Bacille-Calmette-Guerin Non-Responders: How to Manage
Bacille-Calmette-Guerin Non-Responders: How to Manage
Intravesical immunotherapy with bacille-Calmette-Guerin (BCG) is indicated in the treatment of high-risk and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Our goal is to describe the various disease states following induction and maintenance BCG and to describe contemporary treatment options and the current and projected clinical trial landscape for patients who recur following BCG therapy.
The definition of bacille-Calmette-Guerin (BCG) failure must be specified in the context of previous treatments and the time interval of recurrence. Valrubicin is the only FDA approved intravesical agent in this setting and the approval is restricted to patients with BCG refractory carcinoma in situ (CIS) and those who refuse or are not medically fit to undergo radical cystectomy. There are multiple other intravesical therapies available for these patients as well as others with Ta or T1 papillary urothelial cancer. Device assisted treatments designed to improved chemotherapy delivery are another option but await approval in the US. Ongoing clinical trials are testing strategies to augment the immune response including pre-treatment BCG vaccination, immune checkpoint inhibition, gene therapy and other novel delivery systems, targeted agents (e.g., FRFR3 inhibitors) and combination intravesical therapy (Table 1).
BCG is a live-attenuated mycobacterium originally developed as a vaccine against tuberculosis. Dr. Morales first demonstrated its therapeutic potential in bladder cancer in 1976. While the initial application for NMIBC included the co-administration of transdermal and intravesical BCG, the current standard of care is full dose induction intravesical therapy weekly for 6 weeks followed by maintenance therapy.
BCG is approved by the US Food and Drug Administration for treatment of patients with CIS and high-grade papillary Ta and T1 urothelial bladder cancer. Meta analyses of EORTC trials suggest that BCG with maintenance is also an option for treatment of patients with multifocal and or recurrent or large solitary Ta and T1 low-grade disease.
In the current management of NMIBC at least eight different BCG strains are being used which all have been derived from the original BCG strain which was created from the attenuation experiments by Drs. Calmette and Guerin in 1921 at the Pasteur Institute in Lille, France. When the lyophilized form of BCG entered into mass production in 1961, the dispersion caused a drift in the genotype and with resulting substrains that were named after their site of origin and the manufacturer. The strains that are most commonly used are TICE (Chicago) and Connaught (Toronto). With a manufacturing shortage of the latter, the TICE strain is the most commonly available BCG strain at this time.
A Japanese study compared the efficacy of intravesical BCG with the Tokyo strain or the Connaught strain in a randomized study in 133 patients without prior intravesical treatment. The complete response (CR) rate was 90.3% and 85.0% respectively, which was not statistically significantly different. Despite randomization significantly more patients with CIS were allocated to the Tokyo BCG arm.
A recent single center randomized clinical trial reported a significant superiority in the treatment of NMIBC with BCG Connaught versus BCG TICE significantly improving 5-year recurrence-free survival. This has been attributed to a more effective TH-1 immune response as shown in in vitro experiments in mice. A genomic analysis reported in the same study, demonstrated significant differences in the mutation patterns between the strains. While the trial has many limitations in design and power, it raises a provocative question regarding the potential that BCG strain differences may affect relative efficacy in the absence of maintenance BCG. The drift in the genome of BCG has been comprehensively studied as a potential modulator of vaccine efficacy. Investigators hypothesize that early BCG strains may be more effective than BCG strains widely used today likely due to independent tandem duplications (DU1 and DU2).
The AUA, EAU, and NCCN guidelines recommend treatment with BCG for high-grade non-muscle invasive cancer including Ta high grade, CIS and/or T1 high-grade disease, which do not meet the criteria for a primary cystectomy. BCG has been shown to have a durable response rate of about 50% over a median follow-up of 4 years but this number drops to only 30% of patients who are free of tumor recurrence or progression at 10 years. Level I evidence supports the use of full dose BCG plus 3 years of maintenance treatment in patients with high risk disease and meta-analyses suggest that BCG is superior to Mitomycin or Epirubicin for intermediate risk disease but only when administered with maintenance treatment.
SWOG 8507 randomized patients with high-risk disease to BCG induction alone vs. induction plus maintenance BCG for 3 years. Maintenance BCG was associated with both reduced recurrence and disease worsening defined as biopsy proven invasive cancer or a change in treatment strategy implying progression or worsening of the disease state. Five-year RFS was 60% vs. 41% with and without maintenance treatment. EORTC 30962 compared low dose vs. high dose and 1- vs. 3-year maintenance therapy in a non-inferiority trial design. While the trial failed to meet the primary endpoint, subset analyses in patients with high-risk disease confirmed the requirement for full dose and 3 years of maintenance and suggested that patients with intermediate-risk disease could be treated with 1 year of maintenance therapy with a similar efficacy as 3 years of maintenance.
The foremost challenge for the urologist who manages patients on BCG is to recognize and accurately define BCG failure and to determine the optimal treatment strategy. Failure to intervene with definitive radical cystectomy prior to progression to muscle invasive cancer is associated with a significant reduction in long-term survival probability. The definition of BCG non-responders has been modified over time. O'Donnell et al. have recommended the following categories: intolerance to BCG describes the inability of a patient to tolerate side effects from the treatment. Resistance to BCG refers to a recurrence or persistence of bladder cancer at 3 months after the first induction cycle but of lesser degree (stage or grade), which is absent at 6 months after either a re-induction cycle of 6 weeks or a first maintenance cycle of 3 weeks. Patients are refractory to BCG when there is persistent disease after a second course of BCG (either maintenance or second induction course). This also includes any progression or worsening of the tumor with regards to stage, grade and disease extent by 3 months after the first cycle of BCG. Formerly called BCG relapse refers to a recurrence of the disease after initial achievement of a disease free state within 6 months of initiation of treatment. A recurrence may be classified as early (within 12 months), intermediate (12–24 months) or late (>24 months). The 2013 FDA/AUA Workshop on clinical trial design in NMIBC expanded the patient population defined as BCG refractory to include those treated with two induction courses or induction plus 3 weeks of maintenance and fail to achieve a CR within 6 months of initiation of BCG. The FDA has also considered including patients who recur within 6 months after an initial CR. Single arm phase II trials may be considered for registration with this expanded patient population. Patients who recur with T1HG after an initial induction course may also be included in this group considered BCG unresponsive. BCG failure is a unique subset of patients with persistent TaHG or CIS after a single induction course of BCG or recurrent disease more than 1 year after an initial CR. Phase III trials comparing BCG to BCG plus an experimental drug should be considered in this patient population.
Abstract and Introduction
Abstract
Intravesical immunotherapy with bacille-Calmette-Guerin (BCG) is indicated in the treatment of high-risk and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Our goal is to describe the various disease states following induction and maintenance BCG and to describe contemporary treatment options and the current and projected clinical trial landscape for patients who recur following BCG therapy.
Introduction
The definition of bacille-Calmette-Guerin (BCG) failure must be specified in the context of previous treatments and the time interval of recurrence. Valrubicin is the only FDA approved intravesical agent in this setting and the approval is restricted to patients with BCG refractory carcinoma in situ (CIS) and those who refuse or are not medically fit to undergo radical cystectomy. There are multiple other intravesical therapies available for these patients as well as others with Ta or T1 papillary urothelial cancer. Device assisted treatments designed to improved chemotherapy delivery are another option but await approval in the US. Ongoing clinical trials are testing strategies to augment the immune response including pre-treatment BCG vaccination, immune checkpoint inhibition, gene therapy and other novel delivery systems, targeted agents (e.g., FRFR3 inhibitors) and combination intravesical therapy (Table 1).
BCG is a live-attenuated mycobacterium originally developed as a vaccine against tuberculosis. Dr. Morales first demonstrated its therapeutic potential in bladder cancer in 1976. While the initial application for NMIBC included the co-administration of transdermal and intravesical BCG, the current standard of care is full dose induction intravesical therapy weekly for 6 weeks followed by maintenance therapy.
BCG is approved by the US Food and Drug Administration for treatment of patients with CIS and high-grade papillary Ta and T1 urothelial bladder cancer. Meta analyses of EORTC trials suggest that BCG with maintenance is also an option for treatment of patients with multifocal and or recurrent or large solitary Ta and T1 low-grade disease.
In the current management of NMIBC at least eight different BCG strains are being used which all have been derived from the original BCG strain which was created from the attenuation experiments by Drs. Calmette and Guerin in 1921 at the Pasteur Institute in Lille, France. When the lyophilized form of BCG entered into mass production in 1961, the dispersion caused a drift in the genotype and with resulting substrains that were named after their site of origin and the manufacturer. The strains that are most commonly used are TICE (Chicago) and Connaught (Toronto). With a manufacturing shortage of the latter, the TICE strain is the most commonly available BCG strain at this time.
A Japanese study compared the efficacy of intravesical BCG with the Tokyo strain or the Connaught strain in a randomized study in 133 patients without prior intravesical treatment. The complete response (CR) rate was 90.3% and 85.0% respectively, which was not statistically significantly different. Despite randomization significantly more patients with CIS were allocated to the Tokyo BCG arm.
A recent single center randomized clinical trial reported a significant superiority in the treatment of NMIBC with BCG Connaught versus BCG TICE significantly improving 5-year recurrence-free survival. This has been attributed to a more effective TH-1 immune response as shown in in vitro experiments in mice. A genomic analysis reported in the same study, demonstrated significant differences in the mutation patterns between the strains. While the trial has many limitations in design and power, it raises a provocative question regarding the potential that BCG strain differences may affect relative efficacy in the absence of maintenance BCG. The drift in the genome of BCG has been comprehensively studied as a potential modulator of vaccine efficacy. Investigators hypothesize that early BCG strains may be more effective than BCG strains widely used today likely due to independent tandem duplications (DU1 and DU2).
The AUA, EAU, and NCCN guidelines recommend treatment with BCG for high-grade non-muscle invasive cancer including Ta high grade, CIS and/or T1 high-grade disease, which do not meet the criteria for a primary cystectomy. BCG has been shown to have a durable response rate of about 50% over a median follow-up of 4 years but this number drops to only 30% of patients who are free of tumor recurrence or progression at 10 years. Level I evidence supports the use of full dose BCG plus 3 years of maintenance treatment in patients with high risk disease and meta-analyses suggest that BCG is superior to Mitomycin or Epirubicin for intermediate risk disease but only when administered with maintenance treatment.
SWOG 8507 randomized patients with high-risk disease to BCG induction alone vs. induction plus maintenance BCG for 3 years. Maintenance BCG was associated with both reduced recurrence and disease worsening defined as biopsy proven invasive cancer or a change in treatment strategy implying progression or worsening of the disease state. Five-year RFS was 60% vs. 41% with and without maintenance treatment. EORTC 30962 compared low dose vs. high dose and 1- vs. 3-year maintenance therapy in a non-inferiority trial design. While the trial failed to meet the primary endpoint, subset analyses in patients with high-risk disease confirmed the requirement for full dose and 3 years of maintenance and suggested that patients with intermediate-risk disease could be treated with 1 year of maintenance therapy with a similar efficacy as 3 years of maintenance.
The foremost challenge for the urologist who manages patients on BCG is to recognize and accurately define BCG failure and to determine the optimal treatment strategy. Failure to intervene with definitive radical cystectomy prior to progression to muscle invasive cancer is associated with a significant reduction in long-term survival probability. The definition of BCG non-responders has been modified over time. O'Donnell et al. have recommended the following categories: intolerance to BCG describes the inability of a patient to tolerate side effects from the treatment. Resistance to BCG refers to a recurrence or persistence of bladder cancer at 3 months after the first induction cycle but of lesser degree (stage or grade), which is absent at 6 months after either a re-induction cycle of 6 weeks or a first maintenance cycle of 3 weeks. Patients are refractory to BCG when there is persistent disease after a second course of BCG (either maintenance or second induction course). This also includes any progression or worsening of the tumor with regards to stage, grade and disease extent by 3 months after the first cycle of BCG. Formerly called BCG relapse refers to a recurrence of the disease after initial achievement of a disease free state within 6 months of initiation of treatment. A recurrence may be classified as early (within 12 months), intermediate (12–24 months) or late (>24 months). The 2013 FDA/AUA Workshop on clinical trial design in NMIBC expanded the patient population defined as BCG refractory to include those treated with two induction courses or induction plus 3 weeks of maintenance and fail to achieve a CR within 6 months of initiation of BCG. The FDA has also considered including patients who recur within 6 months after an initial CR. Single arm phase II trials may be considered for registration with this expanded patient population. Patients who recur with T1HG after an initial induction course may also be included in this group considered BCG unresponsive. BCG failure is a unique subset of patients with persistent TaHG or CIS after a single induction course of BCG or recurrent disease more than 1 year after an initial CR. Phase III trials comparing BCG to BCG plus an experimental drug should be considered in this patient population.