Year : 2011 | Volume
: 27 | Issue : 2 | Page : 294--295
Bacillus calmette guerin prophylaxis for recurrence after transurethral resection of transitional cell carcinoma bladder: Still the gold standard?
Kapil Singla, SB Viswaroop, G Gopalakrishnan, SV Kandasamy
Department of Urology, Vedanayagam Hospital and Postgraduate Institute, Coimbatore, Tamil Nadu, India
Department of Urology, Vedanayagam Hospital and Postgraduate Institute, Coimbatore, Tamil Nadu
|How to cite this article:|
Singla K, Viswaroop S B, Gopalakrishnan G, Kandasamy S V. Bacillus calmette guerin prophylaxis for recurrence after transurethral resection of transitional cell carcinoma bladder: Still the gold standard?.Indian J Urol 2011;27:294-295
|How to cite this URL:|
Singla K, Viswaroop S B, Gopalakrishnan G, Kandasamy S V. Bacillus calmette guerin prophylaxis for recurrence after transurethral resection of transitional cell carcinoma bladder: Still the gold standard?. Indian J Urol [serial online] 2011 [cited 2019 Dec 13 ];27:294-295
Available from: http://www.indianjurol.com/text.asp?2011/27/2/294/82864
This European Organization for Research and Treatment of Cancer (EORTC) phase 3 trial included patients with biopsy-proven, completely resected, single or multiple, primary or recurrent, stage Ta T1, grades 1-3 urothelial carcinoma of the bladder. Aim of the trial was to compare the efficacy of 6 weekly intravesical instillations of epirubicin, BCG, and BCG plus isoniazid (INH) followed by 3 weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36 in patients with intermediate and high risk stage Ta T1 urothelial bladder cancer without carcinoma in situ (CIS) after TURT. Patients were divided according to their risk of progression and death due to bladder cancer into two risk groups: intermediate-risk group (neither T1 nor grade 3 tumors) and high-risk group (stage T1 and/or grade 3 tumors). Exclusion criteria were a solitary primary tumor; presence of CIS, stage T2 or higher tumors, age >85 years, World Health Organization (WHO) performance status 3 or 4, previous treatment with doxorubicin, epirubicin or BCG, and intravesical treatment during the previous 3 months. Patients were randomized to one of three treatment groups within 24 hours after TURT and prior to receipt of the histology report: (1) Epirubicin 50 mg in 50 ml of saline weekly for six consecutive weeks starting within 24 hours after TURT; (2) BCG 5 × 10 8 colony-forming units weekly for six consecutive weeks starting 7-15 days after TURT; or (3) BCG as above plus INH 300 mg orally, the day before, the same day and the day after instillation. In all three treatment groups, this initial treatment was followed by 3 weekly instillations at months 3, 6, 12, 18, 24, 30, and 36 for a total of 27 instillations for 3 years. Cystoscopy and urine cytology were repeated every 3 months during the first 3 years and every 6 monthly thereafter. The primary end point was the time to first bladder recurrence (any stage or grade) and secondary end points was the time to progression to muscle-invasive disease (T2 or higher), time to distant metastases, overall duration of survival, and time to death due to bladder cancer. A total of 957 patients were randomized by 44 institutions at the EORTC headquarters between January 1992 and February 1997. One hundred and twenty ineligible patients were excluded from the comparisons of treatment efficacy. Patient characteristics were well balanced in the three treatment groups. This study showed that BCG reduced the risk of recurrence (P < 0.001), the development of distant metastases (P = 0.046), the risk of death (P = 0.023), and the risk of death due to bladder cancer (P = 0.026). There was no significant difference in the time to progression (P = 0.55) or in non-bladder cancer mortality (P = 0.21). Because there was no beneficial or adverse effect of the addition of INH to BCG, the two BCG treatment groups were pooled together for comparison purposes. The results on epirubicin in this study were disappointing. The long term results of this study comparing epirubicin with BCG have confirmed BCG's superiority for the time to first recurrence - but this study raised few questions like why is there an effect on distant metastases but not on progression. This study also showed that the benefit of BCG is not limited just to high risk patients but intermediate risk patients also benefit from BCG.
Role of adjuvant BCG to prevent recurrence has been proven without any doubt in many trials and it has now become a routine to administer BCG after TURT for T1G3 TCC bladder. In an analysis of more than 30 randomized controlled trials, the American Urological Association Bladder Cancer Clinical Guidelines Panel noted that intravesical BCG after TUR decreases the recurrence rate by 30% compared with TUR alone.  Although role of BCG was proven long back in 1976 by Morales, but so far exact mechanism of its action has not been elucidated. Initial step involves fibronectin based binding between the BCG and the bladder wall, which is followed by internalization of the BCG in the cells leading to the direct stimulation of cell mediated immunologic response. A recent review has shown that it is predominantly a T-helper/inducer cell mediated response with persistence of inflammatory (Th1-type) cytokines for a long time within the so called BCG-induced granulomas, which might have an important role in the recurrence free status of the patient.  Epirubicin prophylaxis after TUR appeared to be as effective as mitomycin in patients with primary tumors. Recurrence rates and recurrence-free intervals were similar to both mitomycin and epirubicin.  For recurrence prophylaxis, BCG is more effective than the combination of epirubicin and IFN-α2b but there is no difference regarding progression and adverse events between the two treatments and the superiority of the combination therapy group was significant only in the group of patients with associated CIS.  Another study comparing mitomycin C with BCG has clearly shown that BCG with maintenance is superior to mitomycin C for recurrence prophylaxis but progression and mortality rates did not differ significantly between the two. 
This study has also many flaws:
Patients with solitary TCC bladders were included in both inclusion as well as exclusion criteria.Contrary to the expectations this study failed to prove the role of BCG in preventing progression of TCC bladder which has been documented in a meta-analysis by Sylvester et al. showing 27% reduction in relative risk of progression but reason has not been mentioned in the discussion.Rationale behind using epirubicin in the same schedule as BCG.Although this study has proved the role of BCG in intermediate risk groups, it might have overdone.
|1||Smith JA Jr, Labasky RF, Cockett AT, Fracchia JA, Montie JE, Rowland RG. Bladder cancer clinical guidelines panel summary report on the management of non muscle invasive bladder cancer (stages Ta, T1 and Tis). American Urological Association. J Urol 1999;162:1697.|
|2||Bohle A. Recent knowledge on BCG´s mechanism of action in the treatment of superficial bladder cancer. Braz J Urol 2000;26:488-502. |
|3||da Silva FC, Ferrito F, Brandão T, Santos A. 4-epidoxorubicin versus mitomycin C intravesical chemoprophylaxis of superficial bladder cancer. Eur Urol 1992;21:42-4|
|4||Duchek M, Johansson R, Jahnson S, Mestad O, Hellström P, Hellsten S, et al. Bacillus Calmette-Gue´ rin is superior to a combination of epirubicin and interferon-a2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol 2010;57:25-31. |
|5||Malmström PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Gue´ rin for non-muscle-invasive bladder cancer. Eur Urol 2009;56:247-56.|