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When administered intravesically as a cancer therapy, BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with macrophage and lymphocyte infiltration in the urothelium and lamina propria of the urinary bladder. (1) (2) The exact mechanism of action is unknown, but the anti-tumor effect appears to be T-lymphocyte-dependent. (2) (3)
In a multicenter randomized clinical trial, TheraCys (bcg live (intravesical)) was compared to doxorubicin hydrochloride (Adriamycin®) in patients with carcinoma in situ (CIS) of the urinary bladder, recurrent Ta/T1 papillary tumors of the urinary bladder, or both. (4) Patients were stratified by the presence or absence of CIS and analyzed separately. All papillary tumors were completely resected prior to study entry. The study endpoints were disease-free survival and 2-year disease-free survival. TheraCys was administered intravesically weekly for 6 weeks, with an additional single instillation at 3, 6, 12, 18 and 24 months following the initiation of treatment (total of 11 instillations over 2 years). The initial treatment with doxorubicin was given within 3 days of TUR, followed by 4 weekly treatments and then by 11 monthly treatments (total of 16 instillations over 1 year). Cytology and cystoscopy were obtained every 3 months for 2 years. A total of 285 patients were randomized: 142 to treatment with doxorubicin (69 CIS and 73 non-CIS) and 143 to treatment with TheraCys (bcg live (intravesical)) (70 CIS and 73 non-CIS). An intent-to-treat analysis was performed.
For patients with CIS, the complete response rate (ie, negative biopsies and urine cytology) within 6 months of the initiation of treatment was 33% with doxorubicin and 71% with TheraCys (bcg live (intravesical)) (p < 0.001, Fisher's Exact Test). The probability of being disease-free at 2 years was 23% with doxorubicin and 51% with TheraCys (bcg live (intravesical)) (p < 0.001, Z Test). The median disease-free survival was 4.9 months for doxorubicin and 30 months for TheraCys (bcg live (intravesical)) (p < 0.001, Log Rank Test).
For patients with Ta/T1 papillary tumors only, the 2-year disease-free survival was 29% with doxorubicin and 50% with TheraCys (bcg live (intravesical)) (p=0.008, Z Test). The median disease-free survival was 10.5 months with doxorubicin and 22.5 months with TheraCys (bcg live (intravesical)) (p=0.001, Log Rank Test).
The results are summarized in Table 1.
Table 1: US Clinical Trial – Efficacy (4)
|Carcinoma in situ||Ta/T1 Papillary Tumors|
|Complete Response||23 (33%)||50 (71%)||-||-|
|Median Disease-Free Survival*||4.9 Months||30 Months||10.5 Months||22.5 Months|
|2-Year Disease-Free Survival*||23%||51%||29%||50%|
|95% Confidence Interval||(15%, 35%)||(41%, 65%)||(20%, 41%)||(39%, 63%)|
|* Based upon Kaplan-Meier estimates|
1. Mikkelsen DJ, Ratliff TL. Mechanisms of action of intravesical Bacillus Calmette-Guérin for bladder cancer. In: Urologic Oncology. 1989:195-211.
2. O'Donnell MA, DeWolf WC. BCG immunotherapy for superficial bladder cancer. New prospects for an old warhorse. Surg Oncol Clin North Amer 1995;4:189-202.
3. Prescott S, et al. Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 1992:147:1636-42.
4. Lamm DL, et al. A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Eng J Med 1991;325:1205-9.
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