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.

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosal damage and dysregulated intestinal barrier functions. Restoration of barrier functionality by mucosal healing or physical barrier protecting strategies shall be considered as an initial event in the disease suppression and progression. Herein, a biphasic hyaluronan (HA) enema suspension, naïve-HA systems that protect the dysregulated gut epithelium by decreasing the inflammation, permeability, and helping in maintaining the epithelial barrier integrity in the dextran sodium sulfate-induced colitis mice model is reported. Furthermore, HA-based system modulates intestinal epithelial junctional proteins and regulatory signaling pathways, resulting in attenuation of inflammation and mucosal protection. The results suggest that HA-based system can be delivered as an enema to act as a barrier protecting system for managing distal colonic inflammatory diseases, including colitis.

[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.

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.

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.

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.

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.

Manufacturing and the Market: Rationalizing the Shortage of Bacillus Calmette-Guérin.

Bacillus Calmette-Guérin (BCG) is used as first-line intravesical therapy following tumor resection of non-muscle-invasive bladder cancer. Primary producers of BCG announced shortages within the last decade, leading to a worldwide shortage. We review the literature examining the BCG shortage and propose solutions to cope with this problem.

Availability and Patterns of Intravesical BCG Instillations.

PURPOSE: Intravesical BCG instillations improve recurrence free survival in patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: This is a national survey study, covering 223 urological centres, aimed at reliable identification of BCG availability and implemented treatment patterns. RESULTS: Response rate was 93.7%. BCG was used in 56.5% of urological departments. Another 22.7% referred patients to other hospitals for instillations, while 20.8% did not recommend BCG at all. The most common indications for BCG instillations were as follows: T1 tumours (88.5%), carcinoma in situ (83.6%) and high grade tumours (73.8%). Maintenance therapy was routinely abandoned in 16.4% of centres or was scheduled for <1 year, 1 year, 3 years and 1-3 years in 6.6%, 19.7%, 21.3% and 31.2% of centres, respectively. Continuation of BCGdespite treatment failure in carcinoma in situ cases was considered in 21.3% of departments. CONCLUSION: Our findings indicate that BCG is underused, while patterns of maintenance and follow-up are suboptimal.

Steve Reed. Interviewed by Charlotte Schubert.

Steve Reed believes the organization he has founded has the potential to radically increase the developing world's access to vaccines for neglected diseases. The efforts of the Seattle-based Infectious Disease Research Institute (IDRI), which operates as a not-for-profit biotech company, may start to pay off during the H1N1 'swine' flu pandemic. IDRI developed an adjuvant to boost the effectiveness and supplies of flu vaccines and is making the technology available to vaccine manufacturers in developing nations. Charlotte Schubert talks to Reed about how IDRI, a 90-person operation with a $19 million annual budget, could have such a big impact.