For treating patients with superficial bladder cancer and a moderate-to-high risk of tumor recurrence or progression, intravesical BCG has been the key development of the last generation. However, BCG has also brought with it a novel set of challenges. An understanding of when, to whom, and how BCG should be given is critical if optimal outcomes are to be achieved. This article the authors reviews the role that BCG has played in the management of bladder cancer over the last several decades and discusses specific approaches to optimize BCG. It focuses on selection and technical strategies.
Key points
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Bacillus Calmette-Guérin (BCG) is arguably the most effective intravesical treatment option for patients with intermediate-to-high risk superficial bladder cancer.
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A poor understanding of how and when BCG should be used can lead to suboptimal outcomes.
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Careful attention to patient and tumor characteristics can help identify candidates most likely to respond to BCG.
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Specific technical strategies can be employed to optimize BCG outcomes.
Introduction
As discussed throughout this issue, bladder cancer represents a significant physical and emotional burden to patients as well as a substantial financial burden to society (see the article by James and colleagues elsewhere in this issue). For patients at the extremes of risk, treatment algorithms are relatively straightforward; yet the outcomes are variable. Within the spectrum of non-muscle invasive bladder cancer (NMIBC), for patients with the lowest-risk tumors, the mainstay of treatment is complete transurethral resection (TUR) followed by surveillance (see the article by O’Neil and colleagues elsewhere in this issue); for patients with the most advanced risk tumors, radical cystectomy may be the only viable option (see the article by Daneshmand elsewhere in this issue). Among the areas of greatest uncertainty within the discipline of bladder cancer is the management of patients with NMIBC thought to have a high risk of recurrence and/or intermediate-to-high risk of progression. In this setting, intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the current gold standard therapy with the highest response rates; however, despite its frequent use, it remains poorly understood, resulting in usage that is far from optimal.
In this article, the authors review the role that BCG has played in the management of bladder cancer over the last several decades and discuss specific approaches to optimize BCG. They focus on selection strategies to help practitioners identify candidates most likely to respond to BCG as well as on technical strategies to enhance the administration of the drug in such a way as to optimize the response rates, adverse effects, and outcomes ( Box 1 ).
Tumor Characteristics
High-grade tumors with risk of recurrence/progression
No invasive component
No aberrant histology (micropapillary, small cell)
No T1 on prompt repeated TUR
Patient Characteristics
No active immunosuppression (eg, transplant)
Elderly okay
HIV (+) status okay
Personal history of tuberculosis okay
Technical Aspects
Give induction + maintenance (SWOG8507 protocol)
Minimize fluid intake in the hours before instillation
Start with empty bladder
Inspect voided urine for visible hematuria (routine urinalysis/dipstick not necessary)
Catheterize urethra atraumatically
Minimize lubricant (to avoid BCG clumping)
Avoid lidocaine (acidity degrades BCG)
No need for rotisserie-style turning
Statins/aspirin therapy okay to continue
Use antispasmodics for local symptoms
Use antipyretics for influenza-like symptoms
Give 1 dose of quinolone 6 hours after BCG
Admit suspected BCGosis/BCG sepsis for prompt workup and aggressive therapy
Introduction
As discussed throughout this issue, bladder cancer represents a significant physical and emotional burden to patients as well as a substantial financial burden to society (see the article by James and colleagues elsewhere in this issue). For patients at the extremes of risk, treatment algorithms are relatively straightforward; yet the outcomes are variable. Within the spectrum of non-muscle invasive bladder cancer (NMIBC), for patients with the lowest-risk tumors, the mainstay of treatment is complete transurethral resection (TUR) followed by surveillance (see the article by O’Neil and colleagues elsewhere in this issue); for patients with the most advanced risk tumors, radical cystectomy may be the only viable option (see the article by Daneshmand elsewhere in this issue). Among the areas of greatest uncertainty within the discipline of bladder cancer is the management of patients with NMIBC thought to have a high risk of recurrence and/or intermediate-to-high risk of progression. In this setting, intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the current gold standard therapy with the highest response rates; however, despite its frequent use, it remains poorly understood, resulting in usage that is far from optimal.
In this article, the authors review the role that BCG has played in the management of bladder cancer over the last several decades and discuss specific approaches to optimize BCG. They focus on selection strategies to help practitioners identify candidates most likely to respond to BCG as well as on technical strategies to enhance the administration of the drug in such a way as to optimize the response rates, adverse effects, and outcomes ( Box 1 ).
Tumor Characteristics
High-grade tumors with risk of recurrence/progression
No invasive component
No aberrant histology (micropapillary, small cell)
No T1 on prompt repeated TUR
Patient Characteristics
No active immunosuppression (eg, transplant)
Elderly okay
HIV (+) status okay
Personal history of tuberculosis okay
Technical Aspects
Give induction + maintenance (SWOG8507 protocol)
Minimize fluid intake in the hours before instillation
Start with empty bladder
Inspect voided urine for visible hematuria (routine urinalysis/dipstick not necessary)
Catheterize urethra atraumatically
Minimize lubricant (to avoid BCG clumping)
Avoid lidocaine (acidity degrades BCG)
No need for rotisserie-style turning
Statins/aspirin therapy okay to continue
Use antispasmodics for local symptoms
Use antipyretics for influenza-like symptoms
Give 1 dose of quinolone 6 hours after BCG
Admit suspected BCGosis/BCG sepsis for prompt workup and aggressive therapy
History of BCG
The history of BCG dates back to the mid-1800s when scientists identified Mycobacterium bovis as the causative agent for bovine tuberculosis. Extrapolating from the successful use of the cowpox agent to develop a highly effective vaccine against smallpox in humans, clinical trials were performed in the late 19th century using M bovis to prevent tuberculosis in humans. Unfortunately, M bovis was proven to be highly virulent in people, and the approach was quickly abandoned.
Several decades later, in 1908, a French bacteriologist, Albert Calmette and a veterinarian, Camille Guérin observed that incubation of M bovis in a glycerin-bile-potato medium rendered the bacteria slightly less virulent. Over the next 13 years, they serially passaged the bacteria 231 times, and in 1920 ultimately obtained a strain of M bovis that was avirulent in both animals and people. This unique strain came to be known as bacillus of Calmette and Guérin (BCG).
Clinical trials using BCG as a vaccine against tuberculosis were initiated in 1921 but were not met with enthusiasm. Several early catastrophic events caused by cross-contamination with pathogenic strains led to public distrust of the agent. In one particularly disastrous situation in 1930 in Lübeck, Germany, 240 infants vaccinated shortly after birth all developed tuberculosis, and 72 of these newborns died. After several decades of disuse, widespread BCG vaccination was once again implemented outside of North America to minimize the postwar increase in tuberculosis expected after World War II. In the United States, BCG vaccination has never been widely adopted.
In the last half century, there has been renewed interest in the application of BCG to the management of patients with various medical disorders. As a potent stimulus of the immune system, BCG has been studied as a treatment option for diabetes mellitus, multiple sclerosis, and Parkinson disease.
In the field of oncology, the first hint that BCG may have a therapeutic role was present in 1929 when Pearl, a pathologist, observed that tuberculosis patients had fewer malignancies than patients who died of other diseases. In the recent era, BCG has been studied to varying degrees in colorectal cancer, lung cancer, and melanoma. Far and away, the most successful reapplication of BCG in the developed world has been in the field of bladder cancer.
The initial work suggesting a role for BCG within the bladder was performed in 1966 by Coe and Feldman, who demonstrated a consistent and potent T-helper type 1 immune response in pig bladders exposed to intravesical BCG. 10 years later, Morales reported that 9 patients with superficial bladder cancer experienced a decrease in rate of tumor recurrence after intradermal and intravesical treatment with the Armand-Frappier strain of BCG. This led to a prospective, randomized clinical trial in 1980 that confirmed the beneficial findings of the smaller initial report. In this clinical trial, Lamm and colleagues demonstrated that treatment with a single percutaneous injection followed by 6 weekly intravesical administrations of BCG led to a decreased tumor recurrence rate at 1 year.
Since this initial trial, multiple investigators have undertaken larger trials aimed at more clearly identifying the optimal route, dosing, and scheduling parameters of BCG for patients with superficial bladder cancer. These refinements form the basis of current guidelines concerning the optimal use of BCG in the management of bladder cancer and are discussed further in the following sections. In fact, when BCG is used optimally, it has a definite role in reducing progression and deaths from bladder cancer.
Optimizing patient selection for BCG therapy
As with all cancer therapies, successful use of BCG is critically dependent on careful patient selection. For patients with NMIBC, the 2 main indications for the use of BCG are: adjunctive therapy to reduce the recurrence (and progression) of tumors after complete surgical resection of high-grade T a or T 1 papillary tumors, and ii) primary treatment of carcinoma in situ (CIS).
Tumor Characteristics
For patients with low-grade papillary tumors, BCG therapy is typically not recommended, because, the most patients can be managed with surgical resection (plus or minus single-shot postoperative intravesical chemotherapy) alone. BCG has been used to treat residual tumor in patients with a high volume of disease within the bladder where surgical resection was deemed unachievable and/or for patients medically unfit for any operative procedures with complete response rates up to 66% and partial response rates up to 21%. In general, however, complete endoscopic control is recommended before BCG instillation.
For patients with muscle-invasive disease, there is currently no standard role for BCG; the use of BCG or any other intravesical therapy limited to the mucosal surface should be considered insufficient. In 1 report of 13 patients with muscle invasive bladder cancer treated with BCG, only 1 of 13 patients had neither local nor systemic disease recurrence; 10 of 13 patients developed systemic disease, and 7 patients died from metastases. The delay to removal of the bladder that these intravesical therapies impose can have disastrous consequences for patients.
Similarly, for patients with high-risk histologic variants of bladder cancer, BCG therapy may not be sufficient even if the tumors are superficial at diagnosis. For example, in patients found to have micropapillary architecture, the risk of early spread to regional lymph nodes or distant sites is sufficiently high to make conservative local therapy unsafe. For patients with small cell histology or features of neuroendocrine differentiation, the propensity for early microscopic metastases also argues against the use of BCG and other conservative intravesical therapies.
Given the efficacy of BCG in superficial urothelial tumors and the danger of BCG in muscle-invasive tumors and high-risk histologic variants, it is critical to accurately establish the true stage of any bladder tumor before deciding on therapy. Current guidelines recommend a repeat TUR for all patients with T 1 bladder cancer. This is discussed in more detail by Ritch and colleagues elsewhere in this issue, but the guiding principle before intravesical therapy with BCG should be removal of all cancerous tissue, where feasible.
From the specific perspective of optimization of BCG, data from repeat TUR can help stratify patients into those at higher and lower risk of response to BCG. For example, data from Memorial Sloan Kettering Cancer Center (MSKCC) suggest that patients with initial T 1 disease found to have no tumor or stage less than or equal to T a on repeat resection have a 19% chance of progression to muscle-invasive disease within 5 years, whereas those patients with evidence of continued T 1 disease at repeat TUR have an 80% chance of progression to muscle-invasive disease within 5 years. While these data are colored with the particular referral biases (and no use of maintenance), it nonetheless provides an impetus to use the repeat TUR data as 1 variable in discussions with patients.
Given the important prognostic information that can be gained from a second TUR, the authors’ practice is to perform repeat TUR at 4 to 6 weeks on all patients with T 1 bladder cancer being considered for intravesical therapy. In those patients who have had a complete TUR at the first setting and yet have T 1 disease at repeat TUR (ie, early recurrence of aggressive disease), the authors counsel the patients on the potential high failure rate of BCG and the benefit of early radical cystectomy. However, this does not apply to delayed repeat TUR or repeat TUR where the quality of initial TUR is suspect.
Location of tumor within the bladder may also help predict response to BCG. Tumors located in the prostatic urethra may not have adequate exposure to BCG during instillation and may thus have worse outcomes. In these patients, it is the authors’ practice to perform a limited TUR of prostate several weeks before initiation of BCG to facilitate surface contact of the medication with the urothelium of the prostatic urethra.
Patient Characteristics
Aside from staging and histologic concerns, patient selection must also be optimized. Because BCG is a live attenuated bacterium that exerts its effects primarily via a T H 1-driven response, the patient’s immune status is highly relevant. Patients on active immunosuppressive medications following organ transplantation should be considered for BCG therapy only in select cases. Besides the risk from an infective viewpoint, the intense immunostimulatory cytotoxic response evoked by BCG may place the transplanted organ at risk of rejection.
Patients who are very elderly or have poor performance status may have weakened immune systems, but they are still eligible to receive BCG. Although this immunosenescence is not a contraindication to BCG therapy, it may blunt the ability of BCG to evoke a sufficient immunostimulatory response. Patients with a history of human immunodeficiency virus (HIV) infection can usually also be safely treated with BCG. Given that most patients with HIV in the current era have intact immune systems, their bladder cancer can be managed the same as other patients, and similar outcomes can be expected.
Lastly, some practioners mistakenly exclude patients with a personal history of tuberculosis from consideration for BCG therapy. Although there are no data specifically examining this, the authors and others have successfully treated these patients with BCG therapy. In fact, recent data suggest that pre-BCG priming enhances the response of patients. However, given the prior exposure of these patients’ immune systems to mycobacterial antigens, clinicians should be particularly vigilant about optimizing delivery with respect to the reduction of adverse effects.
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