The pooled analysis of RFS was based on 9 studies. Compared with standard dose BCG, low-dose BCG was significantly related to worse RFS (RR, 1.17; 95% CI, 1.06–1.30). There was no obvious heterogeneity (P = .39; I2 = 5%; Fig. 2A). Significant differences were not found in PFS, CSS, and OS between low and standard BCG dose, and there was no interstudy heterogeneity in all analyses (Fig. 2B–D).
A total of 8 studies were included in the meta-analysis of RFS. Compared to maintenance BCG, induction BCG significantly showed a worse RFS (RR, 1.33; 95% CI, 1.17–1.50). The result for the test for heterogeneity was not significant (P = .46; I2 = 0%; Fig. 3A). In contrast, in the meta-analyses of the correlation between BCG duration and secondary endpoints (PFS, CSS, and OS), there were no significant differences according to BCG regimen (induction vs maintenance), and significant interheterogeneity was not observed in the analyses (Fig. 3B–D).
No significant publication bias was found in the meta-analyses of all survival outcomes according to various BCG regimens. Funnel plots for publication bias of the correlation between various BCG regimens (dose and duration) and survival outcomes (RFS, PFS, CSS, and OS) demonstrated a certain degree of asymmetry (supplemental Fig. S1A–D, http://links.lww.com/MD/B903, and Fig. S2A–D, http://links.lww.com/MD/B903).
BCG is an attenuated mycobacterium developed as a vaccine for tuberculosis. It has shown an antitumor effect in several different cancers including bladder cancer. Intravesical BCG is widely used and has been one of the most successful immunotherapies for the management of NMIBC by inducing massive local immune response within the bladder. The preventive effect of BCG on tumor recurrence and progression in NMIBC has already been proven by several investigators.[6,7,9] Therefore, based on risk predicting models, such as the European Organization of Research and Treatment of Cancer risk tables and Spanish Urological Club for Oncological Treatment scoring system,[3,4,37–39] for recurrence and progression after TURBT for NMIBC, the international guidelines have recommended the use of intavesical BCG as an adjuvant therapy in intermediate-to-high risk NMIBC cases to remove the residual tumor and prevent recurrence and progression.[1,2,11]
However, the optimal treatment dose, duration, and strain of BCG have not yet been definitely established. Although there have been a number of prospective trials assessing the optimal duration and dose of BCG in NMIBC, the conflicting results have been reported among studies.
As for BCG dose, 1 prospective RCT comparing standard (81 mg) versus low (54 mg) dose demonstrated that recurrence rates significantly differed (0.71/month in standard vs 1.49/month in low; P < .05) but there were no significant differences in side effects between 2 groups, which supported the superior efficacy of standard dose relative to low dose. Another trial comparing standard (81 mg) with 3-fold reduced (27 mg) dose reported that the standard dose was significantly more effective against recurrences (P = .0151) and progression (P = .048) than the reduced dose in patients with multifocal tumors, and thus recommended continuing to use the standard dose for high-risk tumors. Other trials comparing 2 dose[15,16] or 3 dose BCG group[17,18] described that low-dose BCG showed a similar efficacy on recurrence or progression, and its toxicity was significantly lower compared with standard dose. A recent meta-analysis pooling 8 RCTs comparing BCG dose demonstrated that compared with standard BCG dose, low-dose BCG was not inferior to reduce the risk of tumor recurrence (HR, 1.15; 95% CI, 1.00–1.31; P = .05) and showed no significant difference in progression (HR, 1.08; 95% CI, 0.83–1.42; P = .57). Additionally, the use of low-dose BCG was significantly associated with lower incidence of severe (RR, 0.52; 95% CI, 0.36–0.74; P = .0003) and systemic side effects (HR, 0.57; 95% CI, 0.34–0.97; P = .01).
RCTs regarding BCG duration have mainly focused on the evaluation of the efficacy of maintenance therapy compared to induction therapy only. One trial conducted by the Southwest Oncology Group demonstrated the significant impact of maintenance therapy relative to control (induction only). Patients randomized in the maintenance arm received a 6-week induction course followed by 3 weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years (Southwest Oncology Group regimen) and showed no toxicities above grade 3. Estimated median RFS was 76.8 months in the maintenance arm and 35.7 months in the control arm (P = .0001) and 5-year OS was 78% in the control arm and 83% in the maintenance arm. This preventive impact of BCG maintenance therapy on the recurrence following TURBT was also identified in 2 other RCTs.[24,25] In contrast, recent RCTs have described the insignificant effect of maintenance therapy in terms of the prevention of recurrence or progression.[26,27] The Spanish Urological Club for Oncological Treatment 98013 study compared the recurrence and progression rates between BCG induction once-weekly for 6 weeks (no maintenance arm) and BCG induction followed by 1 BCG instillation every 3 months for 3 year (maintenance arm). Maintenance therapy had no significant advantages on the 5-year recurrence (33.5% in maintenance arm vs 38.5% in no maintenance arm) and progression rates (16.5% in maintenance arm vs 19.5% in no maintenance arm).
Two RCTs provided conflicting results concerning the comparison of BCG strains. One RCT reported that there were no significant differences in RFS and adverse events between BCG Connaught and Tokyo strains. Another recent RCT demonstrated that, compared with BCG Tice, the BCG Connaught strain was significantly associated with greater 5-year RFS (74% in Connaught vs 48% in Tice; P = .0108).
We tried to investigate the effective BCG strategies though a systematic review and meta-analysis for the previously reported RCTs. To the best of our knowledge, this study is the first meta-analysis evaluating the differences of the clinical outcomes according to the dose, duration, and strain of BCG. Standard dose and maintenance BCG therapy showed significant benefits in terms of reduction of recurrence risk following TURBT. These findings are partially consistent with the results of the previous trials,[13,14,22,24,25] On the other hand, other clinical outcomes (PFS, CSS, and OS) were not significantly different depending on the dose and duration of BCG. Although previous meta-analysis on the BCG dose, which included many of the same studies observed in our analysis, concluded low-dose BCG was not inferior to standard dose BCG for reducing the risk of recurrence, the pooled HR for recurrence was marginal in light of 95% CI (1.00–1.31) and P-value (.05). Therefore, we interpreted the result of previous meta-analysis supported the superiority of standard dose BCG rather than noninferiority of low-dose BCG in terms of the prevention of recurrence, which consequently corresponds well with the results of the present study. The BCG strains could not be meta-analyzed because there have been too few studies; no meaningful conclusion on the effective BCG strain could be drawn from this study.
Several limitations should be considered for the interpretation of the present findings. First, in spite of the interstudy differences on the definition for the dose or duration of used BCG regimens in the included trials, we simply compared the clinical outcomes between binary variables (low vs standard dose, nonmaintenance vs maintenance) without head-to-head comparisons among diverse BCG regimens. Thus, we cannot draw a definite conclusion concerning the optimal BCG dose and duration. Some trials[12,17,18] defined 120 mg as a standard dose and half or one/two-third of 120 mg as a low dose, while other trials[13–16] used 80 or 81 mg as a standard dose and half or one/two-third of 80 or 81 mg as a low dose. For BCG duration, various definitions were also applied in terms of the maintenance duration. These nonunified definitions of BCG dose or duration in each trial may diversely affect the prognosis of NMIBC patients treated with TURBT. Second, unknown or uncontrolled variables that could not be clearly identified in the included trials might have affected the results of this analysis. Interinstitutional variation of TURBT techniques (ie, muscle layer resection, restaging TURBT), primary tumor size, and preoperative positive urine cytology, which were suggested as the important prognostic factors of NMIBC in previous studies,[41–45] could not be adjusted through a multivariable analysis along with BCG. Third, the results of this systematic review and meta-analysis were based on unadjusted estimates, because some studies did not provide detailed information (Table 1). Finally, we cannot exclude the possibility of language bias by only including the articles published in English, despite no definite evidence of publication bias.
The current meta-analysis results indicate that in patients with NMIBC, the maintenance intravesical BCG strategies using standard dose may be effective to reduce recurrence risk after TURBT. However, the optimal dose, duration, and strain of BCG could not be definitely determined. Large scale, well-designed, and prospective studies, with stratification of the patients into risk group at randomization, will be required to establish the optimal guideline of BCG use to improve clinical outcomes in NMIBC.
The authors thank the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2016R1A2B4011623) and Samyang Biopharm for the support.
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