Connaught strain Bacillus of Calmette-Guerin 81mg powder for reconstitution for instillation vials

BackgroundIn an era of Bacillus of Calmette-Guérin (BCG) shortages, the comparative efficacy from different adjuvant intravesical BCG strains in non-muscle invasive bladder cancer (NMIBC) has not been clearly elucidated. We aim to compare, through a systematic review and meta-analysis, the cumulative BC recurrence rates and the best efficacy profile of worldwide available BCG strains over the last forty years.MethodsPubMed, Scopus, Web of Science, Embase, and Cochrane databases were searched from 1982 up to 2022. A meta-analysis of pooled BC recurrence rates was stratified for studies with ≤3-y vs. >3-y recurrence-free survival (RFS) endpoints and the strain of BCG. Sensitivity analysis, sub-group analysis, and meta-regression were implemented to investigate the contribution of moderators to heterogeneity. A random-effect network meta-analysis was performed to compare BCG strains on a multi-treatment level.ResultsIn total, n = 62 series with n = 15,412 patients in n = 100 study arms and n = 10 different BCG strains were reviewed. BCG Tokyo 172 exhibited the lowest pooled BC recurrence rate among studies with ≤3-y RFS (0.22 (95%CI 0.16-0.28). No clinically relevant difference was noted among strains at >3-y RFS outcomes. Sub-group and meta-regression analyses highlighted the influence of NMIBC risk-group classification and previous intravesical treated categories. Out of the n = 11 studies with n = 7 BCG strains included in the network, BCG RIVM, Tice, and Tokyo 172 presented with the best-predicted probability for efficacy, yet no single strain was significantly superior to another in preventing BC recurrence risk.ConclusionWe did not identify a BCG stain providing a clinically significant lower BC recurrence rate. While these findings might discourage investment in future head-to-head randomized comparison, we were, however, able to highlight some potential enhanced benefits from the genetically different BCG RIVM, Tice, and Tokyo 172. This evidence would support the use of such strains for future BCG trials in NMIBCs.

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The South West Oncology Group's 2000 randomised-control trial investigated the addition of maintenance intravesical bacillus Calmette-Guerin (BCG) to non-muscle invasive urothelial carcinoma (NMIUC) treatment. The results were published when the efficacy of BCG immunotherapy maintenance was unclear.Randomisation produced two arms, each containing 192 patients assessed to be at high risk of recurrence following induction BCG therapy for NMIUC. The treatment arm went on to receive three successive weekly intravesical and percutaneous BCG administrations at three months, six months and then six monthly for three years from the start of induction therapy.Recurrence free-survival (RFS), was higher in the maintenance arm with 41% (95%CI 35-49) RFS at five years in the control arm and 60% RFS (53-67 95% CI) in the maintenance arm (p < 0.0001). Only 16% of patients in the treatment arm received all of the scheduled maintenance courses of BCG.The study's seminal results correlate with contemporary systematic review and have guided international guidelines.

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BackgroundMost patients with localized bladder cancer are initially managed with endoscopic resection. For high-grade nonmuscle invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guerin (BCG) therapy is the gold standard adjuvant treatment. However, 30%-40% of patients fail BCG treatment with lack of response or disease relapse. An understudied area of treatment failure is BCG intolerance, where patients drop out of treatment due to adverse effects.ObjectivesTo examine the incidence and underlying reasons for BCG intolerance among adult patients with NMIBC.MethodsWe conducted a search on Embase, MEDLINE, and Cochrane Central Register of Controlled Trials for studies from January 1, 1974 to January 10, 2023, retrieving 3340 articles. Two authors independently conducted screening and data extraction with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inclusion criteria include English-language studies reporting dropout rates and reasons for discontinuation of BCG therapy in NMIBC patients.ResultsBCG dropout rates reported among the 28 included studies varied widely from 0% to 52% (estimated summary proportion 12.8%, 95% CI 9%-17%). There was significant heterogeneity in study design. Subgroup analyses show a dose-dependent effect on dropout rates (3.3% vs. 20%, X2 = 83.6, p = -16). Dropout rates vary with BCG strains: the Connaught strain had the highest at 21.1%, while the Pasteur strain had 2%. Clinical outcomes for BCG intolerance are not widely reported.ConclusionsDropout rates due to BCG intolerance average 12.8%. As cessation of treatment could lead to an increased risk in progression or recurrence of disease, strategies to mitigate BCG intolerance would be valuable.

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IntroductionThe Bacillus Calmette-Guerin (BCG) vaccine has a beneficial "off-target" effect that offers heterologous protection against respiratory tract infections by inducing trained immunity. The need for producing antigen-specific COVID-19 vaccines leads to delays in vaccine administration. Current randomized controlled trials (RCTs) report conflicting data on BCG's efficacy in COVID-19 infection.MethodsA comprehensive literature search was conducted using major bibliographic databases to identify RCTs evaluating the outcomes of BCG re-vaccination in COVID-19. For dichotomous outcomes, odds ratios (ORs) with 95% CIs were pooled using the DerSimonian-Laird random-effects model. Statistical significance was set at P less than 0.05.ResultsThirteen RCTs with 13 939 participants (7004 in the BCG re-vaccination group and 6935 in the placebo group) were included. BCG re-vaccination did not lead to a statistically significant difference in the incidence of COVID-19 infection [OR: 1.04; 95% CI: 0.91, 1.19; P=0.56], COVID-19-related hospitalizations [OR: 0.81; 95% CI: 0.38, 1.72; P=0.58), ICU admissions [OR: 0.43; 95% CI: 0.13, 1.46; P=0.18], or mortality [OR: 0.67; 95% CI 0.15, 3.04; P=0.60]. For safety outcomes, BCG re-vaccination led to a significant increase in the local injection site complications [OR: 99.79; 95% CI: 31.04, 320.80; PP=0.33].ConclusionsBCG re-vaccination does not decrease the incidence of COVID-19 infection, COVID-19-related hospitalizations, ICU admissions, COVID-19-related mortality, and serious adverse events; however, it leads to a rise in local injection site complications. Caution should be exercised when overstating BCG's efficacy in COVID-19 prevention.

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BackgroundThe BCG vaccine has long been hypothesised to have non-specific protective effects, and early epidemiological studies on COVID-19 suggested a possible protective effect against SARS-CoV-2 infection and COVID-19 severity. This systematic review and meta-analysis assesses the effect of the BCG vaccine on preventing severe COVID-19 disease, based on the rate of hospitalisation for COVID-19 related disease.MethodsWe performed a literature search of randomised control trials comparing BCG vaccine to placebo in adult participants using EMBASE, MEDLINE, and Web of Science. A random effects model was used to generate summary estimates. Risk of bias was assessed regarding randomisation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases.ResultsWe included 11 studies involving 18,412 participants, reporting COVID-19 incidence. The hospitalisation rate was sought from the authors of papers that did not report on this statistic. There was no significant reduction in COVID-19-related hospitalisation across all studies (relative risk 0.85, 0.51-1.40, p = 0.335), COVID-19 incidence across all studies (relative risk 1.07, 0.94-1.21, p = 0.264), deaths reported in six studies (relative risk 0.67, 0.36-1.26, p = 0.733), and COVID-19-related critical care admissions reported in four studies (relative risk 0.43, 0.13-1.46, p = 0.746).ConclusionsThe findings from this meta-analysis, involving a large number of participants, suggest no protective effect of BCG vaccination against severe COVID-19 outcomes or overall SARS-CoV-2 incidence. Further research may be needed to explore the potential non-specific effects of BCG vaccination in other specific populations and against other infections.

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BackgroundUpper urinary tract carcinoma in-situ (UUT-CIS) is an aggressive disease traditionally managed with radical nephroureterectomy (RNU), often resulting in loss of renal function. Topical Bacillus Calmette-Guérin (BCG) therapy has been explored as a kidney-sparing alternative, although evidence remains limited and heterogeneous. This review aimed to synthesise oncological and safety outcomes of topical BCG therapy for UUT-CIS.MethodsA systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and grey literature (registration No. CRD420261277998). Eligible studies were published 01/01/2000-14/09/25, enrolled adult patients with UUT-CIS treated with topical BCG and reported oncological or toxicity outcomes. Primary outcomes were rates of complete response, recurrence and progression. Where methodological homogeneity permitted, meta-analysis was planned. Risk of bias was assessed using Risk Of Bias In Non-randomised Studies of Interventions (ROBINS)-I V2.ResultsFourteen observational studies comprising 298 renal units (267 patients) were included (weighted mean age of 71.8 years; 19.2% female). Complete response rates following BCG induction ranged 59-100% per renal unit. Recurrence rates after initial response ranged 0-70% and progression rates ranged 0-43%. The proportion of renal units requiring salvage RNU ranged 0-25%. Renal unit preservation ranged 45-100%. Median follow-up varied substantially at 13-88 months. Adverse events were predominantly local and self-limited; severe systemic toxicity was uncommon, and treatment-related mortality was reported in one patient. Substantial heterogeneity existed in follow-up duration, delivery technique, surveillance protocols, and outcome definitions, negating meta-analysis. Most included studies demonstrated a moderate risk of bias across key ROBINS-I domains, reflecting observational study design and the absence of randomized trials.ConclusionsTopical BCG therapy for UUT-CIS is associated with high initial response rates and meaningful renal preservation and may represent a kidney-sparing option in carefully selected or imperative clinical scenarios. However, recurrence and progression rates remain variable. Topical BCG therapy should not be considered equivalent to RNU, which remains the oncological standard of care.

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BackgroundIntravesical bacillus Calmette-Guerin (BCG) instillation is widely used as an adjuvant therapy after transurethral resection of bladder tumor (TURBT) in patients with intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC). However, the effective dose, duration, and strain of BCG have not yet been clearly determined. We aimed to elucidate the relationship between dose, duration, and strain of BCG and clinical outcomes in NMIBC patients treated with TURBT.MethodsWe conducted a literature search in Embase, Scopus, and PubMed databases for all relevant articles published up to October 2016 in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. The relative risks of clinical outcomes, including recurrence, progression, cancer-specific mortality, and all-cause mortality according to dose (standard vs low), duration (induction vs maintenance), and strain of BCG were presented as the pooled risk ratio (RR) and 95% confidence interval (CI).ResultsNineteen studies meeting the inclusion criteria were finally selected in this meta-analysis. The risk of recurrence was significantly highly observed in case of low-dose BCG (RR, 1.17; 95% CI 1.06-1.30) and induction BCG (RR, 1.33; 95% CI 1.17-1.50) only group without heterogeneity among the included studies. Although there were no significant differences between dose or duration and other clinical outcomes. On direct comparison in each study comparing BCG strains, the Tice stain showed a relatively high probability of recurrence compared with the Connaught (RR, 1.29; 95% CI 1.01-1.64) and RIVM (RR, 2.04, 95% CI 1.28-3.25) strains. Funnel plot testing revealed no significant publication bias.ConclusionThe use of standard dose and maintenance BCG instillation may be effective to reduce recurrence rate after TURBT for NMIBC. Further large scale, well-designed, and prospective studies, with stratification of the patients into risk group at randomization, will be required to determine the optimal guideline of BCG use to improve clinical outcomes in NMIBC.

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