The Implications of BCG Shortage for the Management of Patients with Non-Muscle-Invasive Bladder Cancers

Bladder cancer is a global disease. It is the ninth commonest cause of cancer death in the UK, accounting for more than 5000 deaths per year. Around 80% of new cases are Non-MuscleInvasive Bladder Cancers (NMIBC) of which approximately 20% carry a high risk of recurrence or progression to muscleinvasive disease (MIBC) [1]. The closure of BCG production factories, reduction of production, and the withdrawal of the BCG Connaught strain has led to a worldwide shortage of BCG [2]. As BCG is a live attenuated vaccine, there can never be a guarantee on its availability. Licensing other strains may provide an immediate solution [3]. Alternative therapies should be considered in cases of global BCG shortage [4].


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Bladder cancer is a global disease. It is the ninth commonest cause of cancer death in the UK, accounting for more than 5000 deaths per year. Around 80% of new cases are Non-Muscle-Invasive Bladder Cancers (NMIBC) of which approximately 20% carry a high risk of recurrence or progression to muscleinvasive disease (MIBC) [1]. The closure of BCG production factories, reduction of production, and the withdrawal of the BCG Connaught strain has led to a worldwide shortage of BCG [2]. As BCG is a live attenuated vaccine, there can never be a guarantee on its availability. Licensing other strains may provide an immediate solution [3]. Alternative therapies should be considered in cases of global BCG shortage [4].
Dispensing from adjuvant intravesical BCG treatment is associated with increased mortality in patients with T1 highgrade transitional cell carcinoma of bladder [5]. Research efforts are needed in future studies towards the development of effective BCG replacement vaccines [6]. BCG_SD, EPI and MMC exhibited established efficacy for preventing tumor recurrence in postoperative bladder cancer patients [7]. As an alternative is intra arterial, chemotherapy combined with intravesical chemotherapy [8] After resumption of normal production of BCG following the recent global shortage, Medicare Benefits Schedule (MBS) data suggests; prescription patterns for CIS are deficient. Such prescription patterns for CIS are conflicting with international guidelines reporting management strategies for NMIBC. There is a critical need for improved management of CIS in the current state of BCG availability [9].
Providing a second induction course of BCG may not be appropriate. Valrubicin, the only other FDA-approved intravesical therapy in previously defined BCG-refractory disease, has a poor complete response rate. Radical Cystectomy (RC) is the 'gold standard' for BCG-unresponsive disease, however, the high morbidity associated with it excludes many patients from agreeing to undergo RC [10]. The persistent worldwide shortage of BCG began in 2012 with suspension of production of Connaught BCG in Canada due to a risk of fungal contamination. A new facility was constructed to supply BCG. Strict regulatory obstacles, recurrent shortages of production supplies, increased acceptance and use of BCG for bladder cancer. Furthermore, the limited profit in the production of BCG has led to long term, world-wide recurrent shortages. The shortage of BCG has resulted in the removal of bladders that could have been saved and increased tumor recurrence, morbidity, mortality and expense of bladder cancer.
The disastrous shortage of BCG for childhood vaccination is worsened by the increased recognition of the highest benefit and cost effectiveness of intravesical immunotherapy in bladder cancer. A single BCG instillation for bladder cancer requires potentially enough BCG to vaccinate as many as 1000 infants.
As a cancer treatment, BCG has long been criticized as a nonspecific immune stimulant whose mechanism is unclear. Recognition that this non-specificity is associated with protection from unrelated bacterial and viral pathogens, particularly respiratory virus infections possibly including COVID-19 could increase the demand for BCG and risk further reductions in the supply. The low profit of manufacturing BCG using current techniques provide no hope that the shortage will be relieved unless a new, more expensive and reliably-manufactured product such as recombinant BCG is approved.
Immunotherapy is an old treatment for cancer that was nearly discarded following the advent of chemotherapy in the early 20th Century, but recognition of the important role of the immune system in cancer control produced interest in the immune stimulation induced by BCG. In superficial high-risk bladder cancer, was BCG to become the clear treatment of choice.
Randomized clinical trials and real-world population studies have proved current BCG immunotherapy is superior to chemotherapy, and prevention of recurrence is long term in many patients [11]. It has been observed that OncoTICE is associated with a lower recurrence rate [12].
The increasing global demand for BCG led to worldwide shortage of Merck's TICE BCG [13] . The American Urological Association (AUA), American Association of Clinical Urologists (AACU), Bladder Cancer Advocacy Network (BCAN), Society of Urologic Oncology (SUO), the Large Urology Group Practice Association (LUGPA) and the Urology Care Foundation (UCF) remain extremely concerned about this ongoing shortage and its effects on the care of bladder cancer patients. Scott K. Swanson, President, American Urological Association, in his letter to members stated that there are efforts to engage the U.S. Food and Drug Administration to approve additional strains, supplies of BCG are continuing, Merck's stressed that their commitment to TICE BCG, while other companies have stopped production, is at the core of Merck's mission to save and improve lives. Their teams remain focused on maximizing the output and trying hard to provide additional supply of TICE BCG to patients. Although this will take years to be fully realized. BCG should not be used for patients with low-risk disease. Intravesical chemotherapy should be used as the first-line option for patients with intermediate-risk NMIBC. Patients with recurrent/multifocal low-grade Ta lesions who require intravesical therapy should receive intravesical chemotherapy such as mitomycin, gemcitabine, epirubicin, or docetaxel instead of BCG.
In conclusion, the global shortage of the BCG should be contained. Increased production and alternative therapies should be considered.