Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer

Abstract

Purpose: The Southwest Oncology Group conducted a randomized trial of induction bacillus Calmette-Guérin (BCG) with or without maintenance BCG. In these additional retrospective analyses, our goal was to evaluate the association of a complete response (CR) or remaining with no evidence of disease (NED) vs. no CR during induction therapy with subsequent survival after adjusting for other potential confounders. Among all patients randomized to maintenance treatment, we also wanted to identify combinations of baseline covariates in order to define prognostic groups for subsequent worsening-free survival.

Methods: Outcome measures of worsening-free and overall survival were assessed using Kaplan Meier estimates and proportional hazards regression models. For the classification and regression tree (CART) analysis, 434 patients randomized to maintenance vs. no therapy with complete covariate information were included.

Results: Of the 593 evaluable patients, 341 were not randomized to maintenance BCG. Patients who achieved a prior complete response during induction BCG had a 5-year survival probability of 77% compared with 62% for patients who did not [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.44, 0.81; P = 0.0008]. Prior CR retained significance when adjusted for age, gender, prior intravesical chemotherapy, and papillary disease versus CIS (HR = 0.63; 95% CI: 0.46, 0.86; P = 0.003). CART analysis identified 4 prognostic groups. Older patients (> or =62 years old) previously treated with intravesical chemotherapy who failed to achieve a CR had a 5-fold higher risk of a worsening event relative to those who are younger (<67 years old) and achieve a CR (HR = 5.09; 95% CI: 3.37, 7.68; P < 0.0001).

Conclusion: Failure to achieve a complete response after induction BCG is associated with a significant risk of a worsening event and death for patients with CIS or Ta or T1 bladder cancer at increased risk of recurrence.

Figure 1

Kaplan Meier plot of survival following induction BCG stratified by whether the patient had a complete response or not at the initial cystoscopic evaluation following induction therapy.

Figure 2

CART analysis of worsening-free survival from randomization date for 434 subjects with no missing data based on complete response to induction therapy (yes/no), age, body mass index (BMI), prior chemo (yes/no), and gender. At each splitting point in the tree diagram there are three numbers listed. The first number indicates the unadjusted log rank statistic, the second number is the bootstrap log rank and the third number is the p-value corresponding to the bootstrap log rank which takes into account that the same individuals are used to make multiple splits (i.e., tests are not independent). The two numbers listed at each node correspond to the log hazard ratio for worsening-free survival relative to the reference node (whose log hazard ratio = 0), and the sample size for the node, respectively.

Figure 3

Kaplan Meier plot of worsening-free survival following randomization. Groups were defined as in Table 3 and stratified by the CART tree diagram (Figure 2)