[Therapeutic effect of mitomycin C in the immediate postoperative period in patients with intermediate-risk non-muscle-invasive bladder tumors]. Single dose intravesical thiotepa as an adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. Transurethral resection with perioperative instilation on interferon-alpha or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study--Finnbladder III. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. Single-dose versus multiple instillations of epirubicin as prophylaxis for recurrence after transurethral resection of pTa and pT1 transitional-cell bladder tumours: a prospective, randomized controlled study. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, controlled trial. Immediate intravesical instillation of mitomycin C after transurethral resection of bladder tumor in patients with low-risk superficial transitional cell carcinoma of bladder. Effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: interim report from the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party) Randomized study of single early instillation of (2″R)‐4′‐O‐tetrahydropyranyl‐doxorubicin for a single superficial bladder carcinoma Long-term experience with early single Mitomycin C instillations in patients with low-risk non-muscle-invasive bladder cancer: prospective, single-centre randomised trial Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term follow-up. 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. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study.
INTRODUCTION Approximately 70 - 85 % of transitional bladder cell carcinomas are non-muscle-invasive . After an initial surgery , around 60 - 90 % will have a recurrence , being the highest risk period the first two years . Urothelium instability could be the main reason for recurrence in mid grade tumours , reason why a single dose of a chemotherapy after transurethral resection of the bladder ( TURB ) might be insufficient . That is why a deferred therapy in occasions associated with maintenance is recommended . PATIENTS AND METHODS A prospect i ve , controlled and r and omized study was performed . We included non-muscle-invasive mid risk bladder tumours . All patients had initially a TURB performed and were r and omized to receive a single dose of mitomycin C ( MMC ) , in the immediate postoperative period . RESULTS A total of 105 patients were included . Mean follow-up was 22 , 70 + /- 8 , 15 months . MMC was administered to 53 patients . Of these 66 , 0 % had no recurrence and 34.0 % had a non-muscle-invasive recurrence . Of the 52 patients in the non MMC group , 53.8 % had no recurrence and 44.2 % had a non-muscle-invasive recurrence and only 1 patient had a muscle-invasive progression . We did not find significantly differences in time to recurrence in mid risk tumours when using immediate postoperative single dose of MMC or deferred therapy . There was only one case of myelosuppression . DISCUSSION In mid risk non-muscle-invasive tumors , some studies suggest that early intravesical instillation of chemotherapy reduces the risk of recurrence after TURB . We could not show significantly differences when comparing postoperatorive MMC versus traditional deferred instillations Tumour cell implantation may be a factor in the aetiology of recurrent well-differentiated superficial bladder tumours . A prospect i ve trial is reported in which single dose intravesical thiotepa was administered to a group of r and omly selected patients immediately after cystodiathermy .  A control group of patients was treated by cystodiathermy alone and tumour recurrence in the 2 groups was compared . Significantly fewer patients in the thiotepa-treated group developed recurrent tumour and there was also a significantly reduced incidence of pure vault recurrence in this group . The beneficial effects of adjuvant thiotepa were apparent after 1 treatment . In this series of patients no benefit result ed from the continued use of adjuvant thiotepa once a patient developed a recurrent tumor PURPOSE We evaluated the efficacy of single dose of interferon or epirubicin administered immediately after transurethral resection compared with transurethral resection only on the recurrence of primary ( not recurrent ) superficial bladder cancer . MATERIAL S AND METHODS A total of 283 patients with stages Ta to T1 primary superficial , grade s 1 to 3 bladder cancer was r and omized into study groups 1-transurethral resection only , 2-transurethral resection plus 50 million units interferon-a2b and 3-transurethral resection plus 100 mg . epirubicin .  Eligible for final analysis were 200 patients , including 66 in group 1 , 66 in group 2 and 68 in group 3 . Patients were followed with cystoscopy every 3 months for 2 years or until the initial recurrence . RESULTS Group 3 had the most favorable outcome , since 45 of the 68 patients ( 66 % ) were without recurrence after 2 years compared to 24 of the 66 ( 37 % ) in group 2 and 26 of the 66 ( 40 % ) in group 1 ( log rank test p < 0.001 ) . Side effects were mostly mild and transient , and no differences were found among the groups . CONCLUSIONS A single 100 mg . dose of epirubicin given intravesically immediately after transurethral resection is safe , and significantly decreases the recurrence of primary superficial bladder cancer . A 50 million unit dose of interferon-alpha2b is well tolerated but it has no effect on recurrence as a single dose . The long-term effect of this treatment remains to be studied BACKGROUND Recurrence prophylaxis with intravesical gemcitabine ( GEM ) was effective and safe in patients with non-muscle-invasive bladder cancer ( NMIBC ) ; efficacy as single-shot instillation remains to be proved . OBJECTIVE To compare the efficacy of a single GEM instillation versus placebo ( PBO ) immediately after transurethral resection ( TUR ) of tumour in patients with histologically confirmed NMIBC ( pTa/pT1,G1 - 3 ) . DESIGN , SETTING , AND PARTICIPANTS This was a double-blind , r and omised , PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC ( Ta/T1,G1 - 3 ) . Of 355 patients r and omised at 24 urologic centres , 328 underwent TUR and received instillation ( 92.4 % ; GEM/PBO : 166/162 ) . In case of nonmalignancy , carcinoma in situ ( CIS ) , > or = pT2 disease , or intraoperative complications , patients were discontinued . INTERVENTION We used a single , postoperative 30 - 40-min instillation of GEM ( 2000 mg/100 ml of saline ) or PBO ( 100 ml of saline ) followed by continuous bladder irrigation for > or = 20 h. A second TUR ( no instillation ) and adjuvant bacillus Calmette-Guérin ( BCG ) instillations were allowed . MEASUREMENTS Primary outcome was recurrence-free survival ( RFS ) . Secondary outcomes included type of recurrence and adverse events . To detect a difference in RFS , 191 recurrences were required ( 80 % power , log-rank-test , alpha = 0.050 ) . RESULTS AND LIMITATIONS Two hundred forty-eight patients ( 69.9 % , GEM , PBO : 124 , 124 ) had histologically confirmed pTa/pT1 G1 - 3 Gx tumour and were eligible for efficacy ( GEM : 76.6 % male ; median age : 65 yr ; PBO : 83.1 % male ; median age : 67 yr ) . Treatment groups were balanced ( pTa : 75.0 % , 71.0 % ; G1-G2 : 85.5 % , 87.9 % ; recurrent tumour : 24.2 % , 21.0 % ; BCG : 10.5 % , 16.9 % ) . After a median follow-up of 24 mo , there were only 94 recurrences and 11 deaths . The study was terminated early based on predefined decision criteria . RFS was high in both groups ( 12-mo RFS [ 95 % confidence interval ( CI ) ] : GEM : 77.7 % [ 68.8 - 84.3 ] ; PBO : 75.3 % [ 66.3 - 82.3 ] ) . There was no significant group difference ( hazard ratio [ HR ] : 0.946 [ 0.64 - 1.39 ] , log-rank test , p=0.777 ) . CONCLUSIONS In this study of NMIBC , the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS . Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups PURPOSE We studied whether a single instillation of epirubicin  after transurethral bladder tumor resection would influence the interval to and size of the first recurrence . MATERIAL S AND METHODS A total of 404 patients from 13 hospitals were r and omized to 1 instillation of 50 mg epirubicin or placebo within 6 hours after transurethral resection of bladder tumors . RESULTS Of 155 evaluable patients in the epirubicin group 79 ( 51.0 % ) had recurrence compared to 95 of 152 ( 62.5 % ) in the placebo group ( p = 0.04 ) . Of the recurrences 63.3 % were small ( 1 to 5 mm ) . Tumor size was unknown in 5 patients . Of 79 patients with recurrence in the epirubicin arm 33 ( 42.9 % ) vs 29 ( 31.5 % ) of 95 in the placebo arm had larger ( more than 5 mm ) first recurrences ( p = 0.12 ) . Approximately half of the patients with first recurrences were treated as out patients and the other half spent a total of 145 days in the hospital with no difference between the groups . CONCLUSIONS We confirmed the results of previous studies showing that 8.5 patients must be treated with a single instillation to prevent 1 recurrence . Furthermore , our data may indicate that only small recurrences are prevented , which could easily be fulgurated using local anesthesia at followup cystoscopy . The benefit of single instillations can be question ed if this finding is confirmed by others OBJECTIVE To compare single-dose and multiple instillations of epirubicin in the chemoprophylaxis of superficial bladder tumours . PATIENTS AND METHODS In a prospect i ve r and omized and controlled study , 168 evaluable patients were assigned to three groups after transurethral resection of bladder tumour ( TURBT ) and histological confirmation of its superficial nature ( pTa and pT1 ) . The groups were comparable for tumour stage , grade and other tumour characteristics . In group 1 , patients received a single dose of 50 mg epirubicin in 50 mL normal saline immediately after TURBT ; group 2 received 50 mg epirubicin in 50 mL normal saline 1 - 2 weeks after TURBT and the instillations were repeated for 8 weeks and thereafter monthly to complete one year of treatment : group 3 ( control group ) received no adjuvant therapy after TURBT . The patients were assessed by cysto-urethroscopy , urine cytology and DNA flow cytometry 8 weeks after resection and then every 3 months during the first 2 years and 6 monthly thereafter during the next 2 years . Intravenous urography was performed annually and when otherwise indicated . RESULTS The recurrence rate was significantly lower in the patients treated with epirubicin than in the control group ( 24 , 25 and 52 % , respectively ; P < 0.001 ) . In those receiving epirubicin , the rates of recurrence were statistically comparable ( P = 0.9 ) . Patients who had a large tumour burden showed slightly lower recurrence rates with single-dose epirubicin than with delayed maintenance therapy but the difference was statistically insignificant . Patients with a history of bladder tumours before treatment had lower recurrence rates with maintenance treatment than with a single dose ( 34.6 and 22.6 % in groups 1 and 2 , respectively ) ; again this difference was statistically insignificant . Patients with grade 3 tumours showed a marginal difference in favour of maintenance therapy . The rates of progression amongst the three groups were 5.5 , 3.4 and 9.3 % , respectively , with no significant differences . The overall toxicity rates were comparable in the two treated groups ( 22 and 25 % ) . CONCLUSION With the possible exception of grade 3 tumours , single-dose immediate epirubicin is as effective as delayed maintenance therapy , with the advantage of being more cost-effective A total of 431 eligible patients with solitary , primary or recurrent stages Ta and T1 transitional cell carcinoma of the bladder was included in a r and omized multicenter trial to compare a single intravesical instillation of 80 mg . epirubicin with water given immediately after resection , with respect to the disease-free interval and recurrence rate . The interval to initial recurrence was significantly better in favor of the epirubicin group . After a mean followup of 2 years it became evident that the recurrence rate after a single epirubicin instillation was decreased by nearly half with the same trend being found in all subgroups examined . Toxicity was mainly restricted to bladder irritation in plus or minus 10 % of the cases . Pathology review brought considerable changes in T category from stages T1 to Ta ( 53 % ) . Changes in grade were less pronounced but nevertheless important The influence of the instillation of thiotepa or doxorubicin hydrochloride into the bladder at the end of transurethral surgical treatment on the recurrence of bladder cancer  was evaluated . We studied in a r and omized , double-blind , controlled fashion 89 patients with transitional cell epithelioma ( carcinoma in situ or papillary carcinoma ) whose tumors were considered to have been completely removed . Of these patients 28 ( the control group ) received a placebo ( sterile water ) , 30 received thiotepa and 31 received doxorubicin . By 3 to 4 months postoperatively 71 per cent of the control group , and 30 and 32 per cent , respectively , of the patients treated with thiotepa and doxorubicin had recurrences ( p less than 0.01 ) . Additional treatment during the followup interval was ineffective in all groups . Patients studied also were classified according to grade , histological findings , multiplicity of tumors and history of bladder tumor . Treatment was most effective in reducing recurrence in patients with low grade , papillary or multiple tumors and in patients with a history of bladder cancer . No effect was observed in patients with single tumors and only modest effects were found in those with high grade tumors , carcinoma in situ or new tumors . The results support the concept that recurrences may arise from tumor cell implantation at the time of transurethral management of bladder tumors and may be reduced effectively by concomitant intravesical chemotherapy INTRODUCTION The aim of this study was to evaluate the effect of immediate intravesical instillation of mitomycin C after transurethral resection of bladder tumor ( TURBT ) in patients with low-risk superficial transitional cell carcinoma ( TCC ) . MATERIAL S AND METHODS A total of 43 patients with low-risk superficial bladder cancer were r and omly assigned into two groups after the surgery ; 22 patients in group 1 were treated by immediate instillation of mitomycin C after TURBT , and 21 patients in group 2 received placebo . The two groups were compared using urine cytology and cystoscopy during the 24 postoperative months . RESULTS Recurrence within the first 3 months was reported in none of the patients in group 1 and 5 in group 2 ( P = .02 ) . Of these , 4 had recurrence of tumor in the primary site . At 12 and 24 months , there were 1 patient ( 4.5 % ) in group 1 and 8 ( 38.1 % ) in group 2 with recurrence ( P = .007 ) . We had no patients with multifocal recurrence in group 1 , but 3 ( 14.2 % ) in group 2 . Nine-month tumor-free survival rate was 95 % in group 1 . Three- , 6- , 9- , and 12-month tumor-free survival rates in group 2 were 76 % , 71 % , 66 % , and 62 % , respectively ( P = .007 ) . None of the patients in group 1 and 3 in group 2 ( 14.3 % ) experienced some degrees of tumor progression ( P = .06 ) . CONCLUSION Immediate instillation of mitomycin C after TURBT seems to be effective in the recurrence reduction and increase of recurrence-free interval at least in short term A r and omised control trial of intravesical instillation of mitomycin C was conducted in 457 patients with cancer of the bladder that was confined to the submucosa on histological examination . The events studied were the recurrence free rate , the recurrence rate/year , and the number of new tumours developing/year . At the initial cystoscopy the tumours were completely resected and the patients r and omised to have no instillation of mitomycin C , a single instillation of 40 mg in 40 ml of water at that cystoscopy , or a single instillation and then four further instillations . All patients had follow up cystoscopies every three months for the first year , twice in the second year , and yearly thereafter . After a median of 12 months , follow up information was available for 397 patients . Patients receiving both the single instillation of mitomycin C and the instillations at five cystoscopic examinations had significantly lower yearly recurrence rates and tumour rates than those in the control group , and the group receiving multiple instillations fared significantly better than those receiving a single instillation . The figures on progression to invasive cancer were too small to allow conclusions to be drawn Although transurethral resection of a bladder tumor ( TUR‐Bt ) alone has been st and ard treatment for single superficial bladder carcinoma , some authors reported a certain prophylactic effect of a single immediate intravesical instillation of chemotherapeutic agent after TUR‐Bt . A prospect i ve r and omized study was conducted to determine whether a single (2″R)‐4′‐O‐tetrahydropyranyl‐doxorubicin ( THP ) instillation immediately after TUR‐Bt is beneficial to patients with a single superficial bladder carcinoma Purpose To study the benefits of a single , early , intravesical instillation of mitomycin C(MMC ) after  transurethral bladder resection ( TURB ) in patients with low-risk non-muscle-invasive bladder cancer ( NMIBC ) . Methods In this prospect i ve r and omised single-centre trial , 211 patients with primary and low-risk tumours were enrolled between 2000 and 2009 . Patients were r and omly allocated to receive MMC intravesically within 24 h of TUR or no further treatment . The primary end point was recurrence rate reduction . Results A total of 202 patients ( 97 in the MMC group and 105 in the control group ) remained for analysis after exclusions . Median age was 61 years ( IQR 42–78 ) , and median follow-up was 90 months ( IQR 3–112 ) . No significant differences for patients ’ characteristics were observed between the two groups . During the study period , 10 % ( 10/97 ) of the patients in the MMC group and 43 % ( 46/105 ) in the control group experienced a recurrence ( P = 0.0001 ) . Four patients in the MMC group and 11 ( P = 0.008 ) in the control group experienced an early recurrence ( within 2 years ) . One patient in the control group presented a tumour progression ( T2G3 ) . MMC treatment was associated with a 31 % absolute risk reduction of recurrence and a 3.26 numbers needed to treat to prevent one recurrence . Conclusions In this single-centre , long-term follow-up , experience a single , early instillation of MMC after TUR for low-risk NMIBC is associated with a significant reduction in risk of early and late recurrences PURPOSE We analyzed the impact of a single Mitomycin C instillation in patients with low risk superficial bladder cancer with short and long-term follow-up . PATIENTS AND METHODS This study was conducted on 63 patients with low risk superficial bladder transitional cell carcinoma ( TCC ) , admitted to the Urology Department , Theodor Bilharz Research Institute ( TBRI ) during the period from January 2002 to August 2005 . All patients had a 2 cm . or less single , papillary , primary or recurrent tumor and were disease-free for more than 1 year . Patients with muscular invasion , G III tumor or bladder carcinoma in situ on pathological examination were excluded from the study . The tumor was completely resected before patients were divided r and omly into 2 arms : first group who have received no further treatment ( control group ) and a second group with a single immediate instillation of 30 mg . Mitomycin C ( mitomycin C group ) . Recurrences were considered early if they occurred within the first 2 years of follow-up . RESULTS At 24-months follow-up , the recurrence-free interval was significantly increased and recurrence , recurrence per year and tumor per year rates were decreased in the mitomycin C group compared to the control group . Early recurrence was ( 16.1 % ) in the mitomycin C group versus ( 34.3 % ) in the control group . It was noted also that early recurrences were concentrated in the first year in the control group ( 18.7 % ) versus ( 3.2 % ) in the mitomycin C group . However , at long-term follow-up , these differences were not statistically significant ( 26.9 % ) in the mitomycin C group versus ( 28.6 % ) in the control group , and the recurrence-free interval curves were parallel . A significant relationship between early and late recurrences was found in the mitomycin C , but not in the control group . Shorter hospital stay and catheterization periods were noted in the mitomycin C group compared to the control group , but the differences were not statistically significant . CONCLUSION These data confirm the positive effect of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer . This benefit is limited to early recurrence and is not maintained with long-term follow-up . Thus , this approach is an alternative to observation or classic long-term intravesical chemotherapy . Our study also suggests that cell implantation as a mechanism of early recurrence can be controlled or minimized with a single mitomycin C instillation 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 BACKGROUND To decrease recurrences in non-muscle-invasive bladder cancer ( NMIBC ) , the European Association of Urology ( EAU ) guidelines recommend immediate , intravesical chemotherapy after transurethral resection ( TUR ) for all patients with Ta/T1 tumours . OBJECTIVE To study the benefits of a single , early , intravesical instillation of epirubicin after TUR in patients with low- to intermediate-risk NMIBC . DESIGN , SETTING , AND PARTICIPANTS In this prospect i ve r and omised multicentre trial , 305 patients with primary as well as recurrent low- to intermediate-risk ( Ta/T1 , G1/G2 ) tumours were enrolled between 1997 and 2004 . Patients were r and omly allocated to receive 80 mg of epirubicin in 50 ml of saline intravesically within 24 h of TUR or no further treatment after TUR . MEASUREMENTS The primary end point was time to first recurrence . RESULTS AND LIMITATIONS A total of 219 patients remained for analysis after exclusions . The median follow-up time was 3.9 yr . During the study period , 62 % ( 63 of 102 ) of the patients in the epirubicin group and 77 % ( 90 of 117 ) in the control group experienced recurrence ( p=0.016 ) . In a multivariate model , the hazard ratio ( HR ) for recurrence was 0.56 ( p=0.002 ) for early instillation of epirubicin versus no treatment . In a subgroup analysis , the treatment had a profound recurrence-reducing effect on patients with primary , solitary tumours , whereas it provided no benefits in patients with recurrent or multiple tumours . Furthermore , patients with a modified European Organisation for Research and Treatment of Cancer ( EORTC ) risk score of 0 - 2 with and without single instillation had recurrence rates of 41 % and 69 % , respectively ( p=0.003 ) , whereas the corresponding rates for those with a risk score of > or = 3 were 81 % and 85 % , respectively ( p=0.35 ) . CONCLUSIONS A single , early instillation of epirubicin after TUR for NMIBC reduces the likelihood of tumour recurrence ; however , the benefit seems to be minimal in patients at intermediate or high risk of recurrence . Future trials will determine the value of early instillation in addition to serial instillations in NMIBC
The role for a single dose of intravesical chemotherapy ( IVC ) after transurethral resection ( TUR ) remains unclear in patients with non-muscle-invasive bladder cancer ( NMIBC ) .
Several recent r and omized clinical trials ( RCTs ) have evaluated its effect on recurrence , prompting this systematic review of RCTs comparing a single immediate postoperative dose of IVC versus placebo within 24 hours of TUR of NMIBC , and this meta- analysis using a r and om-effects model to predict the pooled relative risk ( RR ) of tumor recurrence .