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Alternative Therapies to Bacillus Calmette-Guerin Shortage for Nonmuscle Invasive Bladder Cancer in Brazil and Other Underdeveloped Countries: Management Considerations.

ABSTRACT: Bacillus Calmette-Guérin (BCG) plays a cornerstone role in the management of nonmuscle invasive urothelial carcinoma of the bladder. However, there has been a worldwide intermittent BCG shortage in recent years that may affect the care of patients with bladder cancer and pose difficult clinical decisions to urologists and clinical oncologists. This literature review aims to clarify alternatives to BCG during a shortage and propose measures to replace BCG, mainly in Brazil and probably in other low- and middle-income countries, where not all studied and commonly suggested treatments are available.

SUBMITTER: Wroclawski ML

PROVIDER: S-EPMC6776038 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Alternative Therapies to <i>Bacillus</i> Calmette-Guérin Shortage for Nonmuscle Invasive Bladder Cancer in Brazil and Other Underdeveloped Countries: Management Considerations.

Wroclawski Marcelo Langer ML Schutz Fabio A FA Cha Jonathan Doyun JD Soares Andrey A

Journal of global oncology 20190801

<i>Bacillus</i> Calmette-Guérin (BCG) plays a cornerstone role in the management of nonmuscle invasive urothelial carcinoma of the bladder. However, there has been a worldwide intermittent BCG shortage in recent years that may affect the care of patients with bladder cancer and pose difficult clinical decisions to urologists and clinical oncologists. This literature review aims to clarify alternatives to BCG during a shortage and propose measures to replace BCG, mainly in Brazil and probably in ...[more]

PMID: 31454284

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Project description: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.

Project description:Whether low-dose Bacillus Calmette-Guerin (BCG) treatment can reduce the side effects while maintaining efficacy for patients with nonmuscle invasive bladder cancer (NMIBC) is controversial.To investigate whether low-dose BCG treatment can reduce the side effects while maintaining efficacy for patients with NMIBC when compared with standard-dose BCG treatment.A comprehensive literature search of PubMed, EMBASE, CINAHL, LILACS, and CENTRAL databases was conducted to identify relevant randomized controlled trials (RCT) or quasi-randomized controlled trials (qRCT) that have assessed the efficacy of low- and standard-dose BCG therapy for patients with NMIBC. Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Criteria.Six RCTs and 2 qRCTs were eligible for meta-analysis. Low-dose BCG instillation was not inferior to reduce the risk of bladder tumor recurrence (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.00-1.31; P?=?0.05), meanwhile no difference was found regarding tumor progression (HR?=?1.08; 95%CI, 0.83-1.42; P?=?0.57). However, low-dose BCG provided a significantly lower incidence of overall side effects (RR?=?0.75; 95%CI, 0.60-0.94; P?=?0.01), systemic side effects (RR?=?0.57; 95%CI, 0.34-0.97; P?=?0.04), severe side effects (RR?=?0.52; 95%CI, 0.36-0.74; P?=?0.0003), and withdrawal due to BCG toxicity (RR?=?0.49; 95%CI, 0.26-0.91; P?=?0.02). In contrast, local side effects were comparable between low- and standard-dose arms (RR?=?0.89; 95%CI, 0.73-1.08; P?=?0.24).Low-dose BCG instillation significantly reduces the incidence of overall side effects, especially severe and systemic symptoms in patients with NMIBC, while the oncological control efficacy of low-dose BCG is not inferior to standard-dose BCG. Further studies with stratification using different risk factors at randomization are required to assess whether the efficacy of low-dose BCG is comparable to standard dose BCG for different risk of patients.PROSPERO registration No CRD42014014871 (http://www.crd.york.ac.uk/prospero/).

Project description:Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for bladder superficial carcinoma and it is being tested in interstitial cystitis patients, but its precise mechanism of action remains poorly understood. It is not clear whether BCG induces the release of a unique set of cytokines apart from its pro-inflammatory effects. Therefore, we quantified bladder inflammatory responses and alterations in urinary cytokine protein induced by intravesical BCG and compared the results to non-specific pro-inflammatory stimuli (LPS and TNF-alpha). We went further to determine whether BCG treatment alters cytokine gene expression in the urinary bladder.C57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-alpha. Morphometric analyses were conducted in bladders isolated from all groups and urine was collected for multiplex analysis of 18 cytokines. In addition, chromatin immune precipitation combined with real-time polymerase chain reaction assay (CHIP/Q-PCR) was used to test whether intravesical BCG would alter bladder cytokine gene expression.Acute BCG instillation induced edema which was progressively replaced by an inflammatory infiltrate, composed primarily of neutrophils, in response to weekly administrations. Our morphological analysis suggests that these polymorphonuclear neutrophils are of prime importance for the bladder responses to BCG. Overall, the inflammation induced by BCG was higher than LPS or TNF-alpha treatment but the major difference observed was the unique granuloma formation in response to BCG. Among the cytokines measured, this study highlighted the importance of IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-17, GM-CSF, KC, and Rantes as discriminators between generalized inflammation and BCG-specific inflammatory responses. CHIP/Q-PCR indicates that acute BCG instillation induced an up-regulation of IL-17A, IL-17B, and IL-17RA, whereas chronic BCG induced IL-17B, IL-17RA, and IL-17RB.To the best of our knowledge, the present work is the first to report that BCG induces an increase in the IL-17 family genes. In addition, BCG induces a unique type of persisting bladder inflammation different from TNF-alpha, LPS, and, most likely, other classical pro-inflammatory stimuli.

Dataset Information

Alternative Therapies to Bacillus Calmette-Guerin Shortage for Nonmuscle Invasive Bladder Cancer in Brazil and Other Underdeveloped Countries: Management Considerations.

Publications

Alternative Therapies to <i>Bacillus</i> Calmette-Guérin Shortage for Nonmuscle Invasive Bladder Cancer in Brazil and Other Underdeveloped Countries: Management Considerations.

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