Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group

Abstract

Purpose: To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer Group.

Methods: We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size.

Results: NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies.

Conclusion: The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.

Fig A1.

International Bladder Cancer Group algorithm for the management of intermediate-risk non–muscle-invasive bladder cancer. Recommendations provided have been simplified for ease of use and will need to be customized to each individual patient, taking into account patient diagnosis, histology, age, previous history, and overall condition. For example, a 75-year-old man with numerous comorbidities who experiences two small (< 1 cm) low-grade recurrences more than 1 year after initial therapy may be a candidate for office fulguration and observation rather than bacillus Calmette-Guérin (BCG) maintenance or intravesical chemotherapy as suggested in this algorithm. *A score of 0 refers to a solitary, recurrent (> 1 year) low-grade tumor. Data adapted. CIS, carcinoma in situ; TURBT, transurethral resection of the bladder tumor.