What Is the Optimal Regimen for BCG Intravesical Therapy?

Zlotta, Alexandre R.; Vooren, J. P. Van; Huygen, Kris; Drowart, Annie; Decock, M.; Pirson, Michael; Jurion, Fabienne; Palfliet, Kamiel; Denis, Olivier; Simon, Jonathan; Schulman, Claude

doi:10.1159/000020170

Cited by 94 publications

(65 citation statements)

References 31 publications

(37 reference statements)

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“…The incidence of bladder retraction in the RD arm was 0.4%; the previous probability estimate [23] was 5 (2-5)%. Also, the present rate of overall systemic side-effects in the RD arm was lower than that reported previously [23], at 15.4% and 23 (19)(20)(21)(22)(23)(24)(25)(26)(27))%, respectively. Nevertheless, there is no consensus about a direct relationship between dosage and toxicity, but some contend that the schedule and number of instillations are the most important [24].…”

Section: Discussioncontrasting

confidence: 74%

“…Another approach would be to have fewer induction instillations; for >20 years the induction schedule included six weekly instillations, and the rationale for this regimen (proposed empirically by Morales) was that the BCG was then manufactured in six ampoules per package! Zlotta et al [26] showed that in most patients the maximal peripheral immune response is already apparent after four weekly instillations (and returns to pre-BCG values at 6 months of follow-up) but patients not previously immunised against mycobacterial antigen require six instillations to achieve the maximum stimulation. Böhle et al [22] also found in a recent clinical cooperative project that the maximum BCG-activated killer activity was apparent after the fourth instillation.…”

Section: Discussionmentioning

confidence: 99%

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Long‐term follow‐up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette‐Guérin with a reduced dose of 27 mg in superficial bladder cancer

̃eiro¹,

Flores²,

Isorna³

et al. 2002

BJU International

192

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Objectives To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille CalmetteGuérin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity. Patients and methods Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weeklyrsix and thereafter fortnightlyrsix) either with the standard or RD instillation. Results All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (SD) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. Conclusion Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with highrisk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediaterisk lesions and for maintenance schedules.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Long‐term follow‐up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette‐Guérin with a reduced dose of 27 mg in superficial bladder cancer

̃eiro¹,

Flores²,

Isorna³

et al. 2002

BJU International

192

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“…The optimal BCG instillation schedule is unknown. The general consensus is 6-weekly induction of BCG instillation introduced by Morales 18 , but the optimal number of inductions and the optimal frequency and duration of maintenance instillations remain unknown 19 . Although BCG has good clinical outcomes in general, we have many patients with BCG failure.…”

Section: Discussionmentioning

confidence: 99%

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Hušek¹,

Pacovský²,

Chmelařová³

et al. 2017

BIOMED PAP

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, Milos Brodak aBackground and Aims. Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). Materials and Methods. We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCGresponsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Results. Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. Conclusion.The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

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“…Assessment of the immune reactivity against mycobacterial antigens (BCG is a mycobacteria)-which is rarely if ever assessed in patients with NMIBC-may also be of significance in determining an appropriate BCG dose. 10 Although it is wellestablished that some patients fail to respond because they did not receive enough BCG (often because of tolerability issues), it is also likely that some patients receive too much BCG. Recently, low doses (sometimes one-tenth or even one-thirtieth of the dose) have been proposed for maintenance therapy.…”

Section: Reasons For Bcg Failurementioning

confidence: 99%

The management of BCG failure in non-muscle-invasive bladder cancer: an update

Zlotta

Fleshner

Jewett

2013

CUAJ

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Up to 40% of patients with non-muscle-invasive bladder cancer (NMIBC) will fail intravesical bacillus Calmette-Guérin (BCG) therapy. There is unfortunately no current gold standard for salvage intravesical therapy after appropriate BCG treatment. Indeed, outcomes are at best suboptimal. The vast majority of low-grade NMIBC are prone to recur but very rarely progress. Failure after intravesical BCG in these patients is usually superficial and lowgrade. At the other end of the spectrum, failure to respond to BCG in high-risk T1 bladder cancer and/or carcinoma in situ (CIS or TIS) is more problematic, since those tumours often have the potential to progress to muscle invasion. In these cases, radical cystectomy remains the mainstay after BCG failure. With appropriate selection, certain patients who "fail" BCG (but with favourable risk factors) can be managed with intravesical regimens, including repeated BCG, BCG plus cytokines, intravesical chemotherapy, thermochemotherapy or new immunotherapeutic modalities. In this review, reasons explaining BCG failure, how to define BCG failure, optimal risk stratification and prediction of response and management of BCG failures are discussed.

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What Is the Optimal Regimen for BCG Intravesical Therapy?

Cited by 94 publications

References 31 publications

Long‐term follow‐up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette‐Guérin with a reduced dose of 27 mg in superficial bladder cancer

Long‐term follow‐up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette‐Guérin with a reduced dose of 27 mg in superficial bladder cancer

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

The management of BCG failure in non-muscle-invasive bladder cancer: an update

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