Abstract

Background: Definitions of BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) have become central to therapeutic decision making and clinical trial eligibility. This perspective synthesizes regulatory frameworks with real-world observations to examine how structural conditions shape the applicability of current definitions. These definitions rely on structural prerequisites—adequate BCG exposure, routine maintenance therapy, standardized surveillance, timely access to early radical cystectomy, and complete tumour-level documentation—that are not consistently achievable across diverse health-care environments. This study examines the structural and operational factors that limit the applicability of current BCG-unresponsive criteria in real-world NMIBC care. Methods: A multilevel analysis was performed and integrated four complementary sources of evidence—regulatory frameworks, national claims datasets, multicenter clinical studies, and real-world practice observation—selected for their ability to capture distinct structural dimensions of NMIBC care. Operational assumptions embedded in contemporary definitions were compared with real-world treatment patterns. Structural barriers were categorized across macro-level system constraints, meso-level institutional practices, and micro-level clinical workflows. Results: As a result, a substantial proportion of patients cannot be classified under existing criteria because the exposure-based and time-dependent conditions required by regulatory definitions are not met in routine practice. Maintenance BCG is infrequently delivered, surveillance intervals vary widely, early radical cystectomy is limited by system-level and institutional factors, and key tumour-level variables required for classification are often missing in large-scale datasets. As a result, many patients cannot be reliably classified using existing criteria—not because of tumour biology or clinician behavior, but because the structural assumptions underlying the definitions are unmet. Conclusions: Current BCG-unresponsive criteria rely on structural conditions that are not universally present in real-world NMIBC care. These findings suggest that context-specific operational definitions, together with complementary strategies such as improving guideline implementation, enhancing data completeness, standardizing surveillance practices, and strengthening healthcare infrastructure, may help align regulatory expectations with real-world practice and support equitable access to bladder-sparing therapies.

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