To standardize treatment definitions and facilitate clinical decision-making, the International Bladder Cancer Group (IBCG) proposed a definition of "adequate BCG"—namely, the receipt of at least five of six induction instillations and either two of three maintenance doses or two doses of a re-induction course within six months. This definition has become crucial for identifying patients with adequate BCG exposure who may be classified as unresponsive and therefore not suitable for further BCG treatment. However, no prior study has directly compared long-term oncologic outcomes between patients who receive adequate versus inadequate BCG, according to this definition.
In our multicenter European study, we sought to address this gap by evaluating whether patients treated with "adequate" BCG experience superior long-term outcomes compared to those with "inadequate" BCG exposure. We analyzed data from 1,558 patients treated between 2010 and 2024 across 12 high-volume tertiary referral centers. All patients in the inadequate BCG group received at least five instillations to ensure they had sufficient initial exposure to be considered BCG-treated.
To mitigate immortal time bias, we performed a 3-month landmark analysis, excluding patients with early events that would preclude assessment of maintenance eligibility. We then used inverse probability of treatment weighting (IPTW) to adjust for baseline imbalances in demographic and disease characteristics. Outcomes of interest included recurrence-free survival (RFS), high-grade RFS (HG-RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific mortality (CSM).
Our results were as follows: adequate BCG administration was associated with significantly improved outcomes across all oncologic endpoints. The 5-year RFS was 72% in the adequate group versus 52% in the inadequate group (HR: 0.40); HG-RFS was 83% versus 68% (HR: 0.43); PFS was 92% versus 85% (HR: 0.47); and OS was 88% versus 71% (HR: 0.52). Interestingly, CSM did not differ significantly between groups, suggesting that the survival disadvantage in the inadequate group may reflect a higher burden of comorbidities and non–cancer-related mortality. Indeed, patients receiving inadequate BCG were generally older and more likely to have discontinued therapy due to intolerance—underscoring the challenge of delivering guideline-concordant treatment in medically vulnerable populations.
These findings support the IBCG definition of BCG adequacy as a clinically meaningful and prognostically relevant benchmark—not merely a criterion for clinical trial eligibility. They highlight the importance of strategies aimed at optimizing BCG delivery, including proactive toxicity management, better patient counseling, and, when needed, early consideration of alternative treatments such as radical cystectomy or bladder-sparing combinations.
In the context of global BCG shortages and growing interest in novel intravesical and systemic therapies (e.g., checkpoint inhibitors or gemcitabine/docetaxel), our study reinforces the message that adequate BCG remains the most effective and cost-efficient treatment when it can be delivered in full.
While causality cannot be confirmed in a retrospective design, the robustness of our findings is supported by multiple methodological safeguards—including landmark analysis, IPTW, and E-value sensitivity analyses. Prospective validation is warranted to confirm these associations and to help inform risk-adapted treatment strategies for patients who may not be able to complete adequate BCG therapy. Particularly, a key future challenge will be to define the optimal criteria for BCG adequacy through prospective studies.
Written by:
- Pietro Scilipoti, MD, Department of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
- Marco Moschini, MD, PhD, Department of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy