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T1 High-Grade Bladder Cancer Recurring After BCG Therapy: Radical Cystectomy Is Still the Best Approach

T1 High-Grade Bladder Cancer Recurring After BCG Therapy: Radical Cystectomy Is Still the Best Approach

The management of patients with recurrent non–muscle-invasive bladder cancer (NMIBC) after receiving intravesical bacillus Calmette-Gurin (BCG) remains one of the most difficult and challenging problems in urology. There are many nuances and factors to consider in making treatment decisions in this setting; these include the patient’s disease characteristics prior to starting BCG, the total dose of BCG administered, the timing of disease recurrence relative to BCG therapy, and the disease characteristics of the recurrence itself. Given this complexity, I will limit the discussion to patients who have high-grade (HG) NMIBC with invasion of the lamina propria (T1), who are treated with a full induction 6-week course of intravesical BCG, and who are found to have persistent HGT1 disease. Here I will make the point that the most appropriate next step in management is to proceed with radical cystectomy and urinary diversion. In making this argument, one must acknowledge that there will always be patients who are either not candidates for surgery due to their comorbid conditions or who refuse radical surgery—and for these patients the choices for management must be individualized.

Arguments in favor of cystectomy for patients who have HGT1 disease after induction BCG really hinge on the goal of offering definitive therapy and avoiding loss of an opportunity to cure the patient. While there are no prospective randomized trials to definitively address this patient scenario, several lines of evidence support an aggressive approach. The first is the alarming rate at which the primary tumor is found to be understaged in patients who are thought to have NMIBC and go on to cystectomy. Several series have demonstrated that tumor upstaging from NMIBC to muscle-invasive bladder cancer can be as high as 30% to 45%.[1-3] Upstaging remains a problem, even in series in which patients have undergone endoscopic re-resection in an effort to avoid such under-staging.[4] Still more concerning is the observation that even among those who have pT1 disease at cystectomy, the rates of lymph node metastases are on the order of 10% to 18%.[1,5,6] These statistics highlight the critical observation that HGT1 bladder cancer has a high propensity to progress and is potentially lethal. The fact that it is “classified” as NMIBC should not lull the clinician into a sense of complacency, or the incorrect belief that all options should be exhausted prior to initiating more definitive therapy.

A second important observation is that patients with NMIBC who do undergo radical cystectomy have highly favorable rates of long-term, disease-free survival. Several large cohort studies of radical cystectomy for patients with pT1N0 disease have shown that estimated 5-year disease-specific survival rates are on the order of 80% to 90%.[1,3,6,7] Thus, timely cystectomy offers an excellent opportunity to cure patients and avoid the danger of having understaged their disease. A distinct counterpoint to this is the result of second-line therapy after BCG failure. The only drug approved for use in patients for whom BCG therapy has failed is valrubicin. Although in the study for which it received US Food and Drug Administration approval valrubicin yielded a modest response rate of about 20%, this occurred not in patients with HGT1 disease but in those with carcinoma in situ.[8] No other standard agents have emerged in the second-line setting after BCG failure, although the list of agents that are being tested is long, and includes mitomycin C, gemcitabine, docetaxel, interferon, as well as other therapies. All such agents are plagued with high rates of associated disease recurrence and progression, often requiring escalation to cystectomy, but at a delayed stage of illness. These delays have been associated with worse outcomes in several series in which patients who underwent immediate cystectomy were compared to those who underwent cystectomy after several courses of intravesical BCG therapy.[7,9,10] These deficiencies again highlight the potentially lethal nature of HGT1 disease and the need for timely, definitive intervention to ensure maximal oncologic control.

It is for all of these reasons that several current guidelines, including those from the American Urological Association (AUA), the National Comprehensive Cancer Network (NCCN), the European Association of Urology (EAU), and the International Consultation on Urological Diseases (ICUD), all endorse radical cystectomy as the preferred option in patients with HGT1 disease after induction intravesical BCG.[11-13] As mentioned previously, there will always be patients who are either not surgical candidates or who refuse radical cystectomy, but in all other cases radical extirpative surgery should be the preferred management for patients with HGT1 disease who fail to respond to intravesical BCG therapy.

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

References

REFERENCES

1. 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.

2. Shariat SF, Palapattu GS, Karakiewicz PI, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol. 2007;51:137.

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.

4. Dalbagni G, Herr HW, Reuter VE. Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology. 2002;60:822.

5. Thalmann GN, Markwalder R, Shahin O, et al. Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol. 2004;172:70.

6. Gupta A, Lotan Y, Bastian PJ, et al. Outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma treated with radical cystectomy. Urology. 2008;71:302.

7. Lambert EH, Pierorazio PM, Olsson CA, et al. The increasing use of intravesical therapies for stage T1 bladder cancer coincides with decreasing survival after cystectomy. BJU Int. 2007;100:33.

8. Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 2000;163:761.

9. Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol. 2001;166:1296.

10. 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.

11. Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013 Jun 12. [Epub ahead of print]

12. Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Compr Canc Netw. 2013;11:446.

13. Burger M, Oosterlinck W, Konety B, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2013;63:36.

 
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