Critical shortage in BCG immunotherapy: How did we get here and where will it take us?

Intravesical Bacillus Calmette-Guérin vaccine, one of the most successful bio-therapies to date, has been the gold standard treatment for non-muscle invasive bladder cancer for 44 years. International shortages have necessitated rationing this life-saving medication with deleterious effects on the primary treatment of high-grade non-muscle invasive bladder cancer. Understanding the history of intravesical Bacillus Calmette-Guérin gives us insight into the current shortages and future perspectives for novel immunotherapy opportunities against this deadly disease.

Epidemiology of childhood tuberculosis after ceasing universal Bacillus Calmette-Guérin vaccination.

Universal Bacillus Calmette-Guérin (BCG) vaccination is recommended in countries with high tuberculosis (TB) burden. Nevertheless, several countries have ceased universal BCG vaccination over the past 40 years, with scarce comparative epidemiological analyses regarding childhood TB after the policy change. We analysed data on childhood TB in countries that ceased universal BCG vaccination. Data sources included national/international databases, published papers, annual TB reports, and public health authority websites. Childhood TB notification rate increased in one of seven countries with available data. Pulmonary TB and TB lymphadenitis were the main causes of increasing childhood cases, while changes in severe forms of TB cases were minor. Maintaining high vaccine coverage for the target group was a common challenge after shifting selective vaccination. In some countries showing no increase in childhood TB after a BCG policy change, the majority of childhood TB cases were patients from abroad or those with overseas parents; these countries had changed immigration policies during the same period. Heterogeneity in childhood TB epidemiology was observed after ceasing universal BCG vaccination; several factors might obscure the influence of vaccination policy change. Lessons learned from these countries may aid in the development of better BCG vaccination strategies.

[BCG strain shortage from 2012 to 2014: Evaluation of its impact on the management of patients with high-risk NMIBC]. / Pénurie en souche de BCG entre 2012 et 2014 : évaluation de son impact sur la prise en charge des patients présentant une TVNIM de haut risque.

INTRODUCTION: BCG instillations are the gold-standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) with a decreased risk of tumor recurrence and muscle infiltration. From 2012 to 2014, a stock shortage of the Connaught strain has led to the cessation of supply for immucyst in France. The objective of this study was to evaluate the potential impact of BCG shortage on the management of patients with NMIBC. PATIENTS AND METHODS: We conducted a retrospective single-center study including patients followed from May 2005 to May 2015 with a high-risk NMIBC (primo-diagnosis). Patients were separated into two groups: not impacted by the shortage (NISG: 56 patients) and impacted by the shortage (ISG: 53 patients). Data on tumour recurrence (RFS), muscle progression (PFS) and overall and specific survival (OS and SS) were also analysed. RESULTS: The BCG induction schedule could not be carried out in 20.8% of cases in the ISG compared to only 5.3% of cases in NISG (P=0.02). Similarly, the maintenance treatment was incomplete for 56.6% of cases versus 37.5% in NISG (P=0.047). Nevertheless, it should be underlined that very high-risk NMIBC received a complete induction BCG schedule. The ISG seems to have benefited with the evolution of the guidelines with the use of diagnosis bladder fluorescence but without significant difference on the rate of second look bladder trans-uretral resection. The cystectomy rate was higher in ISG. No significant difference in RFS, PFS, OS, and SS between the two groups. CONCLUSION: In our experience, RFS, PFS, OS or SS were not impacted by the BCG shortage. These data may be explained by a better selection of very high-risk patients including the recommended BCG schedule and more frequently the use of diagnosis bladder fluorescence. LEVEL OF EVIDENCE: 3.

Recurrence Rate and Cost Consequence of the Shortage of Bacillus Calmette-Guérin Connaught Strain for Bladder Cancer Patients.

BACKGROUND: Between 2013 and 2016, global production of bacillus Calmette-Guérin (BCG) was dramatically reduced due to the collapse of the factory producing BCG Connaught. OBJECTIVE: To evaluate the clinical and economic impact of BCG shortage on a cohort of non-muscle-invasive bladder cancer (NMIBC) patients treated during the period of restricted supply. DESIGN, SETTING AND PARTICIPANTS: This retrospective, before and after, cost-consequence study included patients with intermediate- and high-risk NMIBC. Those resected between November 2011 and September 2013 (control group) were compared with those resected between October 2013 and December 2016 (study group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of tumor recurrence from 30 d after transurethral resection to the end of follow-up at 24 mo; the secondary endpoints included the average cost of primary treatment, average cost of treatment of recurrence, and excess cost due to BCG shortage per patient. RESULTS AND LIMITATIONS: A total of 402 patients were included: 191 in the control group and 211 in the study group. The rate of recurrence at 24 mo was significantly higher in the study group than in the control group (46.9% vs 16.2%; relative risk: 0.7, 95% confidence interval [0.60; 0.82]; p < 0.001). The increased cost due to the decrease in BCG production was estimated to be €783 per patient with a new diagnosis of NMIBC during the period of restricted supply. This is a retrospective analysis at the level of our unit. A more precise evaluation would require a study of a larger cohort of patients. CONCLUSIONS: The shortage of BCG between October 2013 and December 2016 had a significant medical and economic impact; there was an increased rate of bladder cancer recurrence, and the total cost of care for intermediate- and high-risk NMIBC was higher. PATIENT SUMMARY: In this report, we analyzed the medical and economic impact of bacillus Calmette-Guérin (BCG) shortage that occurred between 2013 and 2016. We found a significant increase of bladder cancer recurrence and progression, and an increase in the number of patients who had to be treated by cystectomy. BCG shortage also had a significant impact on the total cost. Since there are no alternatives to BCG for high-risk non-muscle-invasive bladder cancer patients, BCG production has to be maintained by any means.

Contemporary Treatment Patterns for Non-muscle-invasive Bladder Cancer: Has the Use of Radical Cystectomy Changed in the BCG Shortage Era?

OBJECTIVE: To examine recent treatment trends for non-muscle-invasive bladder cancer (NMIBC), and specifically, to assess whether there was a change in use radical cystectomy (RC) between 2008 and 2015 using data from the Surveillance, Epidemiology, and End Results database. METHODS: We identified patients presenting with high-grade T1 (T1HG) NMIBC at diagnosis during the study period. Treatment was dichotomized into "RC" and "local treatment" (which included transurethral resection and intravesical therapies). We then employed multivariable logistic regression models to assess the odds of undergoing RC across the study period. Additionally we examined the rates of RC for T1HG NMIBC during the period of BCG-shortage, defined as 2012-2015. RESULTS: We identified 21,817 individuals diagnosed with T1HG bladder cancer during the study period. The majority of patients underwent local treatment (94.5%). During the shortage period, the rate of RC for T1HG NMIBC was significantly lower compared to the preshortage era (5.1% vs 5.9%, P = .007). Across the study period, the utilization of RC for T1HG NMIBC decreased significantly (odds ratio 0.99 per quarter, 95% confidence interval 0.98-0.99, P = .017). CONCLUSION: In our cohort of patients diagnosed with T1HG bladder cancer, we found a significant decrease in the use of radical cystectomy across the study period. Contrary to the hypothesis of increasing rates of RC in the face of BCG shortage, the rate of RC was significantly higher in the pre-shortage era. Further examination of NMIBC treatment patterns will be necessary to assess the impact of BCG availability on therapeutic pathways and oncologic outcomes in patients with high-grade NMIBC.

BCG versus COVID-19: impact on urology.

PURPOSE: To search for evidence base for using BCG in the fight against COVID-19 and the possible impact of these clinical trials on urology practice. METHODS: A literature review about the basis of the ongoing clinical trials using BCG against COVID-19, as well as the use of BCG in urology and if there are any implications of these trials on our practice. RESULTS: Based on data from some epidemiological studies, there are some current clinical trials on the use BCG as a possible prophylactic vaccine against SARS CoV-2 which can affect urology practice. Urologists are already struggling with the global shortage of BCG which can be even more aggravated by such trials. In addition, if the ongoing trials proved the efficacy of BCG as a prophylaxis against COVID-19, this may open the door to more urological research opportunities to question the possibility that intra-vesical BCG, given its systemic immunologic effect, may have been protective to this subgroup of urological patients. CONCLUSION: The ongoing clinical trials using BCG against COVID-19 can affect our urology practice. We need to stay vigilant to such impacts: BCG shortage and possible new chances for urology research work.

Association of Bacillus Calmette-Guerin shortages with bladder cancer recurrence: A single-center retrospective study.

OBJECTIVE: To examine the association between Bacillus Calmette-Guerin (BCG) shortage and bladder cancer recurrence in high-risk non-muscle-invasive bladder cancer (NMIBC) patients. MATERIALS AND METHODS: This retrospective study included 333 BCG-naive patients who underwent transurethral resection of bladder tumor for high-risk NMIBC between January 2014 and December 2017. The primary outcome was disease recurrence after operation. The secondary outcomes were trends in BCG shortages and differences in post-transurethral resection of bladder tumor intravesical treatments according to shortage. Multivariable Cox regression modeling was used to assess outcomes. RESULTS: Among 333 patients (median age, 67 years; men, 270 [81.1%]), 94 (28.2%) experienced BCG shortage (BCG shortage group). Eleven episodes of BCG shortage occurred during the study period (median 10 days, range 2-97 days). Although we observed no statistically significant differences in clinical and pathological characteristics, there were significant differences in post-transurethral resection of bladder tumor intravesical treatments between the shortage and control groups (BCG: 28.7% vs. 68.1%, mitomycin/epirubicin: 27.7% vs. 1.7%, P < 0.001). The 3-year recurrence-free survival rate was significantly lower in the shortage group than that in the control group (38.0% vs. 60.2%, log-rank test, P = 0.010). In multivariable analysis, shortage (hazard ratio [HR] = 1.55, 95% confidence interval [CI] 1.09-2.21, P = 0.016) and tumor multiplicity (HR = 1.55, 95% CI 1.05-2.29, P = 0.028) were independent factors associated with the recurrence of bladder cancer. CONCLUSIONS: High-risk NMIBC patients who experienced BCG shortage had a high risk of bladder cancer recurrence. Clinical trials of alternative treatment strategies and efforts to increase BCG supply are required.

COVID-19 and Bacillus Calmette-Guérin: What is the Link?

The debate around the role of vaccination with Bacillus Calmette-Guérin has revived right in the time of the Coronavirus disease 19 pandemic. Since Bacillus Calmette-Guérin is one of the most commonly delivered therapies in urology, in this editorial we discuss some points that we think will be of interest and guidance to practicing urologists during this public health emergency.

Treatment options and results of adjuvant treatment in nonmuscle-invasive bladder cancer (NMIBC) during the Bacillus Calmette-Guérin shortage.

PURPOSE OF REVIEW: Given the worldwide shortage of Bacillus Calmette-Guérin (BCG), we review the efficacy of alternative BCG application schedules, doses or strains and intravesical chemotherapy in patients with nonmuscle-invasive bladder cancer (NMIBC). RECENT FINDINGS: Modifying BCG schedules by reducing the dose is preferable to reducing the frequency of BCG that increases recurrence rates and should be avoided if possible. Changing the BCG substrain represents a reasonable option, as current evidence does not suggest different oncological outcomes with specific BCG substrains. Mitomycin C (MMC) alone is inferior to BCG with maintenance, but promising results have been demonstrated when used with chemohyperthermia and electromotive drug administration. Several other intravesical chemotherapies including Gemcitabine and Epirubicin should be used when both BCG and MMC are in short supply. SUMMARY: In case of BCG shortage, much will depend on the severity and length of the BCG shortage, but our review supports several solutions: First, we recommend contacting the local pharmacist or BCG supplier to consider alternative BCG strains or sterile splitting of BCG doses. In the complete absence of BCG, consideration should be given to MMC with chemohyperthermia or electromotive drug administration where available or other intravesical chemotherapy. High-risk patients should be considered for cystectomy.

Safety of the Polish BCG-10 Vaccine During a Period of BCG Vaccine Shortage: An Australian Experience.

Bacille Calmete-Guerin vaccine is widely administered to reduce the risk of severe tuberculosis disease in children. Recent global vaccine supply issues have led to the use of alternative products, which may vary in side effect profile. We report on the safety of the Polish (Moreau strain) "Bacille Calmete-Guerin-10" vaccine in an Australian cohort. Using active surveillance, we identified an adverse event rate of 54.6 per 10,000 doses (95% confidence interval: 38.5-75.2), which was comparable to that reported with the Danish Sanofi-Pasteur and Connaught strains.

Update on the guideline of guidelines: non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guérin shortage and immense novel therapy development.

Current situation, causes, and countermeasures to NIP vaccine shortages in Guangzhou, China.

From 2017 to 2018, Guangzhou experienced a shortage in 3-6 types of National Immunization Program (NIP) vaccines. To evaluate the current situation and causes of the NIP vaccine shortage, we analysed the duration, intensity and causes of the shortage from data in the vaccine information system of the Guangzhou Center for Disease Control and Prevention; we also proposed countermeasures to resolve the shortage. In 2017, there were shortages of three types of NIP vaccines in Guangzhou. The most affected vaccines were inactivated poliovirus (IPV) vaccine and meningococcal group AC (MenAC) vaccine, accounting for 39.5% and 16.5% of the reported shortages, respectively. In 2018, the shortage extended to six vaccine types; the most affected were diphtheria, tetanus and pertussis (DTP) vaccine, MenAC vaccine, and Bacille Calmette Guerin (BCG) vaccine. The four main causes for the shortage were: 1) an insufficient production capacity; 2) a delay in batch issuance; 3) vaccine-related events; and 4) an extended bidding procurement cycle. Four solutions are proposed: 1) expand production output; 2) exempt creditworthy enterprises from batch inspections; 3) establish alternative enterprises and emergency use authorizations; and 4) establish public health funds and stockpile storage systems.

Current Clinical Trials in Non-muscle-Invasive Bladder Cancer: Heightened Need in an Era of Chronic BCG Shortage.

PURPOSE OF REVIEW: BCG is the gold standard agent used in high-risk non-muscle-invasive bladder cancer (NMIBC) that is amenable to bladder sparing management. However, recent BCG shortages appear to be a chronic problem. There are limited effective intravesical options in lieu of BCG or in patients in whom BCG is not effective. This review aims to highlight emerging bladder sparing therapies and trials for NMIBC. RECENT FINDINGS: Patients with high-risk NMIBC who do not respond to BCG are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches including checkpoint inhibition, novel chemotherapy and drug delivery, viral and gene therapy, vaccines, and targeted therapy. In the era of limited supply of BCG, there is a need for both effective first-line alternatives as and options for patients who do not respond to BCG. Fortunately, there are a variety of active trials and mechanisms exploring these areas aggressively.

High-grade T1 Urothelial Carcinoma: Where Do We Stand?

PURPOSE OF REVIEW: Bladder cancer is a deadly and common malignancy, with 24% of new cases presenting as T1 disease. High-grade T1 in particular represents a difficult entity to treat due to its clinical variability and known risks of recurrence, progression, and cancer-specific mortality. The differences in guidelines from major urologic organizations underscore this variability, and the past year has seen another BCG shortage, further complicating management. Advances have been made in the molecular and genomic characterization of high-grade T1, and new clinical trials are available to investigate alternative therapies. In this review, we summarize the variations in guidelines, alternatives to BCG, emerging molecular and genomic discoveries, and recent clinical trials. RECENT FINDINGS: Adherence to guidelines for non-muscle-invasive bladder cancer in the community among practicing urologists remains low, in part due to the variations in available guidelines. In the era of a BCG shortage, decreased dosing schedules and alternative intravesical options are increasingly being used. New biomarkers are being discovered to better risk-stratify patients, with future therapies aimed at targeting aggressive disease. HGT1 urothelial carcinoma remains a highly variable and aggressive disease, but we are making significant progress in better characterizing the clinical and molecular factors that influence recurrence and progression, to better guide management.

Assessing the quality and accuracy of national immunization program reported target population estimates from 2000 to 2016.

BACKGROUND: A common means of vaccination coverage measurement is the administrative method, done by dividing the aggregated number of doses administered over a set period (numerator) by the target population (denominator). To assess the quality of national target populations, we defined nine potential denominator data inconsistencies or flags that would warrant further exploration and examination of data reported by Member States to the World Health Organization (WHO) and UNICEF between 2000 and 2016. METHODS AND FINDINGS: We used the denominator reported to calculate national coverage for BCG, a tuberculosis vaccine, and for the third dose of diphtheria-tetanus-pertussis-containing (DTP3) vaccines, usually live births (LB) and surviving infants (SI), respectively. Out of 2,565 possible reporting events (data points for countries using administrative coverage with the vaccine in the schedule and year) for BCG and 2,939 possible reporting events for DTP3, 194 and 274 reporting events were missing, respectively. Reported coverage exceeding 100% was seen in 11% of all reporting events for BCG and in 6% for DTP3. Of all year-to-year percent differences in reported denominators, 12% and 11% exceeded 10% for reported LB and SI, respectively. The implied infant mortality rate, based on the country's reported LB and SI, would be negative in 9% of all reporting events i.e., the country reported more SI than LB for the same year. Overall, reported LB and SI tended to be lower than the UN Population Division 2017 estimates, which would lead to overestimation of coverage, but this difference seems to be decreasing over time. Other inconsistencies were identified using the nine proposed criteria. CONCLUSIONS: Applying a set of criteria to assess reported target populations used to estimate administrative vaccination coverage can flag potential quality issues related to the national denominators and may be useful to help monitor ongoing efforts to improve the quality of vaccination coverage estimates.

Utilization of Bacillus Calmette-Guerin for Nonmuscle Invasive Bladder Cancer in an Era of Bacillus Calmette-Guerin Supply Shortages.

OBJECTIVES: To study trends in Bacillus Calmette-Guerin (BCG) utilization for nonmuscle invasive bladder cancer (NMIBC) before and during national BCG shortages. METHODS: The National Cancer Database was used to identify patients with localized NMIBC. Multivariate logistic regression was used to assess factors associated with BCG use. Temporal trends in BCG use were studied using segmented regression analysis. RESULTS: We identified 238,279 patients with NMIBC from 2004 to 2015. Overall, 33,660 (14.1%) patients with NMIBC received intravesical BCG during the study period. Segmented regression revealed a slower rate of rise of BCG utilization following major supply interruptions in 2011 and 2012 (2004-2012: +0.62% increase per year [P < .0001]; 2013-2015: +0.29% increase per year [P = .084]). This trend was most pronounced in Ta-low grade patients and least pronounced in T1-high grade patients. CONCLUSIONS: BCG utilization for NMIBC increased significantly over the study period, possibly representing increased adoption of national guidelines for BCG in NMIBC. In the years following interruptions in BCG supply, BCG use appears to have been rationed based on clinical risk, with the steepest declines in BCG use occurring in the lowest risk patients.

What to do during Bacillus Calmette-Guérin shortage? Valid strategies based on evidence.

PURPOSE OF REVIEW: Over the last decade, the world has experienced health-threatening supply shortages of Bacillus Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). We summarize the current literature to assist in treatment decisions in light of suboptimal supply. RECENT FINDINGS: Currently available data do not support a superiority of one BCG strain over the other. Intravesical chemotherapy seems to provide similar results in term of disease progression but not recurrence in intermediate-risk patients. One trial has shown that a 3-year maintenance course of BCG in high-risk NMIBC has no advantage in term of progression or overall survival in comparison with 1-year maintenance. Synergo radiofrequency-induced hyperthermia is a reliable alternative in intermediate or high-risk NMIBC with at least similar recurrence rates compared with BCG. SUMMARY: Patients with intermediate-risk NMIBC can be offered multiple instillations of intravesical chemotherapy for up to 12 months. In high-risk patients and in case of BCG shortage, BCG instillations can be terminated when the patient has completed 1 year of maintenance. Mitomycin C is an alternative in lowest risk high-risk (G3Ta) NMIBC, whereas patients with pT1/carcinoma in situ can be offered Synergo with mitomycin C when radical cystectomy is not feasible. Immediate radical cystectomy should always be considered in highest risk NMIBC after weighing up benefit to risk.