Using Grade of Recurrent Tumor to Guide Further Therapy While on Bacillus Calmette-Guerin: Low-grade Recurrences Are not Benign

Background: Tumors that recur after bacillus Calmette-Guerin (BCG) therapy are considered to be of very high risk, and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. Objective: To characterize the pattern of bladder cancer progression and cancer-specific survival (CSS) in patients with recurrences dichotomized by low grade (LG) versus high grade (HG) after intravesical BCG treatment, and to assess the safety of continued bladder-sparing therapy in these patients. Design, setting, and participants: We performed an Institutional Review Board–approved review of our bladder cancer database. Overall, 146 non–muscle-invasive bladder cancer (NMIBC) patients were found to have NMIBC recurrence while on BCG therapy; this recurrence was LG in 38 and HG in 108. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity, and concurrent carcinoma in situ were also evaluated. The primary endpoint was progression-free survival (PFS), with progression defined as the development of muscle-invasive bladder cancer (MIBC)/distant metastasis. In addition, recurrence-free survival (RFS), HG RFS, cystectomy-free survival (CFS), and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two sided, and p < 0.05 was considered statistically significant. Intervention: Further intravesical therapy versus salvage RC. Results and limitations: Overall, estimated 5-yr PFS was 72.4% (95% confidence interval [CI] 60.4–81.3%). As dichotomized by grade of recurrent tumor, PFS was greater for patients with LG recurrences (85.6%, 95% CI 60.8–95.2%) than for those with HG recurrence (67.9%, 95% CI 54.1–78.4%; p = 0.010). Furthermore, patients whose initial recurrence on BCG therapy was LG had improved subsequent RFS (median 62 vs 34 mo, p = 0.007), HG RFS (median 112 vs 36 mo, p < 0.001), and CFS (estimated 5-yr CFS 80.8% vs 49.8%, p < 0.001) compared with those who had HG initial recurrence. On univariate and multivariate analyses, grade of tumor recurrence after BCG was an independent predictor of time to progression to MIBC/distant metastasis (hazard ratio 3.60, 95% CI 1.18–10.94, p = 0.024). Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/metastatic urothelial carcinoma. While, patients with LG recurrences have less than half the progression events compared with those with HG recurrences, their estimated 5-yr progression rate is still 14.4%. Hence all patients should be carefully counseled on bladder-sparing therapy. This also has implications for clinical trial design. Patient summary: If bladder cancer recurs after bacillus Calmette-Guerin treatment, there are many factors that determine the further clinical outcome. Although low-grade recurrent tumors confer a less aggressive course, disease progression can still occur, and hence continued vigilance is important. If bladder cancer recurs after bacillus Calmette-Guerin (BCG) treatment, there are many factors that determine the further clinical outcome. Although low-grade recurrent tumors confer a less aggressive course, disease progression can still occur and hence continued vigilance is important.