Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer. Update on the Dutch Cooperative Trial: mitomycin versus bacillus Calmette-Guérin-Tice versus bacillus Calmette-Guérin RIVM in the treatment of patients with pTA-pT1 papillary carcinoma and carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group. Sequential Intravesical Mitomycin plus Bacillus Calmette–Guérin for Non–Muscle-Invasive Urothelial Bladder Carcinoma: Translational and Phase I Clinical Trial A prospective comparative study of intravesical bacillus Calmette-Guérin therapy with the Tokyo or Connaught strain for nonmuscle invasive bladder cancer. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. Marker tumour response to Evans and Pasteur bacille Calmette-Guérin in multiple recurrent pTa/pT1 bladder tumours: report from the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). Intravesical BCG treatment for superficial bladder cancer: long-term results using two different strains of BCG.
BACKGROUND The optimal dose and duration of intravesical bacillus Calmette-Guérin ( BCG ) in the treatment of non-muscle-invasive bladder cancer ( NMIBC ) are controversial . OBJECTIVE To determine if a one-third dose ( 1/3D ) is not inferior to the full dose ( FD ) , if 1 yr of maintenance is not inferior to 3 yr of maintenance , and if 1/3D and 1 yr of maintenance are associated with less toxicity . DESIGN , SETTING , AND PARTICIPANTS After transurethral resection , intermediate- and high-risk NMIBC patients were r and omized to one of four BCG groups :  1/3D-1 yr , 1/3D-3 yr , FD-1 yr , and FD-3 yr . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The trial was design ed as a noninferiority study with the null hypothesis of a 10 % decrease in the disease-free rate at 5 yr . Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model . RESULTS AND LIMITATIONS In an intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 yr , there were no significant differences in toxicity between 1/3D and FD . The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1 yr could not be rejected . We found that 1/3D-1 yr is suboptimal compared with FD-3 yr ( hazard ratio [ HR ] : 0.75 ; 95 % confidence interval [ CI ] , 0.59 - 0.94 ; p=0.01 ) . Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG . In high-risk patients , 3 yr is associated with a reduction in recurrence ( HR : 1.61 ; 95 % CI , 1.13 - 2.30 ; p=0.009 ) but only when given at FD . There were no differences in progression or survival . CONCLUSIONS There were no differences in toxicity between 1/3D and FD . Intermediate-risk patients should be treated with FD-1 yr . In high-risk patients , FD-3 yr reduces recurrences as compared with FD-1 yr but not progressions or deaths . The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience . TRIAL REGISTRATION This study was registered at Clinical Trials.gov , number NCT00002990 ; http:// clinical trials.gov/ct2/show/record/NCT00002990 BACKGROUND Potential differences in efficacy of different bacillus Calmette-Guérin ( BCG ) strains are of importance for daily practice , especially in the era of BCG shortage . OBJECTIVE To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high- grade non-muscle-invasive bladder cancer patients . DESIGN , SETTING , AND PARTICIPANTS Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011 . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonr and omized comparison , BCG Connaught and TICE were compared for time to recurrence , progression , and the duration of cancer specific survival and overall survival . RESULTS AND LIMITATIONS Information on the BCG strain was available for 2,099 patients : 957 on Connaught and 1,142 on TICE  . Overall , 765 ( 36 % ) patients received some form of maintenance BCG , 560 ( 59 % ) on Connaught and 205 ( 18 % ) on TICE . Without maintenance , Connaught was more effective than TICE only for the time to first recurrence ( hazard ratio [ HR ] = 1.48 ; 95 % CI : 1.20 - 1.82 ; P<0.001 ) . With maintenance , TICE was more effective than Connaught for the time to first recurrence ( HR = 0.66 ; 95 % CI : 0.47 - 0.93 ; P = 0.019 ) with a trend for cancer specific survival ( HR = 0.36 ; 95 % CI : 0.14 - 0.92 ; P = 0.033 ) . For time to progression and overall survival ,  Connaught  and  TICE  had a similar efficacy . Compared to no maintenance therapy , maintenance BCG significantly reduced the risk of recurrence , progression and death , both overall , and disease specific , for TICE , but not for Connaught . CONCLUSIONS We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used . However , the opposite is true when maintenance is given . PATIENT SUMMARY As there is currently a BCG shortage , information on the efficacy of different BCG strains is important . In this nonr and omized retrospective comparison in over 2,000 patients , we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used , but the opposite is true when maintenance is given Prophylactic intravesical treatment with chemotherapeutic agents or one of the different strains of the immunomodulator bacillus Calmette-Guérin ( BCG ) reduces tumor recurrence and may prevent progression after transurethral resection ( TUR ) of superficial bladder cancer . Clinical and pathological prognostic factors are used to categorize different groups at risk for disease recurrence and progression . Solitary low- grade ( G1 , 2A ) , low-stage ( pTa ) tumors have less than a 5 % risk of progression , while pT1 G3 tumors with concomitant carcinoma in situ ( CIS ) have a considerably higher risk of progression and metastases . Thus , prospect i ve clinical trials should consider the different risks associated with different prognostic groups and stratify patients accordingly . The Dutch Cooperative Trial evaluated mitomycin versus BCG-Tice versus BCG-RIVM in 469 patients with pTA/pT1 carcinoma and CIS of the urinary bladder after TUR . Of 437 evaluable patients , 50 had CIS , 254 had pTA tumors , and 133 had pT1 tumors . No statistical differences were observed in toxicity between the two strains of BCG , but local and systemic side effects were more frequent in the BCG groups versus the mitomycin group . No differences in response rate were observed between the 3 treatment groups in patients with CIS . A statistically significant difference in favor of mitomycin was seen , however , in patients with papillary tumors .  Mitomycin and BCG-RIVM were equally effective , and mitomycin proved significantly more effective than BCG-Tice . No significant difference in efficacy was observed between the two strains of BCG . Disease recurrence during the study in patients with papillary tumors was seen in 43 % of mitomycin-treated patients , 64 % of the BCG-Tice group , and 46 % of patients treated with BCG-Rivm . However , a subgroup analysis for time to first recurrence for pTa versus pT1 and for grade 1 and 2 versus grade 3 papillary tumors showed no statistically significant between-group difference . Further studies comparing identical regimens , doses , and patient groups are needed to define more clearly which patient groups and tumors are more likely to respond to intravesical therapy Purpose : To determine the safety and toxicities of sequential MMC ( mitomycin C ) + BCG ( bacillus Calmette – Guérin ) in patients with non – muscle-invasive bladder cancer ( NMIBC ) and explore evidence for potentiation of BCG activity by MMC . Experimental Design : A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC .  MMC ( 10 , 20 , or 40 mg ) was instilled intravesically for 30 minutes , followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG ( half or full strength ) for 2 hours . Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only . Murine experiments were carried out as described previously . Results : Twelve patients completed therapy , including 3 patients receiving full doses . The regimen was well tolerated with no treatment-related dose-limiting toxicities . Urinary frequency and urgency , and fatigue were common . Eleven ( 91.7 % ) patients were free of disease at a mean ( range ) follow-up of 21.4 ( 8.4–27.0 ) months . Median posttreatment urine concentrations of IL2 , IL8 , IL10 , and TNFα increased over the 6-week treatment period . A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy . In mice , intravesical MMC + BCG skewed tumor-associated macrophages ( TAM ) toward a beneficial M1 phenotype . Conclusions : Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG . This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs . Clin Cancer Res ; 21(2 ) ; 303–11 . © 2014 AACR PURPOSE We prospect ively compared the efficacy and adverse events of the bacillus Calmette-Guérin Tokyo 172 and Connaught strains for nonmuscle invasive bladder cancer . MATERIAL S AND METHODS Between January 2004 and May 2012 patients with pTa/T1 and pTis , multiple tumors and a recurrence-free period of 3 months or less who required intravesical bacillus Calmette-Guérin therapy  were prospect ively allocated r and omly to receive the Tokyo or Connaught strain . The primary study end points were the complete response rate in patients with pTis and concomitant carcinoma in situ ( pTa or pT1 ) , recurrence-free survival in patients with pTa , pT1 and carcinoma in situ who achieved a complete response  after therapy and the frequency of adverse events . RESULTS Administration of the Connaught strain ceased because its production was suspended in June 2012 . Therefore , analysis was performed using data gathered to date . Overall , 66 and 63 patients who received the Tokyo and Connaught strains , respectively , were included in efficacy analysis . Patient and tumor characteristics were well balanced between the 2 groups . Median followup was 855 days . Adverse events were similar in the groups . The complete response rate was 90.3 % and 85.0 % in patients given the Tokyo and Connaught strains , respectively , which did not significantly differ ( p = 0.896 ) . The 2-year recurrence-free survival rate was 73.2 % and 68.8 % , respectively . CONCLUSIONS Results suggest no significant differences between the Tokyo and Connaught strains in the complete response , recurrence-free survival or adverse event rate BACKGROUND Whether the commonly used bacillus Calmette-Guérin ( BCG ) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer ( NMIBC ) is unknown . OBJECTIVES To compare clinical efficacy , immunogenicity , and genetics of BCG Connaught and Tice . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve r and omized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice .  INTERVENTION Patients were r and omized to receive six instillations of BCG Connaught or Tice . For experimental studies , BCG strains were compared in C57Bl/6 mice . Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG . BCG genomic DNA was sequenced and compared with reference genomes . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence-free survival was the primary end point of the clinical study . The Kaplan-Meier estimator was used for estimating survival and time-to-event end points . Nonparametric tests served for the analysis of the in vivo results . RESULTS AND LIMITATIONS Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice ( p=0.0108 ) . Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group ( p=0.09 ) . In mice , BCG Connaught induced stronger T-helper cell 1-biased responses , greater priming of BCG-specific CD8(+ ) T cells , and more robust T-cell recruitment to the bladder than BCG Tice . Genome sequencing of the BCG strains revealed c and i date genes potentially involved in the differential clinical responses . CONCLUSIONS BCG strain may have an impact on treatment outcome in NMIBC immunotherapy . PATIENT SUMMARY We compared the efficacy of two commonly used bacillus Calmette-Guérin ( BCG ) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice . Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught . We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains . TRIAL REGISTRATION NCT00003779 PURPOSE Bacillus Calmette-Guerin ( BCG ) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma . However , controversy remains regarding the role of maintenance therapy , and its long-term effect on recurrence and progression . MATERIAL S AND METHODS All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence . The criteria for increased risk were 2 or more episodes of tumor within the most recent year , or 3 or more tumors within 6 months . At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG . Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ , and then r and omized by central computer to receive BCG maintenance therapy ( maintenance arm ) or no BCG maintenance therapy ( no maintenance arm ) . Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3 , 6 , 12 , 18 , 24 , 30 and 36 months from initiation of induction therapy . The 384 eligible patients who were disease-free at r and omization constitute the primary intent to treat analytic group because they could be followed for disease recurrence . All patients were followed for adverse effects of treatment , recurrence , disease worsening and survival . RESULTS No toxicities above grade 3 were noted in the 243 maintenance arm patients . The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity . Estimated median recurrence-free survival was 35.7 months ( 95 % confidence interval 25.1 to 56.8 ) in the no maintenance and 76.8 months ( 64.3 to 93.2 ) in the maintenance arm ( log rank p<0.0001 ) . Estimated median time for worsening-free survival , defined as no evidence of progression including pathological stage T2 disease or greater , or the use of cystectomy , systemic chemotherapy or radiation therapy , was 111.5 months in the no maintenance and not estimable in the maintenance arm ( log rank p = 0.04 ) . Overall 5-year survival was 78 % in the no maintenance compared to 83 % in the maintenance arm . CONCLUSIONS Compared to st and ard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta , T1 bladder cancer .  Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm , and patients had significantly longer worsening-free survival OBJECTIVE To compare the efficacy of Evans bacille Calmette-Guérin ( BCG ) and Pasteur BCG in eradicating marker bladder tumours  and to compare the toxicity of the two strains . PATIENTS AND METHODS Ninety-nine patients with multiple recurrent pTa or pT1 bladder tumours were allocated at r and om to six instillations at weekly intervals of either Evans BCG or Pasteur BCG . All tumours were resected except one marker tumour . At cystoscopy 3 months after r and omization all tumours including the marker tumour , if still present , were resected . RESULTS The incidence of adverse events was similar in the two groups but numbers were small and only large differences would have been detected . No statistically significant difference in efficacy regarding the response of the marker tumour or the appearance of other tumours at 3 months was noted in the two groups . There was no evidence of stage progression of the marker tumours . CONCLUSIONS In multiple recurrent pTa or pT1 bladder tumours clearing the bladder of all except one marker tumour provides a safe and convenient way of measuring the response to intravesical therapy . No significant difference in efficacy or toxicity was detected between Evans BCG and Pasteur BCG A total of 21 patients received intravesical BCG for the prevention of recurrence of superficial transitional cell carcinoma of the bladder . Twelve patients received the Glaxo strain and 9 the  Pasteur strain of the bacillus .  Although thought to have different anti-tumour activities owing to a difference in antigenicity , these 2 strains produced similar tumour-free rates at 5 years ' mean follow-up with an overall tumour-free rate of 43 %
Purpose : We sought to determine the efficacy of genetically distinct bacillus Calmette‐Guérin strains in preventing disease recurrence in patients with nonmuscle invasive bladder cancer .