Gemcitabine in intravesical treatment of Ta-T1 transitional cell carcinoma of bladder: Phase I-II study on marker lesions. 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. The Effects of Intravesical Chemoimmunotherapy with Gemcitabine and Bacillus Calmette-Guérin in Superficial Bladder Cancer: A Preliminary Study Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study Randomized phase II marker lesion study evaluating effect of scheduling on response to intravesical gemcitabine in recurrent Stage Ta urothelial cell carcinoma of the bladder. Multicenter study on the use of gemcitabine to prevent recurrence of multiple-recurring superficial bladder tumors following intravesical antiblastic agents and/or BCG: evaluation of tolerance. Gemcitabine versus bacille Calmette‐Guérin after initial bacille Calmette‐Guérin failure in non‐muscle‐invasive bladder cancer Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC). Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study. Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a Phase II prospective multicenter study. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. Endoscopic detection of transitional cell carcinoma with 5-aminolevulinic acid: results of 1012 fluorescence endoscopies.
OBJECTIVES To study the ablative activity of intravesical gemcitabine against superficial transitional cell carcinoma of the bladder at different doses and concentrations . METHODS A total of 27 patients were treated with intravesical gemcitabine after transurethral resection during which one to three papillary marker lesions were left unresected . Starting 14 days after transurethral resection , six instillations of gemcitabine were given at weekly intervals . Gemcitabine , diluted in 50 mL of saline solution and maintained for 2 hours , was given at the dose of 500 mg , 1000 mg , and 2000 mg in groups of 9 patients each . A complete response ( CR ) was defined as negative cytology , cystoscopy , and biopsy findings . Patients achieving a CR received monthly maintenance for up to 1 year and underwent cytology and cystoscopy at 3-month intervals . RESULTS Of the 27 patients , 1 was lost to follow-up , and of the remaining 26 patients , 6 ( 23 % ) achieved a CR . A CR was achieved in 1 patient ( 12.5 % ) , 2 patients ( 22.2 % ) , and 3 patients ( 33.3 % ) at a dose of 500 , 1000 , and 2000 mg , respectively . A partial response was obtained in 2 additional patients ( 22 % ) at a dose of 500 and 1000 mg . Bladder Tis was diagnosed in 2 patients with a CR at 3 and 8 months after treatment . The remaining 4 patients were disease free at a follow-up of up to 22 months . Systemic and local tolerability was excellent , and no treatment interruption was required . CONCLUSIONS Our experience has shown the good tolerability and potential efficacy of intravesical gemcitabine against recurrent transitional cell carcinoma of the bladder . Gemcitabine might be proposed , if our results are confirmed by larger studies , as a second-line therapy in patients who can not tolerate more aggressive intravesical therapy 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 This prospect i ve study investigated the long-term effects of intravesical chemoimmunotherapy with gemcitabine ( GEM ) and bacillus Calmette-Guérin ( BCG ; n = 36 ) versus BCG alone  ( n = 51 ) for the treatment of superficial bladder cancer . For the chemoimmunotherapy ( GEM + BCG ) group , GEM ( 1000 mg ) was instilled immediately after transurethral resection of bladder tumour ( TURBT ) and again ( 2000 mg ) 1 week later . From 2 to 7 weeks after TURBT , BCG was instilled into the bladder of all patients once weekly . The recurrence-free period of the GEM + BCG group ( 24.13 months ) was significantly longer than that of the BCG monotherapy group ( 19.81 months ) . The overall recurrence rate was similar between the groups , although at 6 and 9 months post-TURBT , GEM + BCG produced a significantly lower rate of recurrence compared with BCG alone . This study suggests that intravesical chemoimmunotherapy with GEM + BCG is effective in reducing early tumour recurrence and in prolonging the recurrence-free period of superficial bladder cancer Objective : To evaluate the safety , tolerability and efficacy of adjuvant intravesical gemcitabine versus bacillus Calmette-Guérin ( BCG ) in the treatment of high-risk superficial bladder cancer . Method : 64 patients with high-risk superficial bladder cancer ( pT1 and /or G3 and /or CIS ) were assigned to interventions ( gemcitabine or BCG ) in a r and omised controlled trial . All the patients were evaluated for recurrence and progression rates ( primary endpoint ) and safety and tolerability ( secondary endpoint ) . Results : The two groups were comparable in terms of baseline characteristics . Tolerability was better for gemcitabine , whereas the BCG group experienced the need for delayed treatment or withdrawal in 12.5 % of cases . At a mean follow-up of 44 months , the recurrence rate in patients treated with BCG was 28.1 % ; the recurrence rate in patients who received gemcitabine was 53.1 % ( p = 0.037 ) . Time to recurrence was shorter in patients treated with BCG ( 25.6 vs. 39.4 months , p = 0.042 ) . No patients developed disease progression . Conclusions : Gemcitabine is significantly inferior to BCG , but given its favourable toxicity profile , it may be useful for patients intolerant to or otherwise unable to receive BCG OBJECTIVES To evaluate the response rate for intravesical gemcitabine given in three different schedules to patients with recurrent multiple carcinoma of the urinary bladder Stage Ta , grade 1 - 2 , in whom all but one marker lesion was removed . Furthermore , we sought to define the safety profile . METHODS This was a multicenter , open-label , r and omized , Phase II study in which gemcitabine 2000 mg in 100 mL of unbuffered saline was instilled as a single dose ( n = 11 ) , two doses per week for 3 weeks ( n = 11 ) , or once weekly for 6 weeks ( n = 10 ) . Efficacy was evaluated using cystoscopy after 9 weeks . Toxicity was evaluated by assessing the liver , kidney , bone marrow , and coagulation function at defined intervals and by question naire . RESULTS A total of 32 patients were included , 2 of whom were subsequently excluded because of protocol violations . The overall complete remission rate was 31 % . The respective subgroup response rate was 10 % in the single-dose group , 44 % in the once-weekly group , and 40 % in the twice-weekly group . The most common side effect was nausea . One patient withdrew because of nausea and fever , and an additional 2 patients had reversible hematologic toxicity ( mild thrombocytopenia causing delayed instillation and mild anemia ) . The side effects were generally in the multiple-dose groups , with an overrepresentation in women . Ten patients were unable to retain the drug intravesically for the full hour . CONCLUSIONS The results of our study have shown that gemcitabine has a tumor ablative effect when given intravesically for bladder cancer . A single dose seemed ineffective , and the multiple dosing regimens seemed effective . The side effects were generally mild OBJECTIVES The treatment of choice for superficial bladder TCC is endoscopic resection , followed or not by intravesical immuno/chemotherapy . Some patients are not responders to common intravesical therapy and are more exposed to disease progression . In this case the suitable treatment is radical cystectomy . Because gemcitabine is effective against advanced bladder cancer , we have initiated a study to evaluate the efficacy of its intravesical use to prevent relapse and disease progression , and tolerance and safety of this drug in patients with multi-treated bladders . In this preliminary study , we cite only data on tolerance . MATERIAL S AND METHODS 64 patients were selected , and 61 were evaluable ( age range 39 - 84 years ) , with multiple-recurrent bladder TCC . All patients were previously treated with intravesical chemotherapy and /or immunotherapy .  The protocol provided for intravesical instillation of gemcitabine ( 2000 mg ) once per week for 8 weeks . We collected data regarding problems noted by the patients ( both local and systemic ) . RESULTS 53 patients out of 61 ( 86.9 % ) completed the cycle . Side effects appeared in 14 patients , 8 of these had to suspend the treatment . Severe side effects were systemic in 4 patients ( 1 systemic edema , 1 malaise and dysgeusia , 1 hyperthermia and severe strangury , 1 elevated transaminases and asthenia ) , and local in 4 patients ( 1 severe urinary urgency , 1 hematuria , 1 urinary incontinence , and 1 case of pelvic pain ) . In 6 patients we observed pelvic pain , hematuria , strangury and UTI of medium magnitude that did not require treatment interruption . CONCLUSIONS We believe that the severe side effects requiring treatment interruption are attributable primarily to increased sensitivity in patients with multi-treated bladders . In our experience , the side effects responsible for suspension occurred at the start of treatment in 7 cases out of 8 . Our study demonstrates the safety of intravesical gemcitabine in patients with recurrent and multi-treated superficial TCC of the bladder The efficacy of intravesical gemcitabine was evaluated compared with repeated administration of bacille Calmette‐Guérin ( BCG ) after BCG failure in high‐risk , non‐muscle‐invasive bladder cancer ( BC ) OBJECTIVE Phase I studies have so far demonstrated that intravesical Gemcitabine up to a 40 mg/ml concentration is well tolerated and has a substantial ablative activity on high-risk BCG refractory SBC . New treatment options are needed for intermediate-risk SBC recurring after conventional intravesical treatments . The purpose of the present study was to investigate the ablative efficacy of intravesical Gemcitabine on intermediate-risk SBC . METHODS The study was design ed as a two-stage phase II trial , with a sample size of 39 patients . The efficacy of intravesical Gemcitabine at a concentration of 40 mg/ml ( 2000 mg in 50 ml saline solution ) administered weekly for 6 weeks was assessed on a single marker tumour left in the bladder after a complete TUR of all other lesions . Patients underwent TUR or biopsy at the site of the marker lesion 2 weeks after completion of the treatment . RESULTS Complete response was observed in 22 out of 39 patients ( 56 % ) . No progression was observed among the 17 non-responders . Neither systemic nor local side effects generally exceeded grade I toxicity . CONCLUSION The ablative effect of Gemcitabine produced a higher number of responses than the minimum required by the protocol to indicate a significant probability of drug efficacy . It is worth testing the drug in phase III trials to assess for durability of response PURPOSE To determine maximum-tolerated dose , toxicities , and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer . PATIENTS AND METHODS Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied . Two to 4 weeks after complete transurethral resection , gemcitabine was administered intravesically , once weekly for 6 consecutive weeks . Dwell time was 2 hours . Pharmacokinetics of  gemcitabine  and its metabolite , 2'2'-difluorodeoxyuridine  ( dFdU ) , were studied in plasma and urine . Cystoscopy was repeated 6 weeks after therapy . RESULTS Three-patient cohorts were enrolled sequentially at doses of 500 , 1,000 , and 1,500 mg in 100 mL 0.9 % NaCl . Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinical ly relevant myelosuppression was noted . Nine of 13 evaluable patients were recurrence-free at 12 weeks . Low concentrations of gemcitabine  ( < or = 1 microg/mL ) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients . dFdU was undetectable in plasma of patients receiving less than 1,500 mg . At doses > or = 1,500 mg , dFdU concentrations increased until 90 to 120 minutes and then declined little , if any . Plasma dFdU concentrations implied absorption of 0.5 % to 5.5 % of instilled dose . Between 61 % and 100 % of the gemcitabine dose was accounted for in voided urine . No dFdU was measured in voided urine . CONCLUSION Intravesical gemcitabine , at doses up to 2 g/wk , is well tolerated , is associated with minimal systemic absorption , and has promising efficacy in treatment of superficial bladder cancer OBJECTIVES To determine the tolerability and efficacy after 1 year of weekly intravesical gemcitabine therapy in patients with intermediate-risk and high-risk superficial transitional cell carcinoma . METHODS A total of 116 patients with intermediate-risk and high-risk bladder cancer who had undergone transurethral resection were treated with one cycle ( once a week for 6 weeks ) of gemcitabine 2000 mg .  Local and systemic tolerability and efficacy were evaluated . RESULTS In terms of the tolerability of gemcitabine , 14 patients ( 12.0 % ) reported urgency , 6 ( 5.1 % ) dizziness and slight fever ( less than 38 degrees C ) , 1 ( 0.8 % ) severe abdominal pain , with ulcerative lesions of the bladder mucosa at cystoscopy , and 1 ( 0.8 % ) parosmia . The remaining 94 patients ( 81.3 % ) did not report any local side effects during the treatment period . In terms of efficacy , recurrence developed in 29 patients ( 25.4 % ) a mean of 7 months after transurethral resection ; 85 patients ( 74.6 % ) were disease free after 12 months . The univariate analysis showed a greater level of efficacy in patients with a first occurrence ( P = 0.0408 ) , patients who had had no previous treatment ( P = 0.0368 ) , and patients with Stage pTa superficial transitional cell carcinoma ( P = 0.0018 ) . The multivariate analysis did not reveal any significant data . No significant differences were found between the intermediate-risk and high-risk patients in tolerability or efficacy . No recurrence developed in 18 ( 75 % ) of 24 intermediate-risk bacille Calmette-Guérin-refractory or 7 ( 43.7 % ) of 16 high-risk bacille Calmette-Guérin-refractory patients . CONCLUSIONS The results of our study have confirmed the good tolerability and 1 year efficacy of intravesical gemcitabine . The treatment schedule proposed result ed in high patient compliance , and the results can be compared with the results of studies using other intravesical treatments PURPOSE Approximately 30 % to 40 % patients with a superficial bladder cancer treated with Bacille Calmette-Guerin ( BCG ) or epirubicin do not respond ; of the initial responders , 35 % have a relapse within 5 years . We compare the therapeutic efficacy and toxicity of intravescical infusions of gemcitabine ( GEM ) with mitomycin ( MMC ) in patients with a recurrent superficial bladder cancer . PATIENTS AND METHODS Patients with a history of a previously treated , recurrent Ta-T1 , G1-G3 bladder transitional cell carcinoma were enrolled in the study . The patients received a 6-week course of GEM infusions or 4-week course of MMC . In both arms , for the initial responders who remained free of recurrences , maintenance therapy consisted of 10 monthly treatments during the first year . RESULTS A total of 120 patients were enrolled and r and omly assigned to either the MMC or GEM treatment arm . At the end of the study , 109 patients ( 55 in MMC and 54 in GEM ) were assessable . The median duration of follow-up was 36 months for either arm . In the GEM arm , 39 ( 72 % ) of 54 patients remained free of recurrence versus 33 ( 61 % ) of 55 in MMC arm . Among patients with recurrences , 10 in the MMC arm and six in the GEM arm also had a progressive disease by stage . The incidence of chemical cystitis in the MMC arm was statistically higher than in the GEM arm ( P = .012 ) . CONCLUSION This study demonstrates that GEM has better efficacy and lower toxicity than MMC ; therefore , GEM appears as a logical c and i date for intrabladder therapy in patients with refractory transitional cancer OBJECTIVES The initial encouraging results using 5-aminolevulinic acid ( 5-ALA ) induced fluorescence endoscopy ( AFE ) have promised a procedure with an outst and ing sensitivity for the detection of early stage bladder cancer . Summarized here is our clinical experience and data comprising 1012 fluorescence endoscopies . METHODS Two hours , 30 minutes before endoscopy , 1.5 g 5-ALA dissolved in 50 mL of 5.7 % sodium monohydrogen phosphate was instilled in patients intravesically . Before AFE , all patients underwent white light endoscopy , and a bladder washing cytologic specimen was obtained . A special light source provided blue light ( 375 to 440 nm ) for fluorescence excitation . Suspicious sites were identified by their red fluorescence contrasting against backscattered blue light when observed through the long pass filter ( 445 nm ) integrated into the telescope eyepiece . RESULTS Two thous and four hundred seventy-five specimens were obtained ( 2.4 biopsies per AFE ) . In 552 AFEs ( 54.5 % ) , neoplastic urothelial lesions were detected , in 34.2 % only because of their positive fluorescence ; 38.7 % of these additionally detected neoplastic foci had poorly differentiated histologic features . CONCLUSIONS AFE has proved to be a clinical ly feasible procedure with an outst and ing detection rate for flat , urothelial , high-risk lesions
BACKGROUND Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following tumour resection .
However , up to 70 % of patients may fail and new intravesical agents with improved effectiveness are needed .
Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer .
OBJECTIVES To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer ( NMIBC ) .
The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy .