The Role of Bacillus Calmette-Guerin in the Treatment of Non-Muscle-Invasive Bladder Cancer

Department of Urology, University of Turin, Molinette Hospital, Turin, Italy.
European Urology (Impact Factor: 13.94). 11/2009; 57(3):410-29. DOI: 10.1016/j.eururo.2009.11.023
Source: PubMed


Bacillus Calmette-Guérin (BCG) remains the most effective intravesical treatment for non-muscle-invasive bladder cancer (NMIBC), but the clinical development of BCG has been accompanied by controversy. Recent publications have called into question a number of aspects related to its use.
To review the current clinical role of BCG in NMIBC, focusing on efficacy and tolerability as primary objectives and on strategies to predict response and decrease toxicity as secondary objectives.
We performed a systematic literature search of published articles in PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases for the period from 1976 to November 2008. The following "free text" combination was used in the first instance: "BCG and intravesical and bladder cancer." Further free text searches were performed by separately adding the following keywords to the combination "BCG and intravesical": survival, progression, recurrence, maintenance, dosing, toxicity, tolerability, side effects, prognostic factors.
BCG is the most effective intravesical agent for preventing NMIBC recurrence, but its role in disease progression remains controversial. In intermediate-risk NMIBC, the superiority of BCG over chemotherapy is well established for disease recurrence but not for progression and needs to be balanced against higher toxicity. With regard to high-risk NMIBC, there is sufficient evidence to show that BCG is the most effective treatment of carcinoma in situ for ablation, disease-free interval, and progression, but the impact of BCG on the natural history of T1G3 tumors relies on a low level of evidence. Maintenance remains crucial for efficacy. The dose can be safely and effectively reduced to decrease its toxicity, which is slightly greater than chemotherapy.
BCG should still be viewed as the most effective intravesical agent, but its role in the progression of papillary tumors needs to be clarified. BCG remains an alternative to intravesical chemotherapy in intermediate-risk NMIBC, and it is recommended as the standard of care for high-risk NMIBC.

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    • "Recently there have been many trials to reduce the side-effects of BCG therapy without affecting its efficacy [6]. The aim of the present study was to compare the efficacy and safety of full (standard) and half doses of intravesical BCG administration in patients with NMIBC. "
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    ABSTRACT: Objectives: To determine whether a half-dose of bacille Calmette–Gue´rin (BCG) can reduce toxicity without affecting its efficacy in the management of nonmuscle-invasive bladder cancer. Patients and methods: From January 2012 to January 2014, 80 patients with superficial bladder cancer and in the intermediate-risk group were simply randomized to receive two different doses of BCG, i.e., a full dose of 90 mg (group A) or a half-dose of 45 mg (group B). There were no significant differences in clinical and pathological characteristics between the groups. At completion of the study, 40 patients could be evaluated in each group. Results: All patients were evaluated for a follow-up of 12 months after treatment. There was no significant difference in recurrence rate (15 patients, 38%, in group A and 16, 40%, in group B) in the two groups, and no difference in progression rate of the disease, at eight patients (20%) in each group. There were significant differences between groups A and B in toxicity (grade 1 adverse events, 70% vs. 60%; grade 2, 18% vs. 7.5%, respectively). Grade 3 adverse events were only reported in group A (2.5%). Conclusion: The half dose of intravesical BCG instillation can reduce the toxicity and side-effects that are associated with the treatment of superficial bladder cancer, without affecting the efficacy of therapy. ª 2015 Production and hosting by Elsevier B.V. on behalf of Arab Association of Urology. This is an open access article under the CC BY-NC-ND license (http://
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    • "Bacillus Calmette–Guérin (BCG) is considered the most effective treatment to increase disease-free interval and reduce progression of non-muscle invasive bladder cancer (NMIBC) [1]. Although considered safe, BCG can produce both local and systemic side effects leading to treatment discontinuation or interruption. "
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) is considered the most effective treatment to reduce recurrence and progression of non-muscle invasive bladder cancer (NMIBC) but can induce local side effects leading to treatment discontinuation or interruption. Aim of this exploratory study is to investigate if the sequential administration of Hyaluronic acid (HA) may reduce local side effects of BCG. 30 consecutive subjects undergoing BCG intravesical administration for high risk NMIBC were randomized to receive BCG only (Group A) or BCG and HA (Group B). A 1 to 10 Visual Analog Scale (VAS) for bladder pain, International Prostate Symptom Score (IPSS) and number of micturitions per day were evaluated in the two groups before and after six weekly BCG instillations. Patients were also evaluated at 3 and 6 months by means of cystostopy and urine cytology. One out of 30 (3,3%) patients in group A dropped out from the protocol, for local side effects. Mean VAS for pain was significantly lower in group B after BCG treatment (4.2 vs. 5.8, p = 0.04). Post vs. pre treatment differences in VAS for pain, IPSS and number of daily micturitions were all significantly lower in group B. Three patients in group A and 4 in group B presented with recurrent pathology at 6 month follow up. These preliminary data suggest a possible role of HA in reducing BCG local side effects and could be used to design larger randomized controlled trials, assessing safety and efficacy of sequential BCG and HA administration. Trial registration NCT02207608 ( 01/08/2014 Policlinico Tor Vergata Ethics Committee, resolution n 69–2011.
    BMC Urology 08/2014; 14(1):64. DOI:10.1186/1471-2490-14-64 · 1.41 Impact Factor
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    • "Instillation of live BCG-bacilli is an effective therapy to prevent progress of non-muscle invasive bladder cancer [26]. In this study, we have used intracellular cytokine staining to characterise the induction of PPD-specific T cell immunity before and during BCG-treatment. "
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    ABSTRACT: Specific T cell immunity in patients with active tuberculosis is associated with a decrease in multifunctionality. However, it is unknown whether cytokine profiles differ in patients with primary infection and those with prior contact. We therefore used intravesical immunotherapy with attenuated live Bacille Calmette-Guérin (BCG) in patients with urothelial carcinoma as a model to characterise the induction of systemic immunity towards purified protein derivate (PPD) and to study whether cytokine profiles differ depending on pre-existing immunity. Eighteen patients with non-muscle invasive bladder cancer were recruited during the BCG-induction course. Fifty-four healthy individuals served as controls. Interferon (IFN)-γ and interleukin (IL)-2 producing PPD-specific CD4 T cells were analysed longitudinally before each instillation using a rapid flow-cytometric whole blood immunoassay. Baseline levels of IFN-γ producing PPD-specific T cells were comparable to controls. T cells showed a 5-fold increase to 0.23% by week 2/3, and further increased 8-fold by week 4/5 (to 0.42%, p=0.0007). Systemic immunity was induced in all patients, although the increase was less pronounced in patients with pre-existing immunity. As in active TB, cytokine profiling during therapy revealed a lower percentage of multifunctional IFN-γ/IL-2 double-positive T cells compared to controls (60.2% vs. 71.9%, p=0.0003). Of note, when comparing patients with and without pre-existing immunity, cytokine profiles in patients with primary immunity were shifted towards IL-2 single producing T cells (p=0.02), whereas those in patients with pre-existing immunity were shifted towards IFN-γ single-positivity (p=0.01). In conclusion, systemic T cell responses were induced after BCG-therapy, and their kinetics and cytokine profile depended on pre-existing immunity. Decreased functionality is a typical feature of specific immunity in both patients with active tuberculosis and BCG-therapy. Among patients with active infection, a shift towards IL-2 or IFN-γ single-positive cells may allow distinction between patients with primary infection and cases with boosted immunity after prior contact, respectively.
    PLoS ONE 09/2013; 8(9):e69892. DOI:10.1371/journal.pone.0069892 · 3.23 Impact Factor
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