HOW TO DEAL WITH

BLADDER CANCER IN
BCG SHORTAGE ERA
Interhospital Conference

พญ.ม ัชฌิมา ฮวบกอง

22 มกราคม 2564

โรงพยาบาลราชวิถ ี
OUTLINE

• Introduction
• Causes & Problems
• Choices
INTRODUCTION

• 1921 : Albert Calmette and Camille Guérin, M.bovis, first vaccinate to animal
• A few companies for oncologic purpose: 1 dose for bladder cancer = 4000-5000 doses of Vaccination

• 1970s: Immunotherapeutic for bladder cancer

• 2012 : Flooding of Sanofi factory in Canada > mold was found > FDA announce
• 2016 : Rising of global problems
 NMIBC >> intermediate – high risk
 BCG vaccine as childhood immunization >> Tuberculosis prevention

• 2017 : Sanofi stop production

• 2020 - present : COVID-19 : 20 active RCTs of BCG vaccine against COVID-19
CAUSES & PROBLEMS

• Production
 Each lab has their own protocol for mycobacterium strain maintenance and production
 A few companies produce for oncologic purpose
 1 batch needs 3-4 months production time
CAUSES & PROBLEMS

• BCG shortage affects the immunization programs for TB prevention in children around
the world

Working Group on BCG Vaccines S, WHO. Report on BCG vaccine use for protection against Mycobacterial
infections including Tuberculosis, Leprosy, and other nontuberculous Mycobacteria(NMT) infections Prepared by
the SAGE Working Group on BCG vaccines and WHO Srcretariat. 2017:1-77.
Li Z et al. Current situation, causes, and countermeasures to NIP vaccine shortages in Guangzhou, China. Hum
Vaccine Immunotherapy. 2019;1-4.
CAUSES & PROBLEMS

• Utilize
 6 doses for induction
 21 doses for maintenance

 Total 27 doses/1 case NMIBC

 ~135,000 doses of TB vaccination
CAUSES & PROBLEMS

• New Problem : COVID-19

 BCG vaccine as a COVID-19 prevention>> 20 active RCTs
 “May add up to the problem of BCG shortage”

Paul Hegarty.
BACTIR trial
• Demand for BCG Vaccine Due to Unproven Claims of its Role in Preventing COVID-19 Is
Causing Shortages of Vaccines for Infants in Japan

Kuroda, Naoto MD
The Pediatric Infectious Disease Journal: July 2020 - Volume 39 - Issue 7 - p e159-e160
DEATH RATE
TB VS COVID-19
OURFALI ET AL.

• 2013-2016
• Significantly higher rate of recurrence at 24 months after TURBT for current
intermediate- and high-risk NMIBC patients that for their patients diagnose and treated
during the three years before the BCG shortage.

Ourfali et al. Recurrence rate and cost consequence of the shortage of BCG Connaught strain for bladder cancer patients. EUR Urol
Focus. 2019;19:30109.
CAUSES & PROBLEMS

• MMC Prize increasing > 100%

CHOICES

1. Import / increase production

2. Improve BCG treatment strategies
3. Alternative medical choices
 Viral-based vector
 Bacterial-based vector
 Chemotherapeutic treatment +/- Improved delivery
 Immune check-point inhibitor
 Targeted therapy

4. Radical cystectomy
IMPORT / INCREASE PRODUCTION

• Merck & Co : TICE ………. increase production > 100%

• Difference in safety, toxicity and can develop severe complications after treatment strain
switch.
IMPORT / INCREASE PRODUCTION

Sandra Guallar-Garrison et al. BCG therapy for

bladder cancer: an update. ImmunoTargets Ther.
2020;9:1-11.
IMPORT / INCREASE PRODUCTION

• Meta-analysis comparing 10 BCG substrains : comparable

• Retrospective study : similar recurrence-free survival rates between BCG Connaught and
BCG TICE group
• BCG Tokyo , Russian, TICE, Moreau, Connaught and RIVM : comparable

Krajewski W et al. Are there differences in toxicity and efficacy between various BCG strains in bladder cancer patients? Urol Int. 2018;101(3):277-284.
Böhm BE et al. Efficacy of BCG strains for the treatment of non-muscle invasive bladder cancer: a systematic review and network meta-analysis. J Urol.
2017;198(3):503-510.
Guerrero-Ramos F et al. Adjuvant intravesical treatment for non-muscle invasive bladder cancer: the importance of the strain and maintenance. Actas
Urológicas Españolas.2017;41(9):590-595.
Unda-urzaiz M et al. Safety and efficacy of various strains of BCG in the treatment of bladder tumors in standard clinical practice. Actas Urológicas
Españolas.2018;42(4):238-248.
D’Andrea D et al. Pd13-01 comparative effectiveness of intravesical BCG TICE and BCG Moreau in patients with non-muscle invasive bladder cancer. J
Urol.2019;201(Supplement4).
IMPROVE BCG TREATMENT STRATEGIES
BCAN : BLADDER CANCER ADVOCACY
NETWORK
BCAN : BLADDER CANCER ADVOCACY
NETWORK
IMPROVE BCG TREATMENT STRATEGIES : AUA

• Avoid BCG in patient with low risk disease

• Intravesical chemotherapy is first-line : intermediate-risk NMIBC
• Utilize alternative intravesical chemotherapy rather than BCG : intermediate-risk NMIBC
• Induction therapy should be prioritized for full-strength BCG : High-risk NMIBC, high-
grade T1 and CIS. If not available, then employ reduced 1/2 - 1/3 dose. Same day cluster
in group of three.(Who pay bill?)
• If the BCG stocks available for maintenance therapy , 1/3 dose BCG , for 1 year

Http://www.auanet.org/about-us/BCG-shortage-info. Accessed 10 Apr 2020

IMPROVE BCG TREATMENT STRATEGIES : AUA

• During a BCG supply shortage, do not utilize maintenance therapy and limit induction
BCG to BCG-naïve patients with high risk disease
• If no BCG is available, then physicians should consider mitomycin for induction and
maintenance up to 1 year. Other options include gemcitabine, valrubicin, epirubicin,
docetaxel, sequential gemcitabine/docetaxel, and/or mitomycin.
• Patients with high-risk features who after shared decision making are not willing to
accept alternative intravesical agents should be offered initial radical cystectomy.

Http://www.auanet.org/about-us/BCG-shortage-info. Accessed 10 Apr 2020

 IMPROVE BCG TREATMENT STRATEGIES

• Primary boosting strategy : BCG vaccine

• Recombinant BCG : modifying BCG genetically to express additional immunomodulator/ inhibit AMPs
• Decrease dose: 1/3-1/2, induction and maintenance
• Boosting BCG vaccine + Induction only 4 doses
• Induction and maintenance better than induction only
 BCG 1/3 dose maintenance 1 yr

• Preserve BCG only for high risk NMIBC

• Radical cystectomy as a possible choice for high risk NMIBC

Stately RS et al. Background and ppdate for S1602 “A phase iii randomized trial to evaluate the influence of BCG strain differences and T cell priming with in tradermal BCG before
intravesical therapy for BCG-naïve high-grade non-muscle invasive bladder cancer. EUR Urol Focus. 2018;4:522-524.
Garrido SG et al. BCG therapy for bladder cancer : an update. ImmunoTargets Ther. 2020;9:1-11.
 ALTERNATIVE CHOICES

Viral Based
• Enterovirus Coxackievirus A21 phase I
• GM-CSF in fowlpox virus
• Recombinant adenovirus vector: rAD-IFN/Syn3 : phase III
• Oncolytic Serotype 5 adenovirus vector : CG0070, phase II

FKD Therapies Oy. A study to evaluate INSTILADRIN in patients with high-grade, BCG unresponsive NMIBC. Http://clinical trials.gov. NLM identifier:02773849.
Packiam VT et al. An open label, single-arm, phaseII multiventer study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle invasive
bladder cancer:interim results. Urol Oncol.2018;36:440-447.
ALTERNATIVE CHOICES

• Bacterial based
• Salmonella
• Salmonella enterica Ty21a : phase I
• Lactobacillus
• Pseudomonas aeruginosa Mannosesensitive hemagglutinin: available Vaccine in China
• M. phlebitis-derived complex : MCNA
• M. Brumae

University of Lausanne Hospitals. Intravesical Ty21a for the treatment of patients with non-muscle invasive bladder cancer (NMIBC). Http://clinical trials NLM
identifier : NCT03421236
 ALTERNATIVE CHOICES

• Chemotherapeutic treatment +/- Improve delivery

1. Mitomycin C *
2. Epirubicin
3. Pirarubicin
4. Gemcitabine*
5. Gemcitabine+Docetaxel
6. Cabazitaxel+Gemcitabine+Cisplatin

Delto JC et al. Preclinical analyses of intravesical chemotherapy for prevention of bladder cancer progression. Oncotarget. 3013;269-276.
Velaer KN et al. Experience with sequential intravesical gemcitabine and docetaxel as salvage therapy for non-muscle invasive bladder cancer. Curr Urol Rep. 2016;17:38.
DeCastro GJ et al. A prose I trial for the use of intravesical cabazitaxel, gemcitabine, and cisplatin in the treatment of BCG-refractory non muscle invasive urothelial carcinoma of the bladder. J Clinical
Oncol. 2017;35(6suppl):313.
GEMCITABINE INTRAVESICAL

• Intravesical gemcitabine 2 g
• Three bi-weekly dose
or

• Six weekly dose

GEMCITABINE INTRAVESICAL

• gemcitabine vs intravesical mitomycin C (MMC)

• recurrence (28% vs 39%)
• progression (11% vs 18%)
• Gemcitabine is better but did not reach statistical significance.

• The overall incidence of adverse events: less with gemcitabine (38.8% vs 72.2%, P=
0.02).
GEMCITABINE INTRAVESICAL

• Intermediate risk (primary Ta–T1, no carcinoma in situ)

• gemcitabine and BCG were similar recurrence rates of 25% and 30% (P= 0.92) and
overall progression
• Dysuria (12.5% vs 45%, P < 0.05) and frequency (10% vs 45%, P < 0.001) were
significantly less with gemcitabine.
GEMCITABINE INTRAVESICAL

• High‐risk
• Gemcitabine vs BCG
• Recurrence rate was significantly greater with gemcitabine compared with BCG (53.1%
vs 28.1%, P= 0.04%)
• Time to recurrence significantly shorter with gemcitabine (25.5 vs 39.4 months, P=
0.042).
GEMCITABINE INTRAVESICAL

• BCG-refractory
• Recommend
GEMCITABINE INTRAVESICAL

• Recurrent NMIBC and refractory NMIBC

• Gemcitabine vs mytimicin C
• Gem Higher efficacy
• Gem Lower toxicity

Added R. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer :
Evaluation of efficacy and tolerance. J Clin Oncol. 2010;28:543-8
GEMCITABINE INTRAVESICAL

• Immediate / peri-op intravesical

• Gemcitabine vs Placebo
• No significant difference in the rates of tumour recurrence (28% vs 39%, respectively) or
recurrence‐free survival (hazard ratio 0.95, 95% confidence interval 0.64–1.39, P= 0.77).
• The rate of progression to invasive disease was greater with gemcitabine (2.4% vs 0.8%).
ALTERNATIVE CHOICES

• + Improve delivery:
 Hyperthermia + Mitomycin C
 Hyperthermia + Pirarubicin
 Electromotive
 Photodynamic therapy
 Device-assisted therapy: GemRIS device
GEMRIS-DEVICE
 ALTERNATIVE CHOICES

• Immune check-point inhibitors(ICI):

• Successful in MIBC
• NMIBC: Pembrolizumab: antiPD-1 , Merck & Co. “KEYNOTE”
• KEYNOTE057: Pembrolizumab can be concluded to exhibit durable and clinically meaningful
activity in patients with high-risk BCG-unresponsive CIS, with or without papillary tumors.
• Durvalumab+BCG vs BCG alone
• Nivolumab+BCG vs BCG alone

Northwestern University. Pembrolizumab and BCG solution in treating patients with recurrent non-muscle invasive bladder cancer. Http://clinicaltrials. NLM identifier : NCT02808143.
Packiam VT et al. Current clinical trials in non-muscle-invasive bladder cancer: heightened need in an era of chronic BCG shortage. Curr Urol Rep.2019;20(12):1-11.
FDA grants priority review to Merck’s Supplemental Biologics License Application(sBLA) for KEYYRUDA(pembrolozumab) in certain patients with high-risk, non-muscle invasive bladder cancer.2019.
Bilgin B et al. An update on immunotherapy options for Urothelical cancer. Expert Opinion Biol Ther.2019;19(12):1265-1274.
Memorial Sloan Kettering Cancer Center. Pembrolizumab (MK-3475) as first-line therapy for high risk T1 non-muscle invasive bladder cancer. Http://clinicaltrials.gov. NLM identifier: NCT03504163.
University of Oxford. Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) (PemBla). Http://clinicaltrials.gov. NLM identifier: NCT 03167151.
AstraZeneca. Assessment of efficacy and safety of durvalumab plus BCG compared to the standard therapy with BCG in non-muscle invasive bladder cancer (POTOMAC). Http://clinicaltrials.gov
NLMidentifier: NCT03528694.
Altor BioScience. QUILT-3.032: a multi center clinical trial of intravesical BCG in combination with ALT-803 in patients with BCG unresponsive high grade NMIBC. Http://clinical trials.gov NLM
identifier : NCT03022825.
KEYNOTE057
TARGETED THERAPY

• Vicinium
: recombinant fusion protein consisting of an epithelial cell adhesion molecule(EpCAM)-specific
antibody fragment fused to a pseudomonas exotoxin

• Vicinium+durvalumab
RADICAL CYSTECTOMY

• Six-weeks induction BCG cost : 1,745 Euro : 65,000 Bath / 1 patient

• 27%-51% of NMIBC can up stage to MIBC at pathological outcome
• High risk NMIBC have up to 78% recurrent rate and 45% progression rate in 5 year
• Once progress to MIBC after BCG : radical cystectomy give lower OS and lower cancer
specific survival
• NMIBC after radical cystectomy had a greater than 80% chance of being recurrence free
at 5 year.
Mishearing HM et al. Economic impacts of the BCG therapy shortage and the proposed solutions for patients with NMIBC in Asher Province, Saudi
Arabia. J Fam Med Prim Care. 2020;9(6):2758-2762
Fritsche HM et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: Results from an
international cohort. Eur Urol. 2010;57:300–309. 
Moschini M et al. Comparing long-term outcomes of primary and progressive carcinoma invading bladder muscle after radical cystectomy.  BJU
Int. 2016;117:604–610. 
Denzinger S et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: Do risk factors define feasibility of
bladder-sparing approach? Eur Urol. 2008;53:146–152. 
Hautmann RE et al. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: Long-term results in 1100
patients. Eur Urol. 2012;61:1039–1047. 
THANK YOU