Success Rates for Intravesical BCG Treatments for Bladder Cancer

Nearly 60,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year and 300,000 survivors are living in the United States.  The majority of these cancers (>70%) are non-muscle invasive disease, however 40-80% of these tumors will recur within the first year and 10-25% will develop muscle-invasive disease [1]. Intravesical treatments after transurethral resection (TUR) are the mainstay of treatment for non-muscle invasive urothelial cancer (NMIUC), and bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment.  

Many patients are unsure of the implications of a diagnosis of NMIUC and many are confused about BCG and its role in their disease.  They want to know the "success rate" for BCG treatment.  Here we review the data regarding BCG and outcomes for patients with NMIUC.

BCG is a live attenuated strain of Mycobacterium bovis that elicits a variety of local immune responses which appear to correlate with its anti-tumor activity.  Widespread implementation of the BCG vaccine for the prevention of tuberculosis (TB) began in the early 1920s following the work of Albert Calmette and Camille Guérin. In the 1970's and 1980's, BCG was demonstrated to be effective in the treatment of UC of the bladder.  Since then, BCG has been validated as a superior intravesical chemotherapy for high grade NMIBC with regard to both tumor recurrence [2] and progression [3].

Following the initial diagnosis and TUR of bladder cancer, an induction course of BCG can be given.  In general, an induction course is given 2-4 weeks are TUR to prevent bacterial intravasation of a recently resected tumor location.[4] According to the Southwest Oncology Group (SWOG), it may take up to 6 months for an initial induction course of BCG to have full effect. 24% of patients with residual CIS at 3 months after induction were found to be disease free at 6 months without further BCG. A meta-analysis of 6 RCTs totaling 585 intermediate- and high-risk patients (281 TUR alone versus 304 TUR+BCG) demonstrated a 56% reduction in tumor recurrence attributable to BCG (p<0.01) [5].

When an additional 3 BCG instillations (maintenance therapy) were administered, the number of complete responders increased to 64%.  The SWOG 8507 randomized controlled trial studied 384 patients randomized to receive either maintenance BCG or no maintenance following an induction course and demonstrated a significant improvement in recurrence free survival (60% versus 41% at 5 years, p < 0.01), progression or death (76% versus 70% at 5-years, p = 0.04) and suggested an overall  survival benefit (83% at 5-years, p=0.08).[6]  More recently, large trials incorporating the SWOG maintenance protocol have confirmed that maintenance therapy reduces disease progression [7-9].  Therefore, the American Urological Association and the European Association of Urology Guidelines on NMIUC recommend maintenance therapy to include 3 weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months after completion of induction therapy. [10,11]

The biggest predictor of failure after BCG therapy and progression to muscle-invasive UC is persistence of disease following two 6 week cycles or after 6 months on the 3 week maintenance schedule. [12]

BCG is also currently approved (by the U.S. Food and Drug Administration, FDA) for the treatment of carcinoma in-situ (CIS) as well as papillary UC. For CIS, the complete response rate rises to 70% with a median time to treatment failure of 34 months and a 45% 5-year disease-free survival probability [13]. When incorporating maintenance therapy for an additional 3 weeks, the overall response rate for CIS approaches 84% [6]. A meta-analysis of 700 patients with CIS (345 BCG and 355 with alternative chemotherapy) demonstrated a 47% reduction in treatment failure with BCG (OR 0.53, p=0.02) and a 53% reduction in tumor recurrence with BCG maintenance therapy [2].

SUMMARY

• A majority of UC are non-muscle invasive bladder cancer, however a high proportion of which will either recur (40-80%) or progress to muscle invasive disease (10-25%) despite complete resection.
• Bacillus Calmette-Guérin (BCG) intravesical immunotherapy is standard of care and now recommended for high- and intermediate-risk NMIBC with complete response rates of 55-65% for Ta/T1 tumors and 70-75% for CIS.
• Maintenance BCG therapy is recommended after induction therapy using the SWOG schedule of a 6 week induction course followed by 3 weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months.

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Intravesical Immunotherapy - Bladder Cancer: Diagnosis and Clinical Management by Nilay M. Gandhi, Laura A. Bertrand, Donald L. Lamm, and Michael A. O’Donnell which will appear in newest edition of The Textbook of Bladder Cancer.

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[2] Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus Calmette-Guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: A meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174 (1): 86-91.
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