et al. Long-term renal function outcomes after radical cystectomy. J Urol. 2014;191:619-25.

21. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients. Eur Urol. 2015;67:74-82.

22. 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.