Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. 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. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. 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 randomized multicenter trial of adjuvant therapy in superficial bladder cancer: transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guerin. Participating Clinics. Update on the Dutch Cooperative Trial: mitomycin versus bacillus Calmette-Guérin-Tice versus bacillus Calmette-Guérin RIVM in the treatment of patients with pTA-pT1 papillary carcinoma and carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group. Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guérin) in superficial bladder cancer. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma 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).
                In this multicenter, prospective, randomized, phase 2 trial, eligible patients were those with high-risk non-muscle-invasive BC, failing 1 course of BCG therapy. All patients were randomly allocated to Group A, receiving intravesical gemcitabine (at a dose of 2000 mg/50 mL) twice weekly for 6 consecutive weeks and then weekly for 3 consecutive weeks at 3, 6, and 12 months, or Group B, receiving intravesical BCG (Connaught strain, 81 mg/50 mL) over a 6-week induction course and each week for 3 weeks at 3, 6, and 12 months. Outcome measures were recurrence rate, time to first recurrence, and progression rate. Treatment-related complications were also evaluated.
                Eighty participants were enrolled, 40 for each group 52.5% in Group A developed disease recurrence versus 87.5% of those in Group B (P = .002). There was no statistically significant difference in mean time to the first recurrence (Group A, 3.9 months; Group B, 3.1 months; P = .09). Kaplan-Meier analysis of 2-year recurrence-free survival showed significant differences between Group A and B (19% and 3%, respectively, P < .008). Seven of 21 (33%) patients in Group A and 13 of 35 (37.5%) patients in Group B had disease progression and underwent radical cystectomy (P = .12). Both intravesical administrations were generally well tolerated.
                Gemcitabine might represent a second-line treatment option after BCG failure in high-risk non-muscle-invasive BC patients.
                (c) 2010 American Cancer Society. 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.
                64 patients with high-risk superficial bladder cancer (pT1 and/or G3 and/or CIS) were assigned to interventions (gemcitabine or BCG) in a randomised controlled trial. All the patients were evaluated for recurrence and progression rates (primary endpoint) and safety and tolerability (secondary endpoint).
                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.
                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.
                Copyright 2010 S. Karger AG, Basel. 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.
                This was a multicenter, open-label, randomized, 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 questionnaire.
                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.
                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. 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 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.
                A total of 120 patients were enrolled and randomly 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).
                This study demonstrates that GEM has better efficacy and lower toxicity than MMC; therefore, GEM appears as a logical candidate for intrabladder therapy in patients with refractory transitional cancer. 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.
                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).
                This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised 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.
                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.
                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).
                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).
                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. A randomized multicenter trial was done to compare transurethral resection only to transurethral resection plus adjuvant mitomycin C and bacillus Calmette Guerin (BCG) instillation for treatment of superficial bladder cancer (stage pTa/1 grades 1 to 3 except primary stage pTa grade 1).
                Included in the study were 337 patients with superficial stage pTa/1 grades 1 to 3 bladder cancer except primary stage pTa grade 1 tumors. One group underwent transurethral resection alone. Mitomycin C (20 mg./50 ml. sodium chloride) was given every 2 weeks during year 1 and once a month during year 2. BCG (120 mg/50 ml. sodium chloride was instilled once a week for 6 weeks and once a month for 4 months.
                At a median followup of 20.2 months, a decrease in recurrence rate was noted for both drug instillations compared to transurethral resection only. The relative risk of recurrence was 0.508 after mitomycin C and 0.618 after BCG instillation compared to transurethral resection alone. There was no significant difference between the mitomycin C and BCG instillations. The progression rate was comparable in all 3 therapy groups, with an estimated common progression rate of 4.22% per year. Side effects occurred most frequently during or after BCG instillation, most often consisting of cystitis. One patient required cystectomy because of ulcerating cystitis and a prostatic abscess subsequent to unsuccessful tuberculostatic therapy. There were no systemic complications.
                Our study showed a positive effect of adjuvant chemotherapy and immunotherapy on decreasing tumor recurrence rate. No influence was observed concerning progression rate, which was low overall. Prophylactic intravesical treatment with chemotherapeutic agents or one of the different strains of the immunomodulator bacillus Calmette-Guérin (BCG) reduces tumor recurrence and may prevent progression after transurethral resection (TUR) of superficial bladder cancer. Clinical and pathological prognostic factors are used to categorize different groups at risk for disease recurrence and progression. Solitary low-grade (G1, 2A), low-stage (pTa) tumors have less than a 5% risk of progression, while pT1 G3 tumors with concomitant carcinoma in situ (CIS) have a considerably higher risk of progression and metastases. Thus, prospective clinical trials should consider the different risks associated with different prognostic groups and stratify patients accordingly. The Dutch Cooperative Trial evaluated mitomycin versus BCG-Tice versus BCG-RIVM in 469 patients with pTA/pT1 carcinoma and CIS of the urinary bladder after TUR. Of 437 evaluable patients, 50 had CIS, 254 had pTA tumors, and 133 had pT1 tumors. No statistical differences were observed in toxicity between the two strains of BCG, but local and systemic side effects were more frequent in the BCG groups versus the mitomycin group. No differences in response rate were observed between the 3 treatment groups in patients with CIS. A statistically significant difference in favor of mitomycin was seen, however, in patients with papillary tumors. Mitomycin and BCG-RIVM were equally effective, and mitomycin proved significantly more effective than BCG-Tice. No significant difference in efficacy was observed between the two strains of BCG. Disease recurrence during the study in patients with papillary tumors was seen in 43% of mitomycin-treated patients, 64% of the BCG-Tice group, and 46% of patients treated with BCG-Rivm. However, a subgroup analysis for time to first recurrence for pTa versus pT1 and for grade 1 and 2 versus grade 3 papillary tumors showed no statistically significant between-group difference. Further studies comparing identical regimens, doses, and patient groups are needed to define more clearly which patient groups and tumors are more likely to respond to intravesical therapy. Both intravesical mitomycin C (MMC) and bacillus Calmette-Guérin (BCG; Pasteur strain F) were effective in the present prospective randomized multicenter study consisting of 91 patients with frequently recurrent superficial (Ta-T1) bladder cancer. The result was in favour of BCG, as shown by the measurements with complete response (CR), disease-free interval and recurrence rate. CR of 58% with MMC and 40% with BCG were reached in 22 instillation series on carcinoma in situ of 18 patients. Due to side effects, MMC instillations were discontinued in 8.6%, and BCG instillations in 19.6%, respectively. After the 2-year follow-up also 1 case of pulmonary tuberculosis occurred in the BCG group. Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients.
                The aim of the study was to compare the long-term efficacy of BCG and epirubicin.
                From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911.
                Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36.
                End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival.
                With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence (p<0.001), distant metastases (p=0.046), overall survival (p=0.023), and disease-specific survival (p=0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients.
                In patients with intermediate- and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG.
                This study was registered with the US National Cancer Institute clinical trials database [protocol ID: EORTC-30911]. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=77075&version=HealthProfessional&protocolsearchid=6540260.
                Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal.