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. Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose bacillus Calmette-Guérin for superficial bladder cancer recurrence. The value of perioperative mitomycin C instillation in improving subsequent bacillus calmette-guerin instillation efficacy in intermediate and high-risk patients with non-muscle invasive bladder cancer: a prospective randomized study. Clinical experience with BCG alone versus BCG plus epirubicin. Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. Finnbladder Group. Evaluation of a low-dose intravesical bacillus Calmette-Guérin (Tokyo strain) therapy for superficial bladder cancer A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Control group and maintenance treatment with bacillus Calmette-Guerin for carcinoma in situ and/or high grade bladder tumors. 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. A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer. Maintenance intravesical bacillus Calmette-Guérin instillation for Ta, T1 cancer and carcinoma in situ of the bladder: randomized controlled trial by the BCG Tokyo Strain Study Group. Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with superficial bladder cancer. Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Prospective phase II trial of alternating intravesical Bacillus Calmette-Guérin (BCG) and interferon alpha IIB in the treatment and prevention of superficial transitional cell carcinoma of the urinary bladder: preliminary results. Maintenance bacillus Calmette‐Guérin in high‐risk nonmuscle‐invasive bladder cancer Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. Prospective randomized comparison of intravesical BCG therapy with standard dose versus low doses in superficial bladder cancer Urinary interleukin-8 predicts the response of standard and low dose intravesical bacillus Calmette-Guerin (modified Danish 1331 strain) for superficial bladder cancer. Single course versus maintenance bacillus Calmette-Guerin therapy for superficial bladder tumors: a prospective, randomized trial. Language bias in randomised controlled trials published in English and German Maximizing intravesical therapy options: is there an advantage to the administration of perioperative mitomycin C prior to an induction course of BCG? Can early single dose instillation of epirubicin improve bacillus Calmette-Guerin efficacy in patients with nonmuscle invasive high risk bladder cancer? Results from a prospective, randomized, double-blind controlled study. Long-term results of maintenance treatment of mitomycin C or alternating mitomycin C and bacillus Calmette–Guérin instillation therapy of patients with carcinoma in situ of the bladder: A subgroup analysis of the prospective FinnBladder 2 study with a 17-year follow-up
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 Intravesical instillation of bacillus Calmette-Guérin ( BCG ) is the most efficient strategy for prophylaxis of superficial bladder cancer recurrence .  Adverse effects of BCG are major obstacles , but the reduction of BCG dose could minimize these effects . The efficacy and adverse effects of half-dose ( 40 mg ) BCG , Tokyo 172 strain , were prospect ively evaluated . METHODS A total of 93 patients with superficial bladder cancer ( pTa or pT1 ) were sequentially assigned to receive either 40 or 80 mg of BCG after transurethral resection . BCG was administered weekly for 6 weeks postoperatively . Eighty patients observed longer than 12 months after BCG therapy ( 41 , 40 mg group ; 39 , 80 mg group ) were analyzed . RESULTS BCG therapy course was completed in 71 patients . Tumor recurrence was recognized in 11 of 40 patients in the 40 mg group and in 5 of 31 patients in the 80 mg group . There was no significant difference in tumor recurrence rate between the two groups ( P = 0.547 ) . BCG therapy was withdrawn in 1 patient in the 40 mg group and in 8 patients in the 80 mg-group because of BCG-related adverse effects . The morbidity of BCG-related toxicity was significantly higher in the 80 mg group . CONCLUSION Half-dose of BCG Tokyo 172 strain had a similar efficacy and its toxicity was significantly lower compared to the st and ard dose . Thus , half-dose of this strain might be suitable , at least for initial BCG therapy , for the prophylaxis of bladder cancer recurrence . Further study would be necessary to clarify the efficacy of low-dose instillation in high-risk patients PURPOSE We evaluated the efficacy of perioperative mitomycin C ( MMC ) instillation to improve subsequent  bacillus Calmette-Guérin ( BCG )  instillation efficacy in intermediate and high risk patients with non-muscle invasive bladder cancer ( NMIBC ) . MATERIAL S AND METHODS From November 2004 to May 2006 , 51 patients with intermediate or high risk NMIBC were enrolled in this prospect i ve r and omized trial . In group A , patients were treated with perioperative MMC ( 40 mg MMC in 40 mL saline was administered within 6 hours of surgery ) followed by delayed ( at least 15 days from surgery ) BCG instillations ( once a week for 6 weeks , 5 x 108 colony-forming units in 50 mL saline ) . Patients in group B were treated with delayed BCG instillations alone . The primary end points were recurrence-free interval and recurrence rate . RESULTS There were 25 and 26 patients in groups A and B , respectively . Median follow-up was 41.3 months ( range 8 to 64 ) in group A and 40.9 months ( range 6 to 68 ) in group B. Recurrence rate was 36 % ( 9 of 25 ) and 19.3 % ( 5 of 26 ) in group A and B , respectively ( p = 0.052 ) . Median time to the first recurrence was 8 months in group A and 7 months in group B ( p = 0.12 ) . CONCLUSIONS The present study showed no statistically significant difference in terms of recurrence rate and median time to first recurrence between intermediate or high-risk patients with NMIBC who were treated with early single dose instillation of MMC plus delayed BCG and those who were treated with only BCG BACKGROUND Bacillus Calmette-Guérin ( BCG ) and epirubicin have both been shown to be effective in the treatment of superficial bladder cancer . We studied whether the alternating combination of these agents could improve the efficacy with tolerable side-effects in the treatment of high-risk superficial bladder tumors . METHODS Forty-one patients with high-risk superficial bladder transitional carcinoma were included in this study . Twenty-one patients were r and omized into the BCG group and 20 patients were treated with sequential BCG and epirubicin . The patients were followed for 9 - 24 months ( mean 18 months ) . Recurrence rates , median time to the first recurrence , progression rate and complications were compared . RESULTS Fifteen percent of the patients in the BCG and epirubicin group and 19 % of the patients in the BCG alone group developed tumor recurrence . Tumor progression was observed in 4.7 % and 10 % in the BCG/epirubicin group and the BCG alone group , respectively . Median time to first recurrence was 11 months for the BCG/epirubicin group and 16 months for the BCG group ( P > 0.05 ) . Three patients in the BCG/epirubicin treatment group developed serious side-effects , which necessitated antituberculosis treatment . CONCLUSION Because the efficacy of combination was no better than the st and ard treatment and the alternating combination seemed to be related to a higher incidence of side-effects , this study albeit small , does not recommend combination therapy of BCG and epirubicin in high risk patients with superficial bladder cancer PURPOSE We attempted to prove if alternating chemoprophylactic and immunoprophylactic instillations improved efficacy and decreased toxicity in patients with recurrent superficial bladder cancer . MATERIAL S AND METHODS A total of 188 patients with rapidly recurring stage Ta or T1 cancer was r and omly treated with mitomycin C ( group 1 ) or alternating mitomycin C and Pasteur strain bacillus Calmette-Guerin ( BCG ) instillations ( group 2 ) for 2 years . Mean followup was 34 months . RESULTS Median times to initial recurrence were 12 months in group 1 and 7 months in group 2 ( p = 0.976 ) , and treatment failed in 21.5 % and 18.9 % , respectively . Recurrence rates during the instillation period were 1.01 in group 1 and 0.86 in group 2 ( p = 0.376 ) . There was no difference in the disease-free interval between the 2 groups ( p = 0.976 ) . Instillations were discontinued because of adverse effects in 6 cases ( 6 % ) in both groups . CONCLUSIONS Efficacy of alternating mitomycin C and BCG was equal to mitomycin C monotherapy , and both methods were effective in prophylaxis of recurrent papillary bladder cancer . Less toxicity occurred in the alternating treatment group compared to earlier BCG monotherapy results To examine whether intravesical instillation of low-dose bacillus Calmette-Guérin ( BCG ) therapy is effective with low toxicity , we review ed data for 111 patients with superficial bladder cancer ( stages Ta and T1 ) . Among them , 74 received the BCG treatment for prophylaxis of intravesical recurrence after transurethral resection , and the remaining 37 therapeutically for Ta or T1 tumours . The patients were divided into two groups by instillation dose of BCG ( Tokyo 172 strain ) : 40 mg ( n=55 ) and 80 mg ( n=56 ) , and statistically compared for recurrence , antitumour effect and toxicity . The mean instillations were done 8.4 times in the 40 mg dose group and 8.6 times in the 80 mg dose group . Among the 74 patients with BCG therapy for prophylaxis those with a previous episode of bladder cancer treatment ( n=47 ) experienced a significantly ( p=0.006 ) shorter recurrence-free interval than those with no episode ( n=27 ) . Among 47 patients with a previous treatment episode , those receiving the 80 mg dose demonstrated a significantly longer recurrence-free interval than those given the 40 mg dose ( p=0.03 ) . Among the 27 patients without previous treatment no significant difference in recurrence-free intervals was found between the two dose groups . Univariate and multivariate aalyses using Cox 's proportional hazards model confirmed the above findings . The drecurrence index was also significantly reduced after BCG therapy in the 80 mg and 40 mg groups and similar antitumour effects for Ta or T1 tumours were observed in the two dose groups . The degree of toxicity due to BCG therapy was significantly ( p=0.02 ) lower with the 40 mg dose . The present study suggests that ( 1 ) a 40 mg BCG low-dose ( Tokyo 172 strain ) regimen is useful for preventing recurrence , with sufficient therapeutic efficacy and low frequency of toxicity , among patients without a previous treatment , and ( 2 ) prophylactic effects with the 80 mg dose regimen are much superior for previous treatment cases OBJECTIVE The primary aim was to search for lower doses of Bacillus Calmette-Guerin ( BCG ) that are effective and have lower toxicity . METHODS A low dose of BCG 27 mg was compared with BCG 13.5 mg , using mitomycin C ( MMC ) 30 mg as the third arm of comparison . A total of 430 patients with intermediate-risk superficial bladder cancer were r and omised into three groups . Instillations were repeated once a week for 6 wk followed by another six instillations given once every 2 wk during 12 wk . RESULTS There was a significantly longer disease-free interval for BCG 27 mg versus MMC 30 mg ( p=0.006 ) . There were no statistically significant differences between BCG 27 mg and BCG 13.5 mg ( p=0.165 ) or between BCG 13.5 mg and MMC 30 mg ( p=0.183 ) . Cox proportional hazards regression showed that disease-free interval in the multivariate analysis was significantly better for primary disease and treatment with BCG 27 mg . There were no significant differences among the three groups with regards to time to progression and cancer-specific survival time . Local and systemic toxicity were higher in both BCG treatment groups . CONCLUSIONS One third of the st and ard dose , BCG 27 mg , seems to be the minimum effective dose as adjuvant treatment for intermediate-risk superficial bladder cancer , being more effective than MMC 30 mg . One sixth of the st and ard dose , BCG 13.5 mg , has the same efficacy as MMC 30 mg but it is more toxic PURPOSE Intravesical instillations of bacillus Calmette-Guerin have demonstrated satisfactory results in the treatment of vesical carcinoma in situ and high grade superficial bladder tumors . We design ed a protocol to evaluate the decrease in tumor recurrence with maintenance therapy . MATERIAL S AND METHODS Between June 1989 and May 1995 an initial course of 6 intravesical instillations of Connaught strain bacillus Calmette-Guerin  was administered in patients with carcinoma in situ and /or high grade superficial bladder tumors . Six months later 131 disease-free patients were r and omly assigned to a control group or a maintenance therapy group that received 6 instillations every 6 months ( 6 x 6 ) for a 2-year period . RESULTS Of the 126 evaluable patients at a mean followup of 79 months there were no significant differences in recurrence nor progression . A total of 16 patients ( 26.2 % ) in the control and 10 ( 15.1 % ) in the maintenance group had superficial relapse at a mean of 24 and 20 months , respectively ( p = 0.07 ) . Eight patients underwent radical cystectomy due to bladder contraction in 1 , high grade superficial recurrence in 4 and disease progression in 3 . Of the 65 patients on maintenance therapy 22 ( 33.85 % ) completed the planned 2-year treatment . CONCLUSIONS Six-month maintenance therapy in patients treated initially for carcinoma in situ and /or high grade superficial bladder tumors who are disease-free at 6 months did not significantly decrease recurrence or progression 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 Between August 1981 and July 1984 , 93 patients with polychronotopic superficial papillary carcinoma ( Ta and /or T1 ) , flat carcinoma in situ ( Tis ) , or concomitant superficial papillary and in situ bladder carcinoma were entered into a prospect i ve r and omized trial of maintenance v nonmaintenance intravesical bacillus Calmette-Guérin ( BCG ) therapy .  Forty-six patients who received BCG weekly for 6 weeks were compared with 47 patients receiving the six-weekly doses of BCG plus monthly BCG for 2 years . Both groups were evaluated every 3 months by cytology , cystoscopy , and biopsy . A significant reduction in the number of recurrent tumors per patient-month was demonstrated for both groups ( P less than .0001 ) ; however , the difference in reduction of tumors between the two groups was not significant . Additionally , patients receiving maintenance and nonmaintenance therapy had similar tumor recurrence and progression rates . These results indicate that monthly maintenance BCG does not prevent , delay , or reduce tumor recurrence or progression observed with the 6-week regimen . Maintenance BCG was associated with increased local toxicity , primarily dysuria , frequency , and urgency . Dosage reduction was required in 22 of 47 patients ( 46.8 % ) . When the data were subjected to multivariate analysis , the presence or absence of tumor following induction BCG and PPD skin test results were found to be significant variables . Controlling for either the presence or absence of tumor following induction BCG , tumor recurrence and progression rates were not significantly different for the two treatment groups . However , the absence of tumor after induction BCG was associated with a longer disease-free duration ( P = .00001 ) and time to progression ( P = .095 ) . Patients with a reactive tuberculin skin test before and after induction BCG had significantly less tumor recurrences than patients with different PPD skin tests results ( P = .02 ) . Tumor progression was not related to tuberculin skin testing OBJECTIVES We carried out a prospect i ve , r and omized , controlled trial to investigate the efficacy and safety of both induction and maintenance therapy with intravesical instillation of bacillus Calmette-Guérin ( BCG ) for high-risk non-muscle invasive bladder cancer ( NMIBC ) . METHODS Intravesical instillation of 80 mg Tokyo strain was given to patients with high-risk NMIBC , including carcinoma in situ ( CIS ) , once weekly for eight consecutive weeks as induction therapy . Patients who achieved complete response ( CR )  were r and omly assigned to either the maintenance group or the observation group . RESULTS A total of 90 patients were enrolled . After induction therapy , 75 % of the patients achieved CR and 53 of them were enrolled in the r and omized comparative phase . A total of four maintenance instillations were given . Median follow-up was 26.5 and 28.7 months after r and omization in the maintenance and the observation group , respectively . Although it was not statistically significant , the 2-year recurrence-free survival rate in the maintenance group ( 95.8 % ) was higher than that in the observation group ( 74.1 % , P = 0.078 ) . Univariate analysis identified maintenance therapy as a significant factor influencing recurrence . During induction therapy , 82.2 % of patients experienced urination-related adverse drug reactions , but most events were not serious . There were fewer adverse drug reactions with maintenance therapy than with induction therapy . Neither induction therapy nor maintenance therapy reduced patients ' quality of life ( QOL ) . CONCLUSIONS These findings show high levels of efficacy and safety of BCG induction treatment for high-risk NMIBC , and suggest that the number of maintenance instillations could probably be reduced without reducing treatment efficacy or influencing QOL PURPOSE We study toxicity and efficacy of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin ( BCG ) in patients with intermediate or high risk superficial bladder cancer compared to the use of intravesical mitomycin C alone . MATERIAL S AND METHODS Patients with intermediate and high risk papillary superficial bladder cancer and carcinoma in situ were r and omized after transurethral resection between 4 weekly instillations with 40 mg . mitomycin C followed by 6 weekly instillations with BCG ( group 1 , 90 patients ) or 10 weekly instillations with mitomycin C ( group 2 , 92 patients ) . RESULTS The frequency of bacterial and chemical cystitis , and other local side effects was similar in both groups . Allergic reactions , including skin rash , were more frequent in the mitomycin C only group ( 12 of 92 patients versus 5 of 90 , p = 0.08 ) , and other systemic side effects were more frequent in the sequential group ( 16 of 90 versus 8 of 92 , p = 0.07 ) . After a median followup of 32 months the number of recurrences ( sequential 35 of 90 patients versus mitomycin C only 42 of 92 , p = 0.36 ) and progression ( 5 of 90 versus 4 of 92 respectively , p = 0.70 ) were similar in both groups . CONCLUSIONS We did not find any major differences in toxicity or treatment efficacy with intravesical mitomycin C and the sequential use of BCG or mitomycin C for intermediate and high risk superficial papillary bladder cancer OBJECTIVES To evaluate whether , in patients with carcinoma in situ ( CIS ) of the urinary bladder , alternating instillation therapy with mitomycin C ( MMC ) and bacillus Calmette-Guerin ( BCG ) was more effective and less toxic than conventional BCG monotherapy . METHODS Patients were stratified prospect ively for primary , secondary , and concomitant CIS and r and omized to one of two regimens . Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg , followed by alternating monthly instillations of BCG 120 mg and MMC for one year . In the monotherapy group , only BCG was instilled on the same schedule . RESULTS Of 323 enrolled patients , 304 were eligible for analysis . After an overall median follow-up of 56 months , the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy ( p=0.03 ; log rank test ) . Risk for progression appeared lower in the BCG monotherapy group ( p=0.07 ) , but no differences existed in survival . Besides the regimen , CIS category also predicted outcome to some extent . BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy . However , no differences were observed in the number of serious side-effects . CONCLUSION One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series . The alternating therapy was better tolerated BACKGROUND Both bacillus Calmette-Guérin ( BCG ) and interferon-alpha ( IFN-alpha ) express activity against superficial bladder cancer . The results of a national multicenter phase II trial of a combination of these 2 agents used in a wide range of patients are reported . MATERIAL S AND METHODS Patients previously having BCG failure received IFN-alpha ( 50 million units ) plus reduced dose BCG , while patients naïve to BCG received the same IFN-alpha dose with st and ard dose BCG . All patients who were relapse free received an additional 3 series of 3-week reduced dose BCG plus IFN-alpha treatments at 3 , 9 , and 15 months after completing induction . Any relapse during the 3-month evaluation was counted as a failure of therapy for Kaplan-Meier analysis . Multivariate analysis was performed to identify factors associated with recurrence . RESULTS Of 1,007 valuable patients , 59 % and 45 % of patients naïve to BCG and those having BCG failure , respectively , remained disease free at 24-month median follow-up . Stage T1 , tumor size>5 cm , prior BCG failure more than once , and multifocality were all statistically significant risk factors for recurrence . CONCLUSIONS Although BCG plus IFN-alpha can be effectively applied to both patients naïve to BCG and those having BCG failure , certain patient and tumor characteristics influence durable response BACKGROUND The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer , for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination . We aim ed to do a prospect i ve , r and omised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer . METHODS After transurethral resection and multiple biopsies , 212 patients with stage pT1 bladder cancer were r and omly assigned to : 81 mg BCG infused over 120 min once a week for 6 weeks ( n=105 ) ; or to 81 mg BCG infused over 120 min once a week for 2 weeks , followed by 40 mg electromotive mitomycin ( intravesical electric current 20 mA for 30 min ) once a week as one cycle for three cycles ( n=107 ) . Complete responders underwent maintenance treatment : those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months , and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months , followed by 81 mg BCG once a month as one cycle for three cycles . The primary endpoint was disease-free interval ; secondary endpoints were time to progression ; overall survival ; and disease-specific survival . Analyses were done by intention to treat . This trial has been su bmi tted for registration at the US National Cancer Institute website . FINDINGS Median follow-up was 88 months ( IQR 63 - 110 ) . Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone ( 69 months [ 95 % CI 55 - 86 ] vs 21 months [ 15 - 54 ] ; difference between groups 48 months [ 42 - 54 ] , log-rank p=0.0012 ) . Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence ( 41.9 % [ 32.7 - 51.5 ] vs 57.9 % [ 48.7 - 67.5 ] ; difference between groups 16.0 % [ 2.7 - 29.3 ] , log-rank p=0.0012 ) ; progression ( 9.3 % [ 3.8 - 14.8 ] vs 21.9 % [ 17.9 - 25.9 ] ; difference between groups 12.6 % [ 3.0 - 22.2 ] , log-rank p=0.004 ) ; overall mortality ( 21.5 % [ 13.5 - 29.5 ] vs 32.4 % [ 23.4 - 41.4 ] , difference between groups 10.9 % [ 0.6 - 21.2 ] , log-rank p=0.045 ) ; and disease-specific mortality ( 5.6 % [ 1.2 - 10.0 ] vs 16.2 % [ 6.1 - 23.3 ] , difference between groups 10.6 % [ 2.5 - 18.7 ] , log-rank p=0.01 ) . Side-effects were mainly localised to the bladder . INTERPRETATION BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect BACKGROUND AND OBJECTIVE Evaluate the efficacy and toxicity of alternating intravesical instillation of Bacillus Calmette-Guerin(BCG ) and Interferon alpha2-b ( IFN ) in the treatment and prevention of recurrence of superficial transitional cell carcinoma ( TCC ) of the urinary bladder . METHODS Patients with Ta , T1 tumors and carcinoma in situ , either recurrent ( TaG1 , T1G1 ) or primary /recurrent TaG2 TaG3 , T1G2 , T1G3 and Tis ( T : Tumor stage , G : grade ) are eligible . All patients received intravesical BCG 81 mg on Weeks 1 , 3 , 5 and 7 and IFN 100 million units on Weeks 2 , 4 , 6 and 8 . Cystoscopy performed 4 weeks after completion of therapy , and every 3 months thereafter . RESULTS There was a total of 37 patients . Thirteen had TaG2 , 13 T1G2 , 1 T1G1 , 4 TaG1 , 1 TaG3 , 3 T1G3 and 7 Tis ( 5 concurrent with other above tumors ) . Index lesion cleared in 7/10 patients . With a median follow-up of 26.2 month , 22 patients ( 59 % ) failed above therapy . Median time to treatment failure was 7 months . Seven , 6 and 9 patients recurred at a higher , lower and same stage or grade respectively . No grade 3 or 4 toxicity was encountered . CONCLUSIONS Alternating intravesical BCG and IFN is effective and well tolerated therapy for superficial TCC of urinary bladder Intravesical bacillus Calmette‐Guérin ( BCG ) immunotherapy is effective in preventing recurrence and progression in nonmuscle‐invasive bladder cancer but the dosing schedule and duration of treatment remain empirical . The outcome of BCG therapy was prospect ively evaluated on patients according to the number of maintenance cycles received PURPOSE In a multicenter , prospect ively r and omized study we evaluated bacillus Calmette-Guérin alone vs bacillus Calmette-Guérin plus interferon α-2b and megadose vitamins vs recommended daily allowance vitamins during induction and maintenance intravesical therapy in the treatment of nonmuscle invasive bladder cancer . MATERIAL S AND METHODS Patients who were bacillus Calmette-Guérin naïve with carcinoma in situ , Ta or T1 urothelial cancer were r and omized to receive intravesical bacillus Calmette-Guérin or bacillus Calmette-Guérin plus interferon α-2b .  Patients were further r and omized to receive a recommended daily allowance or megadose vitamin preparation . Induction bacillus Calmette-Guérin treatment was given weekly for 6 weeks , and patients who were recurrence-free received maintenance treatment at 4 , 7 , 13 , 19 , 25 and 37 months . Patients were followed with quarterly cystoscopy for 2 years , then semiannually through year 4 and then annually . The primary end point was biopsy confirmed tumor recurrence or positive cytology . RESULTS A total of 670 patients were accrued and r and omized . At 24-month median followup recurrence-free survival was similar in all groups with 63 % in the bacillus Calmette-Guérin with recommended daily allowance vitamins group , 59 % in bacillus Calmette-Guérin with megadose vitamins , 55 % in bacillus Calmette-Guérin/interferon α-2b with recommended daily allowance vitamins and 61 % in bacillus Calmette-Guérin/interferon α-2b with megadose vitamins ( p > 0.05 ) . The addition of interferon α-2b was associated with a more frequent incidence of fever ( 11 % vs 5 % ) and constitutional symptoms ( 18 % vs 11 % ) vs bacillus Calmette-Guérin alone ( p < 0.05 ) . CONCLUSIONS Interferon α-2b added to bacillus Calmette-Guérin induction and maintenance intravesical therapy did not decrease tumor recurrence in bacillus Calmette-Guérin naïve cases , but was associated with increased fever and constitutional symptoms . No difference in time to recurrence was present in patients receiving recommended daily allowance vs high dose vitamins In this study , we evaluated low dose intravesical bacillus Calmette-Guerin ( BCG ) therapy following transurethral resection ( TUR ) in 80 patients with superficial bladder cancer . The patients were divided into two groups . Of the Connaught BCG strain 81 mg was given to 40 patients in Group 1 and 54 mg to the remainder of 40 patients in Group 2 . BCG was introduced once a week for 6 weeks . Tumour recurrence was seen in 6 patients in Group 1 and in 10 patients in Group 2 . Recurrence rates per month were 0.71 and 1.49 , respectively . There was no significant difference in complication rates . These data suggest that while the st and ard dose ( 81 mg ) intravesical therapy of BCG is more effective than the low dose , there was no significant difference in side effects between the two groups PURPOSE We determined whether the proinflammatory cytokine interleukin-8 ( IL-8 ) can serve as a predictor for the response to st and ard ( 120 mg . ) and low ( 40 mg . ) dose intravesical bacillus Calmette-Guerin ( BCG ) ( modified Danish 1331 strain ) for managing superficial bladder cancer in patients at risk for recurrence and progression . MATERIAL S AND METHODS We r and omized 26 patients with superficial bladder cancer to receive a 6-week course of st and ard dose 120 mg . or low dose 40 mg . intravesical BCG . Voided urine sample s were collected immediately before and after ( 2 and 4 hours ) BCG instillation . Urine sample s were centrifuged at 1,500 rpm for 8 minutes and stored at -80C . IL-8 was measured using a commercial enzyme-linked immunosorbent assay . Patients were monitored for recurrence , progression and side effects of BCG treatment at 3-month intervals . RESULTS At a median followup of 24 months ( range 12 to 30 ) , 5 and 6 patients who received a st and ard and low dose , respectively had disease recurrence and /or progression ( nonresponders ) . At 4 hours after BCG mean Il-8 levels plus or minus SD were significantly higher in responders than in nonresponders ( 1,099.33 + /- 708.51 versus 261.82 + /- 182.66 pg./ml . , p = 0.001 ) . There was no difference at 4 hours in mean IL-8 levels in the st and ard and low dose groups ( 596.92 + /- 546 and 893 + /- 798.67 pg./ml . , respectively , p = 0.28 ) . In all patients who remained disease-free IL-8 levels were greater than 400 pg./ml . In 9 of the 11 patients with disease recurrence/progression IL-8 levels were less than 400 pg./ml . CONCLUSIONS IL-8 secretion after the initial intravesical BCG instillation strongly correlates with the possibility of future recurrence/progression . The quantitative IL-8 response to low and st and ard dose intravesical BCG ( Danish 1331 ) is similar A total of 42 patients with recurrent superficial bladder tumors or carcinoma in situ entered a prospect i ve , r and omized trial to compare the efficacy of bacillus Calmette-Guerin therapy with and without quarterly maintenance instillations of bacillus Calmette-Guerin . Maintenance therapy did not reduce further bladder tumor recurrence rates or the interval to recurrence in patients who responded to the initial course of therapy . However , prolongation of toxicity was observed with maintenance bacillus Calmette-Guerin therapy BACKGROUND Some r and omised controlled trials ( RCTs ) done in German-speaking Europe are published in international English- language journals and others in national German- language journals . We assessed whether authors are more likely to report trials with statistically significant results in English than in German . METHODS We studied pairs of RCT reports , matched for first author and time of publication , with one report published in German and the other in English . Pairs were identified from reports round in a manual search of five leading German- language journals and from reports published by the same authors in English found on Medline .  Quality of methods and reporting were assessed with two different scales by two investigators who were unaware of authors ' identities , affiliations , and other characteristics of trial reports . Main study endpoints were selected by two investigators who were unaware of trial results . Our main outcome was the number of pairs of studies in which the levels of significance ( shown by p values ) were discordant . FINDINGS 62 eligible pairs of reports were identified but 19 ( 31 % ) were excluded because they were duplicate publications . A further three pairs ( 5 % ) were excluded because no p values were given . The remaining 40 pairs were analysed . Design characteristics and quality features were similar for reports in both language s. Only 35 % of German- language articles , compared with 62 % of English- language articles , reported significant ( p < 0.05 ) differences in the main endpoint between study and control groups ( p = 0.002 by McNemar 's test ) . Logistic regression showed that the only characteristic that predicted publication in an English- language journal was a significant result . The odds ratio for publication of trials with significant results in English was 3.75 ( 95 % CI 1.25 - 11.3 ) . INTERPRETATION Authors were more likely to publish RCTs in an English- language journal if the results were statistically significant . English language bias may , therefore , be introduced in review s and meta-analyses if they include only trials reported in English . The effort of the Cochrane Collaboration to identify as many controlled trials as possible , through the manual search of many medical journals published in different language s will help to reduce such bias INTRODUCTION This study sought to evaluate cancer-specific outcomes among patients who received perioperative mitomycin C ( MMC ) prior to induction BCG  versus those who received induction BCG alone .  MATERIAL S AND METHODS Between January 2000 and August 2010 , 260 patients were identified who underwent a course of induction BCG with or without concomitant perioperative MMC .  Specifically , patients who received 40 mg MMC following transurethral resection of all visible tumor followed by an induction course of BCG  were compared to a similar cohort of patients who received induction BCG alone . The primary endpoints were overall and recurrence-free survival ( RFS ) . RESULTS A total of 212 patients were identified who received induction BCG alone , and 48 who received perioperative MMC with induction BCG .  The aggregate patient cohort was comprised of those with non-muscle invasive disease ( NMI ) , and there was no difference between groupings with respect to common demographic and pathologic variables . Over a median follow up of 34.5 months , there was no difference in overall survival between cohorts . RFS was superior among patients who received combined therapy ( 5 year survival : 37.5 % versus 56.3 % , p = 0.023 ) . Nevertheless , the regimen of intravesical therapy did not reach significance as an independent predictor ( HR 0.61 , p = 0.055 , CI 0.36 - 1.01 ) . CONCLUSION Although the combination therapy group demonstrated a significant RFS advantage , the intravesical therapy regimen did not independently modulate this benefit . Further investigation is warranted to determine if immediate MMC prior to a course of induction BCG confers a benefit to RFS . Nevertheless , this pilot investigation sets an important precedent on the management of NMI bladder cancer , nonwithst and ing the absence of contemporary large scale , r and omized trials PURPOSE We evaluated the impact of epirubicin perioperative instillation in improving subsequent bacillus Calmette-Guerin instillation efficacy in high risk patients with nonmuscle invasive bladder cancer . MATERIAL S AND METHODS Between January 2005 and June 2007 , 161 patients affected by high risk nonmuscle invasive bladder cancer were enrolled in this prospect i ve , r and omized , controlled , double-blind study . A total of 80 patients were assigned to group A ( perioperative epirubicin 80 mg/50 ml normal saline ) plus delayed bacillus Calmette-Guerin instillations ( 5 x 108 colony-forming units in 50 ml saline ) and 81 to group B ( delayed bacillus Calmette-Guerin alone ) . The main outcome measures were time to first recurrence and recurrence rate . All data obtained from a median followup of 15.3 months in group A and 14.8 months in group B , were analyzed . RESULTS At the end of followup 46 of 80 patients in group A ( 57.5 % ) had no evidence of disease , just like 41 of 81 in group B ( 50.6 % ) . No statistical difference was observed between the 2 groups in terms of recurrence rate ( p = 0.82 ) or time to first recurrence ( p = 0.095 ) . Kaplan-Meier analysis of recurrence showed no significant differences between group A and group B ( p = 0.0952 ) . On multivariate analysis the early single dose instillation of epirubicin was not indicated as an independent prognostic factor ( HR 0.50 , 95 % CI 0.32 - 1.18 ) . CONCLUSIONS The present study showed no statistically significant differences in terms of disease-free time and recurrence rate between high risk patients with nonmuscle invasive bladder cancer who had undergone perioperative epirubicin instillation plus delayed bacillus Calmette-Guerin and those who had undergone delayed bacillus Calmette-Guerin alone Abstract Objective . Only a few studies with a long-term follow-up exist on patients with carcinoma in situ ( CIS ) treated with instillation therapy . The objective was to study the long-term outcome of patients with CIS after mitomycin C ( MMC ) monotherapy or alternating therapy with MMC and bacillus Calmette – Guérin ( BCG ) . Material and methods . The study population comprised 68 patients with CIS belonging to a larger material of 256 patients with non-muscle-invasive bladder carcinoma who were r and omized between 1987 and 1992 in a prospect i ve multicentre study . Patients received the same induction period with MMC and continued with maintenance treatment comprising either monthly instillations of MMC alone or alternating MMC and BCG instillations for up to 2 years . Primary endpoints were cancer-specific and overall mortality . Secondary endpoints were time to first recurrence and time to progression . The principal statistical methods were the Kaplan – Meier method and cumulative incidence analysis . Results . The overall median follow-up time of the patients with CIS was 7.2 years and the median follow-up time of the patients still alive was 17.1 years . The non-stratified probability of dying from bladder carcinoma at 5 , 10 and 15 years was 13 % , 25 % and 28 % , respectively . No significant difference was found between the study groups with respect to time to first recurrence , progression , or disease-specific or overall mortality . Conclusions . The long-term bladder cancer-specific mortality was unexpectedly low despite the relatively ineffective instillation therapy and the poor outcome of the patients after progression
Background To explore the necessity of maintenance , efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin ( BCG ) in treatment of superficial bladder cancer ( BCa ) .