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. Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guérin) in superficial bladder cancer. Intravesical 4'-epi-doxorubicin (epirubicin) versus bacillus Calmette-Guérin. A controlled prospective study on the prophylaxis of superficial bladder cancer. BCG versus epirubicin in the prophylaxis of multiple superficial bladder tumours: results of a prospective randomized study using modified treatment schemes. 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 bacillus Calmette-Guérin versus epirubicin in the prophylaxis of recurrent and/or multiple superficial bladder tumours. 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. Bacillus Calmette-Guérin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study. Controlled clinical trial of adjuvant immunotherapy with BCG and neuraminidase-treated autologous tumour cells in large bowel cancer.
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. 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. The selection of the most appropriate antineoplastic agent and optimal treatment schedule for the prophylaxis of superficial bladder cancer against tumor recurrences is the subject of continual investigations.
                A controlled prospective trial involving 161 patients evaluated and compared the efficacy of intravesical epirubicin and bacillus Calmette-Guérin (BCG) administration as prophylaxis against recurrences after complete transurethral resection of superficial bladder cancer. The treatment schedule, consisting of one 6- or 8-week course of instillations (50 mg epirubicin or 150 mg BCG per instillation) followed by single maintenance doses to the responders at follow-up examinations, was modified for those of the initial responders who were at high risk for recurrence and who received an additional separate 4-week course of treatment 6 months after the start of therapy.
                Sixty percent of the patients treated with epirubicin, 68% of the patients treated with BCG, and 41% of the control subjects, who underwent resection only, remained free of recurrences for a mean follow-up of 32.9 months. The only significant difference was found between patients treated with BCG and control subjects, in favor of the former. Conversely, recurrence rate per 100 patient-months and mean interval to recurrence showed both drugs to be superior to resection alone regarding several tumor characteristics. However, a significant benefit in favor of BCG when compared with epirubicin was shown in those patients who had Stage T1 and Grade 3 tumors at presentation.
                Intravesical epirubicin and BCG were superior to transurethral resection alone in the prophylaxis of superficial bladder cancer, but with respect to superficially invasive and high-grade tumors, BCG demonstrated a remarkable advantage. A prospective randomized trial on 94 eligible patients evaluated and compared the efficacy of adjuvant intravesical epirubicin and bacillus Calmette-Guérin (BCG) after complete resection of multifocal superficial bladder cancer. BCG treatment schedule consisted of an induction 6-week course of instillations (150 mg Pasteur BCG per instillation) and single maintenance doses to patients who remained free of recurrences at follow-up examinations for a total treatment period of 2 years. These initial responders received additionally a separate 4-week course of therapy 6 months after the start of treatment. Chemoprophylaxis included an early (on the second postoperative day) instillation followed by 4 weekly treatments with epirubicin (50 mg per instillation) and then by 10 monthly treatments for the initial responders during the first year of follow-up and at every follow-up examination for a total treatment period of 2 years. The overall treatment results did not differ significantly between the 2 arms (54% of patients of the epirubicin group remained free of recurrences compared to 65% of those treated with BCG) for an identical mean follow-up of 35.1 months. However, a significant benefit in favour of BCG when compared with epirubicin was shown in patients who had stage T1 and grade 3 tumours and in terms of relative risk of recurrences, disease-free interval and recurrence rate per 100 patient-months. Both drugs were proved to be safe with manageable toxicity. 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. A prospective, randomized trial was conducted to evaluate and compare the effects of modified adjuvant intravesical bacillus Calmette-Guérin (BCG) and epirubicin regimens in patients with superficial bladder cancer. One hundred thirty-two individuals with recurrent and/or multiple neoplasms, i.e. at high risk for tumour recurrence and progression, were enrolled. After complete transurethral resection of their tumours, the patients received a 6-week course of BCG instillations or an early 4-week course of epirubicin instillations as their initial therapy. Those with stage Ta and grade 1 neoplasms who remained free of recurrences received maintenance therapy consisting of single quarterly instillations. However, for those with stage T1 cancer of any grade or stage Ta of grade 2 or 3 neoplasms who also remained free of recurrences, the treatment schedules were modified: they received, instead of single maintenance doses, 3 weekly instillations of epirubicin at months 3 and 6 of follow-up, or a 3-week course of BCG at month 6 of follow-up. The recurrence-free rates did not differ significantly between the two study groups (44% for epirubicin versus 55% for BCG), for an identical median follow-up of 43 months. However, in terms of relative risk of recurrences, disease-free intervals and recurrence rate per 100 patient-months, a significant benefit in favour of BCG when compared with epirubicin was demonstrated in patients who had stage T1 or grade 3 neoplasms. 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. 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. A controlled, randomised clinical trial of immunotherapy was performed in 301 patients with stage B or C colorectal cancer. The immunotherapy treatment consisted of 18 vaccinations over a 2 year period following surgery with a combination of BCG given by scarification plus subcutaneous injection of Vibrio cholera neuraminidase (VCN)-modified autologous tumour cells. Five year follow-up has now been completed in all patients. The immunotherapy did not alter either the disease-free interval or the overall survival of patients in comparison with a control group of patients not receiving immunotherapy.
In patients with medium/high risk Ta or T1 bladder cancer, immunotherapy with intravesical BCG following TUR appears to provide a significant advantage over TUR alone in delaying tumour recurrence.