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BCG is the standard treatment of T1HG bladder cancer
14th Meeting of the EAU Section of Oncological Urology (ESOU) BCG is the standard treatment of T1HG bladder cancer M. Babjuk, Prague (CZ) Prognosis and treatment strategy in high risk non-muscle invasive bladder cancer There is no doubt that T1G3 tumours are connected with unfavourable prognosis. According to the European Organization for Research and Treatment of Cancer (EORTC) risk tables, the risk that the tumour will progress within 5 years is 17-45% depending from further tumour characteristics. Moreover, 5 years disease related death was observed in 11.3% of BCG treated patients from 30962 EORTC prospective randomized trial. Apparently, T1G3/HG tumour represent life threatening disease and our approach must respect that. The treatment strategy is based on complete TURB associated with reTURB at 2-6 weeks. Essential point however is to reduce the risk of progression by applying effective adjuvant treatment. Bacillus Calmette-Guerin (BCG) intravesical immunotherapy in high risk non-muscle invasive bladder tumors Intravesical BCG is used 40 years for the treatment of non-muscle invasive bladder cancer. Its application in high risk tumors is widely accepted and is recommended also by EAU Guidelines. The impact of BCG on the risk of tumor recurrence was addressed by five meta-analyses (1-5). These studies showed that: • TURB + BCG is better than TURB alone in prevention of tumor recurrence •
TURB + BCG is better than TURB + MMC in prevention of tumor recurrence if BCG is used in maintenance schedule (at least 12 months)
•
The relative benefit of BCG is greatest in high-risk groups
There has been a long debate about whether BCG improves progression and survival. It is a very important question which has been addressed by two independent meta-analyses. Sylvester et al. examined 24 studies that contain progression information. The median follow-up was 30 months. They found 27% reduction in the odds of progression, but only in those patients who were treated with maintenance regime, with progression in 13,8% of those not receiving BCG and 9,8% of those who were treated with BCG. No conclusion regarding survival was possible. Unfortunately only 7,6% of patients with papillary tumors were grade 3. This low number prevents the separate conclusion for high-risk tumors (6). In 2004 Böhle et al. published meta-analysis of 9 trials comparing the role of BCG and MMC on disease progression. The risk of tumor progression at 26 months median followup was 7,7% in BCG comparing to 9,4% in MMC group. Interestingly, again the statistical superiority with BCG was confirmed only in trials with maintenance schedule. The subanalysis of high-risk tumors was not meaningful because of low number of studies dealing with such patients (7). A meta-analysis of individual patient data was not able to confirm any statistically significant difference between MMC and BCG for progression, but even here was possible to observe the trend in favour of BCG maintenance (2). Eur Urol Suppl 2017; 16(2):92
14th Meeting of the EAU Section of Oncological Urology (ESOU) Based on these arguments, BCG remains nowadays the only modality which can, at least in some cases, prevent disease progression into muscle invasive disease. It was confirmed, that to achieve optimal efficacy, BCG must be used including the maintenance schedule. The optimal duration and frequency of maintenance instillations however are not fully specified. We know, that at least one year of maintenance is necessary, but theoretically, the most effective schedule can be different for each individual patient. In a RCT of 1,355 patients, the EORTC has shown that when BCG is given at full dose, 3 years’ maintenance (three-weekly instillations 3, 6, 12, 18, 24, 30 and 36 months) reduces the recurrence rate compared to one year in high- but not in intermediate-risk patients. There were no differences in progression or OS (8). In conclusion, BCG including maintenance instillations remains the most effective intravesical adjuvant approach in high risk non-muscle invasive bladder cancer. We should however not forget the crucial role of initial TURB followed with re-TURB for optimal outcome. References: Bohle A, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol, 2003. 169(1): p. 90-5. 1.
Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data metaanalysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. European urology 2009;56:247-56.
2. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU international 2001;88:209-16. 3. Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67:1216-23. 4. Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU international 2004;93:485-90. 5. Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 2004;63:682-6; discussion 6-7. 6. Sylvester RJ, van der MA, 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. 7. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and highrisk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. European Urology 2013;63:462-72.
Eur Urol Suppl 2017; 16(2):93
TURB + BCG is better than TURB + MMC in prevention of tumor recurrence if BCG is used in maintenance schedule (at least 12 months)
•
The relative benefit of BCG is greatest in high-risk groups
There has been a long debate about whether BCG improves progression and survival. It is a very important question which has been addressed by two independent meta-analyses. Sylvester et al. examined 24 studies that contain progression information. The median follow-up was 30 months. They found 27% reduction in the odds of progression, but only in those patients who were treated with maintenance regime, with progression in 13,8% of those not receiving BCG and 9,8% of those who were treated with BCG. No conclusion regarding survival was possible. Unfortunately only 7,6% of patients with papillary tumors were grade 3. This low number prevents the separate conclusion for high-risk tumors (6). In 2004 Böhle et al. published meta-analysis of 9 trials comparing the role of BCG and MMC on disease progression. The risk of tumor progression at 26 months median followup was 7,7% in BCG comparing to 9,4% in MMC group. Interestingly, again the statistical superiority with BCG was confirmed only in trials with maintenance schedule. The subanalysis of high-risk tumors was not meaningful because of low number of studies dealing with such patients (7). A meta-analysis of individual patient data was not able to confirm any statistically significant difference between MMC and BCG for progression, but even here was possible to observe the trend in favour of BCG maintenance (2). Eur Urol Suppl 2017; 16(2):92
14th Meeting of the EAU Section of Oncological Urology (ESOU) Based on these arguments, BCG remains nowadays the only modality which can, at least in some cases, prevent disease progression into muscle invasive disease. It was confirmed, that to achieve optimal efficacy, BCG must be used including the maintenance schedule. The optimal duration and frequency of maintenance instillations however are not fully specified. We know, that at least one year of maintenance is necessary, but theoretically, the most effective schedule can be different for each individual patient. In a RCT of 1,355 patients, the EORTC has shown that when BCG is given at full dose, 3 years’ maintenance (three-weekly instillations 3, 6, 12, 18, 24, 30 and 36 months) reduces the recurrence rate compared to one year in high- but not in intermediate-risk patients. There were no differences in progression or OS (8). In conclusion, BCG including maintenance instillations remains the most effective intravesical adjuvant approach in high risk non-muscle invasive bladder cancer. We should however not forget the crucial role of initial TURB followed with re-TURB for optimal outcome. References: Bohle A, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol, 2003. 169(1): p. 90-5. 1.
Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data metaanalysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. European urology 2009;56:247-56.
2. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU international 2001;88:209-16. 3. Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67:1216-23. 4. Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU international 2004;93:485-90. 5. Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 2004;63:682-6; discussion 6-7. 6. Sylvester RJ, van der MA, 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. 7. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and highrisk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. European Urology 2013;63:462-72.
Eur Urol Suppl 2017; 16(2):93