Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study

Abstract

Background: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG).

Methods: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed.

Results: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts.

Conclusions: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

Keywords: Bacillus Calmette-Guérin (BCG); Intravesical therapy; Landmark analysis; Non-muscle invasive bladder cancer; Propensity score matching; Urinary bladder neoplasms.

Fig. 1

Flow chart for creation of the patient cohort dataset. Patients were stratified according to the 2019 European Association of Urology NMIBC guidelines into four as follows: low-, intermediate-, high-, and highest-risk groups. Abbreviations: NMIBC, non-muscle invasive bladder cancer; BCG, Bacillus Calmette–Guérin; iBCG, induction BCG; mBCG, maintenance BCG; PSM, propensity score matching

Fig. 2

Survival curves of outcomes after iBCG according to BCG treatment patterns. a Recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) of a total of 2669 patients treated with intravesical BCG are plotted and the estimated 2-, 5-, and 10-year survivals after initiation of induction BCG (iBCG) are shown on the right. RFS (b), PFS (c), and CSS (d) are plotted and compared among five groups as follows: Group a (i-6), non-maintenance six-dose iBCG; Group b (i-6 + m), six-dose iBCG plus mBCG; Group c (i-7/8), non-maintenance seven−/eight-dose iBCG; Group d (i-7/8 + m), seven−/eight-dose iBCG plus mBCG; and Group e (i ≤ 5), 5 or fewer BCG doses in iBCG. e The hazard ratios (HRs) and 95% confidence intervals (CIs) for groups b-e relative to Group A were calculated using the log-rank test and tabulated. P values are also listed

Fig. 3

Distributions of propensity scores in the unmatched and matched groups. The propensity score was calculated for each patient using a multivariable logistic regression model based on the covariates shown in Table S2 (Additional file 3) and Table S3 (Additional file 4). Comparison of variables according to patterns of intravesical BCG treatment: after propensity score matching. One-to-one matching with a caliper width of 0.2 was applied to maintain a large sample size and balance between two groups: Group a vs. Group b (upper panels), Group b vs. Group c (middle panels), and Group a vs. Group c (lower panels)

Fig. 4

Sequential landmark analyses of recurrence among patients treated by non-maintenance induction BCG (iBCG) or iBCG plus maintenance BCG (mBCG). a Recurrence-free survival curves (RFS) after iBCG are plotted and compared using the log-rank test among three groups as follows: Group a (i-6), non-maintenance six-dose iBCG; Group b (i-6 + m), six-dose iBCG plus mBCG; and Group c (i-7/8), non-maintenance seven−/eight-dose iBCG. After propensity score matching, RFS curves were compared between groups a and b and between groups b and c. b Landmark RFS curves at 6, 12, and 18 months for recurrence among patients treated with non-maintenance iBCG or iBCG plus mBCG were plotted and compared between matched groups a and b (left panels) and between matched groups b and c (right panels). The P values, hazard ratios (HRs) and 95% confidence intervals (CIs) are shown in the figures