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Prognostic implication of the United States Food and Drug Administration-defined BCG-unresponsive disease

  • Roger Li 1,
  • William B. Tabayoyong 1,
  • Charles C. Guo 2,
  • Graciela M. Nogueras González 3,
  • Neema Navai 1,
  • H. Barton Grossman 1,
  • Colin P. Dinney 1,
  • Ashish M. Kamat 1
1 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

The category “BCG-unresponsive disease”, formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p = 0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p = 0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27–16.67; p < 0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49–10.0; p = 0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG.

Patient summary

Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.

Commented by Francesco Soria

Recently, a new definition of Bacillus Calmette Guerin- (BCG) unresponsive (identifying those patients who will no longer benefit from further BCG) has been proposed and adopted from United States Food and Drug Administration and will soon be incorporated in international guidelines. To be categorized as BCG-unresponsive, the patient should harbor a high-grade recurrence after receiving an adequate BCG therapy, defined as an induction cycle (at least 5/6 instillations) plus a maintenance cycle (at least 2/3 instillations). The aim of the current study was to externally validate the prognostic value of this definition by comparing oncological outcomes of BCG unresponsive patients to those of patients experiencing disease recurrence after BCG induction therapy alone without any maintenance scheme. Overall, 83 patients were enrolled in this retrospective single-center study (55 BCG-unresponsive and 28 recurring after induction alone). BCG-unresponsive patients showed worse high-grade recurrence-free, progression-free and cystectomy-free survival rates (all p < 0.005). Conversely, no difference in terms of cancer-specific survival was seen. 

Patients failing Bacillus Calmette-Guerin (BCG) therapy represent a challenge for oncologic urologists, due to the extremely high-risk of progression to muscle-invasive disease. Standard treatment for BCG failure patients is represented by radical cystectomy with bilateral pelvic lymphadenectomy. However, radical cystectomy on top of being a challenging procedure coming with a certain degree of morbidity/mortality, may represent an overtreatment in some patients harboring less aggressive disease such as those with low-grade recurrences. Moreover, patients may be considered unfit for surgery (ie.; cardiac and respiratory failure) or decline it. Clinical trials are ongoing in order to propose in the near future other conservative salvage therapies to our patients.

The new definition of “BCG unresponsive”, now widely adopted, is of fundamental importance since represents a sort of guideline for enrollment for the next generation of bladder-sparing trials. However, to date, the prognostic implications of this definition were mostly unknown. For the first time, in this single center retrospective study, the authors showed that patients recurring after adequate BCG therapy (true “BCG unresponsive”) carry out worse oncological outcomes compared to those recurring after BCG induction alone. Based on these findings these patients should be treated by radical cystectomy or enrolled in clinical trials. However, the small sample size and the single center nature of the study limit the strength of the results and external validations of these findings are urgently needed.