Oncologists must continue to ration the critical bladder cancer therapy bacillus Calmette-Guérin (BCG) among high-risk patients as the global shortage of the immunotherapy is set to continue well into 2021.
The bacteria-based immunotherapy, which has been standard care for non muscular invasive bladder cancer for more than three decades, beats out both surgery and chemotherapy in keeping bladder tumours at bay say experts speaking to the limbic about the latest shortage. It’s substantially cheaper, too they say at around $140 a cycle in Australia and up to $200 in the US.
But ongoing large-scale production problems are forcing clinicians to turn to more expensive – and less effective – therapies so they can can continue to offer patients treatment.
The product is the Tice strain of bacille Calmette-Guérin (BCG), from MSD. Last year the TGA, along with other drug regulators around the world, added TICE BCG to its official list of drugs in short supply, and says that constraints are expected to last through to December 2021.
BCG supplies have been erratic for several years, beginning in 2011, when the US FDA shut down Sanofi’s vaccine laboratory in Canada after flooding led to mould problems.
Ongoing regulatory issues prompted the company to stop BCG production in 2016, leaving MSD to supply the drug for most of the world. And while the pharmaceutical company has ramped up its capacity to make more of the drug, it continues to struggle to meet growing demand.
Rationing to continue
Dr Sia Daneshmand, Director of Urologic Oncology, and Director of Clinical Research at Keck School of Medicine of the University of Southern California was set to speak about the shortage at the Urological Society of Australia and New Zealand’s annual scientific meeting until it was cancelled as a COVID-19 precautionary measure.
Speaking to the limbic from the US, Dr Daneshmand says clinicians have ‘weathered’ through BCG shortages before and must now anticipate the frustrating state of having to prioritise access to continue.
The traditional regimen for patients is an induction course of intravesical BCG administered once weekly for 6 weeks, followed by maintenance therapy for 1 to 3 years comprising 3 cycles of instillations once per week in months 3, 6, 12, 18, 24, 30, and 36 after induction, explains Dr Daneshmand.
But those kinds of doses are now out of research for most doctors and their patients
International guideline committees have come up with treatment guidelines to help navigate the shortage. The suggestions include reducing doses to 1/3 and stopping maintenance therapy entirely during periods of BCG shortage so that BCG-naive patients with high-risk disease can be prioritised for induction BCG.
“Of course ideally we want to give maintenance therapy to people but if you are a treating institution and you only have a small amount of BCG the question is the added benefit of maintenance therapy versus giving it as induction therapy to the high-risk patient,” says Dr Daneshmand, acknowledging the unfortunate situation where patients who do get induction therapy are not getting the ideal maintenance therapy either because it’s simply not available.
“So how can we prioritise access? I would say patients with high-grade T1 who are getting BCG for the first time particularly those who also have CIS should be prioritised. Then it would be patients with high-grade Ta tumours and CIS,” says Dr Daneshmand, adding that for patients with low-grade multifocal or intermediate risk BCG should really not be used.
“Currently my recommendation is to give intrarvesical chemotherapy, if anything, to the low- to intermediate-risk patients,” he says.
Meanwhile 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, he suggests.
“There are clinical trials ongoing showing the efficacy [of these agents] however, none of them are meant to replace BCG in the induction setting I don’t think anyone should be using any new agents or any new treatment methods if a patient is eligible for BCG,” he cautioned.
The Australian situation
In Australia, Professor Dickon Hayne, Head of Urology for South Metropolitan Health Service and Professor of Urology at The University of Western Australia cautions against advice to stop maintenance therapy.
“At the moment its difficult to know how bad the BCG shortage is going to get and certainly [it] should only be reserved for patients where it’s clearly indicated – but if it is given it should be given with maintenance,” he tells the limbic.
“The wrong advice is just to give people six weeks and stop because there is level one evidence that BCG with maintenance is better than BCG induction alone.
Exactly what maintenance regime is best is hotly disputed, though a large number of Australian centres give six weeks of BCG followed by monthly BCG maintenance for another 10 months – a regime that fits with the European developed guidelines and one that Professor Hayne agrees is considered an ‘adequate’ maintenance schedule.
Meanwhile, Dr Daneshmand says another recommendation is to reduce the BCG to one third of the full dose and group patients, if possible, by three’s because instillations occur in triplicate also making it an effective strategy for maintaining supply.
Commenting on the evidence to support that recommendation, Dr Daneshmand adds that while there hasn’t been any good quality head-to-head trial data to show that the one third dose in the induction phase is as good as the full dose it is a common practice and has not been shown to compromise efficacy.
But for patients whose disease progresses on BCG Dr Daneshmand says more aggressive therapy such as cystectomy or chemo-radiation should be considered.
“In general 80% of patients are going to be responsive to intravesical BCG and there are around 20% of high-risk patients who are not. Typically those 20% are the target group that we currently have very limited therapies for,” says Dr Daneshmand.
“Typically we would try another either induction or maintenance course of BCG for those patients if it’s available but if anyone went from a high-risk Ta to a T1 certainly that is very high risk and we should move on to cystectomy rather than continuing with BCG.”
“At the end of the day that is the most curative therapy and we need to revisit who the patients at highest risk are who should be going to cystectomy early rather than to keep looking for intravesicular treatment when really the most effective therapy would be cystectomy.”
The role of surgery
Acknowledging the contention around the surgery Dr Daneshmand said while it is ‘hardly ever’ considered, even for high-grade Ta disease, even when its recurrent, high-grade T1 disease is another story.
“I think people need to realise that high-grade T1 is invasive, can metastasise and certainly can go to lymph nodes. Continuing on with various intravesicular therapies definitely puts the patients at risk for metastases and death from disease.”
But Professor Hayne maintains that while cystectomy might be the best for cancer cure, there is a desperate need to protect against the procedure.
“The highest cure rate for non-muscular invasive bladder cancer is cystectomy but it’s a major procedure with all sorts of risks and side effects and subsequent morbidities. It’s a pretty impactful treatment and we desperately need better treatments for high-risk non muscular bladder cancer to try and preserve the bladder and protect against the need for cystectomy.
At the moment for that high-risk group BCG is the mainstay of treatment.
“That’s why it’s so outrageous that there’s a shortage and that no one seems to care. If this was tamoxifen and patients couldn’t get access because companies decided to stop making it there would be absolute mayhem,” he adds.
A new standard of care?
Professor Hayne is looking at a new standard of care – one that could see the addition of inravesical mitomycin chemotherapy to standard intravesical BCG in patients with resected, high-risk non-muscle-invasive bladder cancer.
The randomised phase III trial will compare the efficacy and safety of the combination therapy with standard BCG therapy and has already accrued half of the 500 participants needed for the study with Professor Hayne saying that, so far, there seems to be reasonable access to BCG for patients taking part in the trial, which is run by the Australia and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group.
While Professor Hayne agrees that BCG for non muscular invasive bladder cancer is not a panacea he says it’s “the best we’ve got”.
“It would be a shame to stop at BCG as the answer to everything because it certainly isn’t. A lot of people fail on BCG, it is toxic and difficult to give but it’s the best that we’ve got and simply accepting that we can’t get it and that we’ll start using systemic and extraordinarily expensive checkpoint PDL1 inhibitors for instance is ridiculous in my opinion.”