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1.  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 
European urology  2009;57(5):766-773.
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.
Design, setting, and participants
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.
Results and limitations
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.
PMCID: PMC2889174  PMID: 20034729
Bacillus Calmette-Guérin; Epirubicin; Instillation therapy; Isoniazid; Non–muscle-invasive bladder cancer; Randomized clinical trial; Urothelial carcinoma of the bladder
2.  Combining a molecular profile with a clinical and pathological profile: Biostatistical considerations 
The use of molecular markers and gene expression profiling provides a promising approach for improving the predictive accuracy of current prognostic indices for predicting which patients with non-muscle-invasive bladder cancer will progress to muscle-invasive disease. There are many statistical pitfalls in establishing the benefit of a multigene expression classifier during its development. First, there are issues related to the identification of the individual genes and the false discovery rate, the instability of the genes identified and their combination into a classifier. Secondly, the classifier should be validated, preferably on an independent data set, to show its reproducibility. Next, it is necessary to show that adding the classifier to an existing model based on the most important clinical and pathological factors improves the predictive accuracy of the model. This cannot be determined based on the classifier's hazard ratio or p-value in a multivariate model, but should be assessed based on an improvement in statistics such as the area under the curve and the concordance index. Finally, nomograms are superior to stage and risk group classifications for predicting outcome, but the model predicting the outcome must be well calibrated. It is important for investigators to be aware of these pitfalls in order to develop statistically valid classifiers that will truly improve our ability to predict a patient's risk of progression.
PMCID: PMC2748188  PMID: 18815933
Area under the curve; biostatistics; molecular profile; nomograms; non-muscle-invasive bladder cancer; predictive accuracy; prognosis; progression; validation
3.  The Schedule and Duration of Intravesical Chemotherapy in Patients with Non–Muscle-Invasive Bladder Cancer: A Systematic Review of the Published Results of Randomized Clinical Trials 
European urology  2008;53(4):709-719.
Intravesical chemotherapy has been studied in randomized clinical trials for >30 yr; however, the optimal schedule and duration of treatment are unknown. The objective is to determine the effect of schedule and duration of intravesical chemotherapy on recurrence in patients with stage Ta T1 bladder cancer.
A systematic review was conducted of the published results of randomized clinical trials that compared intravesical instillations with respect to their number, frequency, timing, duration, dose, or dose intensity.
One immediate instillation after transurethral resection (TUR) is recommended in all patients. In low-risk patients, no further treatment is recommended before recurrence. In patients with multiple tumors, one immediate instillation is insufficient treatment. Additional instillations may further reduce the recurrence rate; however, no recommendations can be made concerning their optimal duration. A short intensive schedule of instillations within the first 3–4 mo after an immediate instillation may be as effective as longer-term treatment schedules (grade C). Instillations during ≥1 yr in intermediate-risk patients seem advisable only when an immediate instillation has not been given (grade C). Higher drug concentrations and optimization of the drug's concentration in the bladder may provide better results (grade C).
The optimal schedule and duration of intravesical chemotherapy after an immediate instillation remain unknown. Future studies should focus on the eradication of residual disease after TUR and the prevention of late recurrences.
PMCID: PMC2587437  PMID: 18207317
Intravesical chemotherapy; Non-muscle-invasive; bladder cancer; Recurrence; Schedule; Systematic review

Results 1-3 (3)