Interruption of BCG Therapy for NMIBC During COVID-19 Crisis, Dilemma in Its Continuation: a Review of Available Evidence and Suggested Management Strategies

Abstract

The COVID-19 disease, caused by SARS-CoV-2 virus, has been one of the worst pandemics ever to hit the human mankind. Undoubtedly the start of the second wave of COVID-19 has literally ripped apart the hearts of millions of people. Cancer patients have been left of the beaten track to their fate, with no access to treatments. Intravesical BCG instillation is the standard of care for patients with non-muscle invasive bladder cancer (NMIBC). Several patients were in the middle of their treatment regimen when this pandemic struck. As slowly the word is recuperating from concussion effect of this pandemic and routine health services are being restored, uro-oncologist will face a unique scenario with respect to intravesical BCG therapy i.e., whether to restart the course of BCG therapy or to continue course from where it was interrupted. There are no studies in literature to directly answer this peculiar question and to resolve this dilemma. So, we in this review article propose to explore the literature for the most appropriate therapeutic regimen for these patients with interruption of intravesical BCG therapy. We plan to divide the patients with interruption to BCG therapy into the following three groups:

• Group 1: Patients who had interruption during the induction period.

• Group 2: Patients who completed the induction course but maintenance course could not be started.

• Group 3: Patients who had interruption during maintenance phase of BCG therapy.

We will compile the recent recommendations by NCCN, AUA, and EAU for the administration of intravesical BCG in non-muscle invasive bladder cancer. We herein want to review the literature to propose the most appropriate strategy, its safety profile for these subsets of patients.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13193-023-01742-8.

Introduction

The COVID-19 disease, caused by the SARS-CoV-2 virus, has been one of the worst pandemics ever to hit mankind. It all started on December 31th 2019, in a small province (Hubei) in China, and was declared an international public health emergency [1]. Since then, it has been spreading like wildfire all across the world, creating fear and panic among health care professionals. Even the countries with the best health care system are under peer pressure to control it. Cancer patients have been left off the beaten track to their fate, with no access to treatments.

Intravesical Bacillus Calmette–Guerin (BCG) therapy is the standard of care in non-muscle invasive bladder cancer (NMIBC) patients [2]. Intravesical BCG is associated with decreased risk of progression and recurrence when used in NMIBC patients. It is used as upfront therapy in intermediate-risk patients and preferred therapy in high-risk patients. Induction cycle of intravesical BCG for 6 weeks alone is not adequate for obtaining an optimal response in most patients and that minimum of 1 year of maintenance therapy in intermediate risk and 3 years course in high-risk patients is required.

As the world is recuperating from the concussion effect of this COVID-19 and routine health services are being restored in phased manners, uro-oncologist are faced with a unique scenario concerning intravesical BCG therapy: whether to re-restart the BCG therapy once again or to continue from the point from where it was interrupted. As there is no evidence-based guideline for this perplexing situation, we reviewed the available literature and proposed a viable road map to salvage the situation.

Materials and Methods

We conducted a PubMed search using combinations of keywords “BCG,” “BCG shortage,” “mechanism of action of BCG,” “intravesical chemotherapy,” “interruption of BCG,” “bladder cancer,” “malignancy,” and “neoplasm”. All publications related to our topic, published until 3rd of June 2021, were thoroughly studied and reviewed. Those in non-English literature and animal studies were excluded. A total of 36 articles were selected including some relevant guidelines which were thoroughly studied and reviewed.

BCG: How Does It Act?

The year 1976 marked the milestone in the history of urology, as Morales et al. first reported using BCG as a novel immunotherapeutic agent to manage bladder cancer [3]. It is a live attenuated vaccine developed from Mycobacterium bovis and is now being processed in a glycerinated potato medium [4, 5]. BCG acts through a complex series of immune reactions to augment the host’s immune system. It improves the recognition and eradication of tumor cells [6]. Kawai et al. proposed immunological mechanism of intravesical BCG instillation on the tumor cells [7]. Initially the fibronectin on the extracellular matrix of BCG gets attached to the urothelium which initiates an immune reaction, after internalization of BCG. Subsequently, increased expression of antigen-presenting cells like granulocytes, dendritic cells, and macrophages leads to cytokine storm, and further activation of CD4 helper and CD8 cytotoxic cells resulting in antitumor activity [8].

Recommendations for the Use of BCG in NMIBC

The patients of NMIBC are risk-stratified after TURBT into low, intermediate, and high-risk groups for further management and surveillance (Table 1).

Table 1.

Strategies used in patients with NMIBC who are recently diagnosed and those who have already started therapy with Bacillus Calmette-Guerin (BCG) but face BCG supply shortage during therapy

Risk parameters	Recently diagnosed patients (Wroclawski et al.) [16]	BCG already started (Wroclawski et al.) [16]
Low risk	Single dose of gemcitabine (GC) f/b follow-up	Single dose of gemcitabine (GC) f/b follow-up
Intermediate risk	BCG unavailable: (gemcitabine) induction weekly/6 weeks + maintenance once monthly for 1 year	1. BCG available A. Maintenance $\ge$ 1 year; observation/follow-up
High risk	BCG unavailable (no CIS and HG): (gemcitabine) induction weekly/6 weeks + maintenance once per month for 1 year	B. Maintenance $\le$ 1 year; 2. BCG unavailable: (gemcitabine) maintenance once per month for 1 year
Highest risk (CIS and T1-HG/large tumor/multiple recurrent/variant histology/prostatic urethra involvements)	Radical cystectomy

The EAU and AUA recommend a single direct instillation of intravesical chemotherapy after TURBT in low-risk NMIBC patients. In intermediate and high-risk patients, along with single immediate instillation of intravesical chemotherapy, the EAU and AUA recommend induction weekly, six consecutive cycles of BCG immunotherapy, and maintenance for 1–3 years [9].

BCG Protocol

Induction Phase

The intravesical BCG therapy is one of the most effective and successful immunotherapies in the field of science, with a 55-70% initial complete response rate in NMIBC patients [10]. Induction BCG has been shown to decrease the risk of bladder cancer recurrences after TURBT, and 23% decrease in mortality which was reported in SEER database [11]. The weekly six consecutive doses of BCG is the standard induction regimen recommended by recent AUA [12], EAU [13], and NCCN [14] guidelines.

Maintenance Phase

In 2000, the SWOG group reported the most significant impact on maintenance therapy. Patients received SWOG/Lamm regimen which included 27 total dose instillations of BCG over 36 months. For the clinicians following the SWOG regimen, maintenance therapy is started at 3 months and then followed biannually for 3 years. This long-duration maintenance regimen was associated with poor compliance, and adverse effects, with only a small number of patients completed the 3-year schedule [15].

To overcome this shortcoming, the monthly maintenance intravesical BCG protocol for 12 months is being followed in some parts of the world. It has shown equal efficacy and tolerability in preventing recurrence and progression in NMIBC as in the SWOG regime. In a prospective study of 126 patients, monthly BCG protocol demonstrated a 2-year RFS of 52.6% vs. 77.3%, 2-year PFS of 80.5% vs. 91.1%, 2-year DSS 91.4% vs. 97.7%, and overall adverse effects of 44.1 vs. 40.2% in non-maintenance vs. maintenance group respectively [16]. Okamura et al. also reported the monthly BCG protocol to be an efficacious treatment for Ta NMIBC. They reported a 5-year RFS of 83% vs. 51.9% (p = 0.006) in the maintenance vs. non-maintenance group [17]. A recent study by Gupta et al. showed that the recurrence, progression, and adverse events in the monthly BCG protocol were not statistically different from the SWOG protocol [18].

Interrupted BCG Treatment Due to Short Supply: Lessons Learnt

In 2011, the closing down of BCG production in Pasteur’s Institute (manufacturing facility in Canada) leads to a significant shortage of availability of BCG. The situation due to scarcity of BCG then was somewhat similar to this present situation, wherein the ideal BCG regimen was discussed during this famine of drug therapy [19, 20]. The American Urological Association (AUA) came up with the following recommendations to resolve this issue of acute BCG shortage [21].

AUA recommendations for BCG treatment for NMIBC during scarcity of BCG are as follows:

• 1. Low-risk NMIBC patients should not be offered BCG.

• 2. Intermediate-risk NMIBC should be offered intravesical chemotherapy as the first-line treatment option.

• 3. Alternative intravesical chemotherapy should be used during BCG shortage rather than BCG in intermediate-risk NMIBC if BCG is planned to be administered as second-line therapy.

• 4. High-risk NMIBC should be given full-strength BCG during induction therapy, and during BCG shortage, the dose should be reduced to 1/2 to 1/3 amount, if feasible.

• 5. Patients planned for maintenance therapy should receive 1/3 dose, and the dose is limited to 1 year.

• 6. BCG-naive patients with high-risk diseases should be prioritized for induction BCG over maintenance BCG therapy.

• 7. Mitomycin C should be offered during the unavailability of BCG (induction and monthly maintenance up to 1 year). Alternative chemotherapy can also be used for induction and maintenance regimens like gemcitabine, epirubicin, docetaxel, valrubicin, or sequential gemcitabine/docetaxel or gemcitabine/mitomycin.

• 8. Radical cystectomy should be offered to high-risk group patients if they are surgical candidates who are not willing for alternative intravesical agents.

Wroclawski et al. proposed some changes in the treatment plan according to risk stratification to meet the acute shortage of BCG (summarized in Table 1). Gemcitabine instillation in induction and maintenance therapy has shown better DFS than BCG therapy, with a median follow-up of 15 months [22].

Management of NMIBC During COVID-19

Professional bodies in various countries worldwide have come up with guidelines to manage cancers during this pandemic. The recommendations issued by AUA [21], EAU [23], BAUS [24], and BCAN [25] to help urologists to make a prudent decision during this demanding period are summarized in Table 2.

Table 2.

Summary of recommendations by international societies for intravesical BCG therapy in COVID-19 pandemic

Risk parameters	AUA guidelines [21]	EUA guidelines [23]	BAUS [24]	BCAN [25]
Low risk	Follow-up should be done	Immediate instillation of intravesical chemotherapy after TURBT can be deferred by 6 months. (level 1 evidence and low priority)	Follow-up with flexible cystoscopy at 3 and 12 months	1. Patients who already received four doses of induction cycle should ideally wait for the 5th and 6th dose of induction BCG for few weeks 2. If a patient has received the 3rd dose of induction, then the 4th induction dose should be given and should wait for further treatment 3. If a patient is on maintenance therapy, he should receive first and second doses of maintenance, and further doses can be skipped
Intermediate risk	Induction: We should prioritize and can delay further treatment depending on the risk-to-benefit ratio Maintenance: Delayed indefinitely (Induction phase is responsible for causing a maximum decrease in recurrence and progression)	Intravesical BCG or chemotherapy instillations in patients with intermediate-risk NMIBC can be deferred by 6 months. (level 1 evidence and low priority)	Complete induction BCG and defer further treatment/consider the risk to benefit ratio to continue maintenance therapy
High risk	Induction: We should prioritize and can delay further treatment depending on the risk-to-benefit ratio Maintenance: Stopped and re-evaluated after 3 months	Intravesical BCG immunotherapy to be started within 6 weeks of TURBT with 1-year maintenance in patients with high-risk NMIBC. (level 3 evidence and high priority)	Complete induction BCG and consider the risk-to-benefit ratio to continue maintenance therapy
Highest risk (CIS and T1-HG/large tumor/multiple recurrent/variant histology/prostatic urethra involvements)	Radical cystectomy	Radical cystectomy

Viewpoints and Proposed Strategies with Interrupted BCG Regimen in NMIBC Patients

There will be some patients visiting the clinics due to interruption of treatment after transurethral resection of bladder tumor (TURBT). After proper follow-up evaluation, they will be started with induction followed by a maintenance regimen. Interruption of intravesical BCG treatment for NMIBC would lead to one of the following situations:

• Group 1: Interruption during the course of induction.

• Group 2: Completed induction but maintenance course could not be started.

• Group 3: Interruption during the maintenance phase.

Before starting any treatment in this subset of patients, a follow-up evaluation for tumor recurrence should be completed. Recurrence would automatically guide to group-specific management. Continuation of BCG treatment can be considered in the absence of recurrence. Based on available evidence from studies dealing with the physiological basis of intravesical BCG and management of NMIBC following interruption of BCG treatment regimen and extrapolating the recommendations, we propose the following strategies to salvage this situation.

Patients with on SWOG/Monthly Regimen with Interruption of BCG Therapy

(A) Evidence Synthesis (SWOG/Monthly): Group 1

The standard induction BCG cycle consists of weekly six consecutive cycles described by Morales in 1976 [26]. Those patients receiving consecutive six weekly induction cycles will develop an immune response, but any interruption will weaken the immune response [15]. After three doses of induction BCG, the concentration of IL-1 increases and reaches a plateau between 3 and 6 weeks, but IL-2, TNF-alpha was detected only after repeated BCG instillations, with the highest TNF levels, were found after the 5th dose of induction BCG. This increased cytokine level plays an essential role in the antitumor activity by BCG [27]. Alhunaidi et al., in a retrospective analysis of 333 patients, examined the impact of BCG interruption. Of the 55 patients who had an interruption in the induction phase, 74.5% of patients had a recurrence, and 19% of patients had disease progression in this subset [28]. Kamat et al. in a consensus statement on immunotherapy for the treatment of bladder carcinoma proposed the adequate BCG therapy to be at-least 5 of 6 doses of the induction therapy [29]. Zlotta et al. studied the weekly evolution of immune response induced by intravesical BCG instillations and found the maximum peripheral immune response was detected around the fourth week of the 6-week induction BCG cycle in patients previously reactive to mycobacterial antigens. But in patients non-reactive to the antigens, complete 6 weeks of induction was necessary to have an adequate immune response. This activation of the non-specific immune response during the induction phase helps in developing lymphoproliferation. They suggested that there is still a possibility of giving only four cycles of induction BCG [30].

A recent randomized multicenter non-inferiority trial, the NIMBUS trial, was conducted in over 51 sites and five countries to see the effectiveness of the reduced number of BCG instillations as compared to the standard BCG instillation. The treatment arms were stratified into the following:

• Standard frequency (SF): Induction cycle of BCG weekly for 6 weeks; maintenance cycles at months 3, 6, and 12 (thrice-weekly at 1, 2, 3).

• Reduced frequency (RF): Induction cycle at weeks 1, 2, and 6; maintenance cycles at months 3, 6, and 12 (twice weekly at 1, 3).

Group of RF arm had 27.1% recurrence compared to just 12% recurrence in the SF arm. At 6, 12, and 24 months, the recurrence rate was 18%, 24%, and 34%, respectively, in the RF arm and 8%, 11%, and 15%, respectively, in the SF arm. The gap widened further at 12 months (24% and 11%) and 24 months (34% and 15%), respectively. Hence, this trial was pre-terminated [31]. It made us wiser in this noble quest by concluding that reducing the frequency of the induction cycle will hamper the outcome.

Lamm et al. suggested that immune stimulation peaks at 6 weeks with an initial induction course, so using too little or too excess of BCG can reduce it as the dose–response curve is bell-shaped. So, if patients have received less than six doses of induction therapy, then immune stimulation may not be adequate, and these should undergo re-initiation of induction and maintenance BCG therapy [15]. Lenfant et al. emphasized completing the induction dose of BCG (weekly for 6 weeks) in high-risk NMIBC in patients not affected by COVID-19. If a patient is COVID-positive, then the induction should be delayed by 3 weeks [32].

(B) Quest

1. Whether to continue or reinitiate the BCG regimen in the event of interruption of induction phase?

2. What if the patient has received 5 doses of induction BCG regimen?

3. How to proceed with intravesical BCG therapy in COVID-positive patients?

(C) Summary

1. COVID-negative status: Repeat induction course followed by maintenance therapy. When interruption occurred following the completion of five doses of induction, then it is under physician discretion whether to continue or reinitiate induction.

2. COVID-positive status: Wait for 3 weeks before starting the repeat induction course.

(A) Evidence Synthesis (SWOG/Monthly): Group 2

In 1985, SWOG investigators conducted a randomized clinical trial (RCT), where they showed a superiority of intravesical maintenance BCG over those who did not receive maintenance, and it demonstrated a better median RFS (77 vs. 35.7 months) and 5-year OS (83% vs. 78%), respectively [15]. High-grade NMIBC tends to progress in 15–40% cases, and death is seen in 10–20% due to bladder cancer. In a meta-analysis of RCTs by Sylvester et al., intravesical maintenance BCG therapy showed improved outcomes and also improved PFS [33]. SWOG regimen suggests the start of intravesical maintenance BCG therapy, three weekly at 3 months but Muto et al., in their study, administered three weekly maintenance BCG starting at 6 months followed by 12, 18, 24, and 36 months and found a significant difference in 5-year RFS (72.4 vs. 62%; P = 0.019), and 5-year PFS (100 vs. 69.3%; P = 0.047) in maintenance vs. induction only group [34]. The immunological effects of the intravesical BCG therapy with a rise in cytokine levels after 3 weeks of the first instillation and peaks at 3 months and the lymphocyte infiltration decreases after 6 months helped us to extrapolate our strategy for the intermediate and high-risk group category [22, 27].

(B) Quest

• Q1: Whether maintenance therapy to be given or not?

• Q2: Whether induction course to be repeated and followed up with maintenance therapy or only maintenance therapy to be started?

(C) Summary

1. Yes, maintenance therapy is necessary, as it significantly reduces the chance of future recurrence and progression.

2. When the patient has completed the induction course, but could not start the maintenance dose, then the treatment should be planned according to the risk group:

A. Intermediate/high-risk group (interruption within 3 months):

SWOG: Continue the maintenance phase according to the SWOG regimen.

MONTHLY: Change the monthly protocol to the SWOG regimen.

B. Intermediate/high-risk group (interruption between 3 and 6 months):

SWOG/MONTHLY: BCG maintenance therapy to be continued.

C. Intermediate/high-risk group (interruption after 6 months):

SWOG/MONTHLY: Repeat induction of BCG treatment.

The option of early cystectomy should be offered.

D. Highest risk group:

SWOG/MONTHLY: Radical cystectomy should be offered if feasible.

But before starting the maintenance therapy, the status of the disease recurrence should always be documented, which helps to mould further decisions.

As suggested by the meta-analysis of the EORTC, maintenance BCG therapy has been shown to produce a significant reduction of tumor progression in patients with maintenance treatment. The standard maintenance schedule including 27 full-dose instillations of BCG over 36 months was reported by the South West Oncology Group.

(A): Evidence Synthesis (SWOG): Group 3

The European Organisation for Research and Treatment of Cancer Genito-Urinary

Cancers group (GU group) cancers group reported the 1-year full-dose maintenance to be superior to the 3-year full-dose maintenance in intermediate-risk patients, and the addition of 2 years of full-dose maintenance BCG in high-risk patients did not improve the progression or death but had an impact on decreasing the recurrence [35]. The patients receiving BCG induction six cycles followed by the first maintenance cycle (6 + 3) have shown a superior response on disease recurrence, progression, and outcomes [15]. Decobert et al., in a multicentre non-randomized prospective study, tried to answer the question “How much is enough?”. They reported a significantly decreased risk of recurrence in patients receiving a minimum of three cycles of maintenance BCG with an RFS of 89% compared to 67% RFS in those who received two cycles and 41% in those who received one cycle of maintenance BCG (p = 0.003) [36]. There is a rise in cytokine levels after 3 weeks of the first BCG instillation, and the lymphocyte infiltration decreases after 6 months [22, 27]. This result was extrapolated in our strategy for the intermediate and high-risk group category.

(B) Quest

1. How to proceed with BCG instillation, if a patient has received at-least one cycle of BCG (SWOG regimen) and the interval of interruption varies?

2. How to proceed with BCG instillation, if a patient has received at-least one cycle of BCG (monthly regimen) and the interval of interruption varies?

3. How to manage a patient if he has received at-least 1 year of maintenance BCG regimen (SWOG—maintenance cycles at 3, 6, 12 months)?

(C) Summary

The patient has completed the induction course but visits the hospital after interruption of maintenance; then, the treatment can be planned according to the risk group:

• A. Intermediate/high-risk group (SWOG):

  • Interruption less than 3 months: Continue the maintenance phase according to the SWOG regimen.
  • Interruption between 3 and 6 months; received at-least one cycle of maintenance BCG: BCG maintenance therapy to be continued.
  • Interruption more than 6 months; received at-least one cycle of maintenance BCG: Patient can be followed up in intermediate risk and in high risk, reinitiate BCG treatment.

• B. Intermediate/high risk (received at-least 1-year maintenance): BCG therapy can be safely terminated.

• C. Intermediate/high-risk group (monthly): The strategy is discussed in Table 3.

Table 3.

Demonstrating the strategies in patients with interruption of BCG therapy and number of maintenance cycles received

	Months of interruption
No. of BCG cycles received	3 months	3–6 months	> 6 months
3 cycles	To shift to SWOG regimen	Under clinician discretion to reinitiate or continue maintenance	Reinitiate BCG regimen
6 cycles	To shift to SWOG regimen
> 6 cycles

Conclusion

This pandemic has paved the way to learn, unlearn, and relearn the optimum management options for these patients. The need of the hour is to modify the basic treatment protocols to improve oncological outcomes and minimizing exposure of COVID-19 infection to a minimum.

Even though our article has many limitations, we suggest an extensive follow-up of patients as the recurrence and progression of the disease in different regimens needs to be assessed. Decision-making is tricky when little evidence exists. The views put forward are pragmatic expert opinions for the management of NMIBC during this pandemic or in situations where BCG treatment has been interrupted.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Competing Interests

The authors declare no competing interests.