During the year 2012, there was a worldwide shortage of the Connaught strain of BCG (InmuCyst®) following a flood and the finding of mold in the sterile manufacturing facility in Toronto (Canada). Other manufacturers had to increase production in order to keep up with demand, leading to production related issues in other facilities such as Merck Sharp & Dohme Limited (Hertfordshire, United Kingdom) producer of OncoTICE (TICE strain) and Medac Laboratories (Wedel, Germany) producer of the RIVM strain.4
Worldwide BCG shortage has led to suboptimal courses administered to patients due to limited availability. Reducing both induction and maintenance schemes has been shown to be a clear risk factor for tumoral recurrence.5 In our center, BCG shortage and subsequent dose limitation started during the year 2019 allowing a total of nine instillations per patient (six induction doses and a total of three for maintenance).
We conducted a retrospective cohort study to study the effect of BCG shortage in bladder cancer patients treated in our institution. A total number of 158 subjects were analyzed, 64 treated during the 2019 shortage period were compared against another historical cohort of 94 patients treated during 2017 with full BCG availability. Median follow-up in the 2019 sample was 24 months and 50 months in the 2017 group with a median number of instillations of 8 and 12 respectively.
The primary endpoint was relapse free-survival time; defined as time to recurrence and/or progression to muscle invasive disease, metastatic disease or cancer-specific death. Secondary outcomes included specific recurrence and progression free survival rates and characteristics of tumoral relapse.
Median time to relapse of 285 days (145-448) during 2019 and 382 days (215-567) in 2017 were observed (logRank p=0.025). Further multivariable analysis revealed a proportional Hazard ratio (HR) for disease-free survival rate of 1.87 (95% CI: 1.04-3.37 p=0.036). In the case of recurrence, a HR 1.99 (95% CI: 1.01-3.91; p=0.046) was obtained. Regarding progression no statistically significant differences were observed between groups (HR 1.54 95% CI: 0.45-5.22; p=0.490). No statistically significant differences in tumoral relapse characteristics were observed.
With this study, we tried to reflect the reality of the effect BCG shortage in a tertiary single high-volume center urology department with its obvious design and methodological limitations. In real life, decisions during periods of scarcity are not only based on the best available evidence in “perfect-setting scenarios”, but attend to other matters such as economic, cost-efficiency, administrative, and even political policies which are exclusive and specific to each healthcare center. Frequently, these decisions are beyond the scope of the physician in charge and respond to other figures in the algorithm of decision making.
In conclusion, patients undergoing suboptimal courses of BCG due to limited availability, seem to be at a higher risk of tumoral recurrence. In our study, we observed a clear association with early recurrence and less likely with late oncological events such as late recurrence or tumoral progression. A lower rate of adverse effects was observed in patients undergoing a reduced BCG schedule. Reduced BCG courses do not seem to be a valid alternative and policies should aim at the prevention of BCG shortage as the only valid option in this scenario.
Written by: Xabier Pérez Aizpurua, MD & Juan Ignacio Monzó Gardiner, Department of Urology, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
References:
- Sylvester RJ, van der Meijden APM, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. European Urology. 2006 Mar;49(3):466–77.
- Krajewski W, Rodríguez-Faba O, Breda A, Pisano F, Poletajew S, Tukiendorf A, et al. Validation of the CUETO scoring model for predicting recurrence and progression in T1G3 urothelial carcinoma of the bladder. Actas Urológicas Españolas (English Edition). 2019 Oct;43(8):445–51.
- Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology Guidelines on Non–muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). European Urology. 2022 Jan;81(1):75–94
- Mostafid AH, Palou Redorta J, Sylvester R, Witjes JA. Therapeutic Options in High-risk Non–muscle-invasive Bladder Cancer During the Current Worldwide Shortage of Bacille Calmette-Guérin. European Urology. 2015 Mar;67(3):359–60
- Alhogbani Mm, Picard Ja, Fassi-Fehri Mh, Badet Jl, Colombel Cm. Prognostic impact of Bacillus Calmette-Guérin interruption at the time of induction and consolidation. Urol Ann. 2017;9(4):315.