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Management of NMIBC during BCG shortage and COVID‐19

Shortages of Bacille Calmette‐Guérin (BCG) have implications for the management of patients with non‐muscle‐invasive bladder cancers. Further complications come as a result of COVID‐19 for which BCG also shows some promising prospects.

B ladder cancer is the ninth commonest cause of cancer death in the UK, accounting for more than 5000 deaths per year. 1 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). 2 The current gold standard for management of NMIBC is transurethral resection of bladder tumour (TURBT) followed by intravesical instillation of Bacille Calmette-Guérin (BCG) in intermediate-to high-risk tumours. In recent times, several obstacles have arisen that have limited the use of BCG therapy, including shortage of BCG supply and the impact of the current COVID-19 pandemic.
This review provides an update on the use of BCG therapy in NMIBC patients, including recommendations on the use of BCG during times of shortage and COVID-19.

Methods
A search of MEDLINE using combinations of key words 'BCG', 'immunotherapy', 'intravesical therapy', 'bladder cancer', 'malignancy', and 'neoplasm' for articles published between 1 January 2015 and 12 May 2020 was performed. Non-English literature, case reports, letters, and animal studies were excluded.

Response to BCG BCG strains
Intravesical instillation of BCG has been used in the management of bladder cancer for over 40 years. Despite this, many unknowns still exist regarding its mechanism.
BCG is a live attenuated strain of Mycobacterium bovis that is used as a vaccine against tuberculosis. However, when the strain is instilled into the bladder, a robust immune response leading to adaptive immunity and antitumour activity can be observed. 3 Various commercialised substrains of BCG have been produced that vary genetically, leading to immunogenic and phenotypical differences. Whether the substrains differ with regard to oncological outcomes is yet to be ascertained, with diverging results in the limited published literature. 4,5 However, an ongoing randomised trial comparing the substrains (NCT03091660) as well as an early phase trial of a genetically modified strain (known as VPM1002BC) will shortly add to the evidence base. 6

Treatment stratified by risk groups
The mainstay of BCG use is in its role as induction and subsequent maintenance therapy for NMIBC after The side-effects of BCG can vary from self-limiting, cystitis-type symptoms (experienced in the vast majority of patients) to severe infectious complications and hypersensitivity reactions (see Table 1). 8,9,10 Such events may lead to delay or even cessation of BCG instillations; this is known as BCG intolerance and can be associated with inferior cancerspecific outcomes.
In the past, tumour recurrence after initiation of BCG therapy was known simply as BCG failure but it is now recognised that this covered two distinct subgroups of patients with different outcomes: disease persistence or progression between induction and one maintenance course is called BCG refractory disease; whereas reappearance of a tumour after one maintenance cycle is termed BCG relapse.
In BCG refractory disease, radical cystectomy without neoadjuvant chemotherapy and limited lymph node dissection is the standard of care; whereas in BCG relapse, particularly after many years, re-challenge with a further induction course of BCG may be reasonable in selected cases.
In patients unwilling to undergo cystectomy or deemed unfit for surgery (as a result of significant comorbidities, frailty or anaesthetic risk) several bladder-preserving approaches are under investigation, including maintenance therapy with intravesical chemotherapy, deviceassisted instillation, intravesical and systemic immune checkpoint inhibitors, 11 and most recently adenoviral therapy. 12

Treatment in times of BCG shortage
The closure of BCG production plants, reduction of production, and the withdrawal of the BCG Connaught strain manufactured by Sanofi Pasteur has led to a sustained worldwide shortage of BCG. Given the methodological complexity and high demands of BCG production, future shortages are to be expected.
In times of BCG shortage, we recommend that urologists contact their local pharmacist or BCG supplier to consider alternative BCG strains or sterile splitting of BCG doses. Splitting BCG doses, though potentially logistically difficult, may be a viable alternative -but a one-third dose is likely the minimum required to maintain clinical effectiveness. 13 It should be noted that reducing the number of instillations appears to be suboptimal. A multicentre phase III randomised-controlled trial (NIMBUS) assessing non-inferiority of reduced number of instillations versus standard of care was recently halted midrecruitment after an interim safety analysis determined inferiority of the reduced schedule arm. 14 Limited evidence exists for the use of other intravesical agents such as epirubicin or gemcitabine, though MMC is the most extensively investigated alternative and has the additional benefit of a reduced side effect profile in comparison to BCG. 15 In the complete absence of BCG, consideration should be given to MMC with chemohyperthermia or electromotive drug administration (EMDA) where available. Hyperthermia potentiates the effect of chemotherapeutic agents and local radiofrequency-induced hyperthermia can be utilised for intravesical chemotherapy with MMC. EMDA uses a grounding pad on the anterior abdominal wall and an intravesical electrode applying a current causing MMC to be transported across the bladder urothelium, leading to deeper tissue penetration. 11 Nevertheless, high-risk NMIBC can be difficult to manage, and in times of BCG shortage upfront cystectomy may be the most sensible option.

Treatment in times of COVID-19
The COVID-19 pandemic presents an altogether new challenge in managing NMIBC patients as application of BCG might be delayed. Furthermore, many patients with bladder cancer share risk factors for adverse outcomes after COVID-19 infection. 16 Minimising these patients' risk of acquiring COVID-19 while maintaining BCG therapy is therefore of utmost importance. Strategies to reduce patient contact must be enforced with the construction of dedicated care pathways to minimise hospital visits.
A number of vaccines against COVID-19 have been approved by regulatory bodies across the globe with many more in development, though their impact has yet to be felt. Early epidemiological data suggest that vaccination with BCG may be have a role to play in the COVID-19 pandemic. 17 Since the vaccine has shown protective effects against other respiratory tract infections (for example, respiratory syncytial virus), 18 it has been theorised that BCG vaccination might be a potent preventive measure against COVID-19 infection and may reduce disease severity. The mechanism by which this may occur remains under active investigation, but it is likely due to long-term activation and reprogramming of innate immune cells (so-called 'trained immunity'). 19 While observational studies have shown that countries with routine BCG vaccination programs have lower reported cases and deaths from COVID-19, such studies are prone to significant bias and require validation. Indeed, there are already more than ten randomised controlled trials recruiting internationally to assess the impact of BCG on transmission and disease severity in both patients and healthcare workers (summarised in Table 2).
The decades of previous experience in inoculating patients with the BCG vaccine with extremely low side-effect rates, as well as its low cost and almost global availability, make it an ideal interim measure for use in preventing COVID-19 should the RCTs provide encouraging outcomes.