Alternatives for Bladder Cancer Tx During Ongoing BCG Shortage

Pam Harrison

September 06, 2019

The ongoing shortage of bacillus Calmette-Guérin (BCG), used intravesically to treat early-stage bladder cancer, continues to motivate experts to identify alternatives for the treatment of nonmuscle invasive bladder cancer (NMIBC).

There has been a worldwide intermittent shortage of BCG for some years. The problem is compounded in low- and middle-income countries, where costs can make alternatives to BCG too expensive to use.

One such country is Brazil. A team of experts there describes how they have been dealing with the shortage crisis in an article published online August 27 in the Journal of Global Oncology.

Most of the recommendations from senior author Andrey Soares, MD, Hospital Israelita Albert Einstein, Sao Paulo, and colleagues are in line with what is happening in the United States, says an expert from a top US center. However, Brazil may have an advantage in that it can import other strains of the bacillus, whereas in the United States, only the Tice strain is approved.

Intravesical BCG Is Standard Treatment

Transurethral resection is the surgical gold standard for the initial treatment of NMIBC, the Brazilian authors write.

Following surgical resection, intravesical BCG therapy has been the standard treatment for preventing recurrence, they continue.

However, in periods of BCG shortages, clinicians must be creative to ensure their patients receive at least some treatment when this therapy is indicated.

Risk stratification is a first step.

Normally, patients who are considered to be at low risk do not need to be treated with intravesical BCG, the authors comment. This recommendation is shared by the Brazilian Society of Urology and the American Urological Association (AUA), which recently published an advisory on how to manage NMIBC during a BCG shortage.

However, for patients with high-risk or intermediate-risk disease, both societies recommend an induction course of intravesical BCG once a week for 6 weeks, followed by maintenance therapy for 1 to 3 years.

Currently, only one laboratory (Fundacao Ataulpho Paiva) supplies BCG for intravesical use in Brazil. The strain available in Brazil is the Moreau Rio de Janeiro strain.

However, given the current shortage of BCG in Brazil, it is reasonable to import other strains of BCG, the researchers argue, especially for patients with high-risk bladder cancer.

The main drawback to securing other strains of BCG in Brazil is cost.

For example, the Tice strain from Merck & Co — the only strain and the only supplier of BCG in the United States — costs approximately $720 per vial to import, compared to only $65 for the strain produced in Brazil.

In their article, Soares and colleagues argue that it is "probably valid" to split vials of the available BCG so as to treat several patients with partial or reduced doses to increase the number of patients who can be treated with BCG while reducing waste.

This recommendation is also promoted in the AUA's BCG shortage advisory. The AUA indicates that if patients with high-risk NMIBC cannot be given full-strength BCG, they should be given one half to one third of the usual dose, if feasible.

Use of Chemotherapy Instead

For patients with intermediate-risk NMIBC, the AUA guidelines recommend intravesical chemotherapy with either mitomycin, gemcitabine, epirubicin, or docetaxel as a first-line option. (The guidelines also recommend such treatment for these patients as second-line therapy when that is indicated.)

The Brazilian researchers similarly suggest that clinicians consider using mitomycin-C for induction and maintenance therapy in high-risk patients.

"Unfortunately, mitomycin-C is not widely available in Brazil and patients and health care providers need to import it, thus increasing treatment costs that are usually not reimbursed by the health care system," they write.

Intravesical epirubicin is more widely available than mitomycin-C, the researchers point out, although they do not directly recommend its use.

Soares and colleagues single out intravesical gemcitabine as a potentially "promising" alternative to BCG in both intermediate- and high-risk NMIBC patients.

If gemcitabine is used, the researchers recommend that clinicians administer it at a dose of 2000 mg in six instillations once a week (induction), plus maintenance instillation once a month for 1 year.

This regimen is only appropriate for high-risk patients who do not have carcinoma in situ or whose tumor is not of high grade, they emphasize.

The Brazilian experts suggest that radical cystectomy be considered when BCG is in short supply. However, such surgery must be carefully considered, and patients must be carefully selected, because the risks for morbidity, mortality, and compromised quality of life are real with this radical surgical approach, they add.

Supply Still Limited in US

Approached by Medscape Medical News for comment, Alexander Kutikov, MD, chief of urologic oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, confirmed that for many centers in the United States, the supply of BCG is still limited.

At his own center, which is a high-volume facility, "the supply is being delivered to us preferentially, so we've been able to keep our heads above water and continue to treat our own patients as well as referrals from other practices that are out of BCG right now," he noted.

However, the supply of BCG is not infinite anywhere in the United States, "so we're doing dose reduction routinely as well," he added.

The main difference Kutikov sees between Brazil and the United States regarding recommendations for use of BCG during periods of shortage is what he describes as the "luxury" that countries such as Brazil have in being able to import strains of BCG other than the ones produced in their own country.

"The US is locked out of everything but the Tice strain, so Tice is the only FDA-approved strain in the US, but in Brazil, this is one of the ways they are suggesting to try and augment their own supply," Kutikov explained.

Although there is hope that the FDA will approve the so-called Tokyo strain of BCG that is currently being evaluated in the United States, at the moment, there is still only one supplier of BCG in the United States, Kutikov pointed out. Brazil may be able to overcome this limitation by importing other strains of BCG, he suggested.

Kutikov also felt that it was interesting that Brazilian researchers appear to be advocating use of intravesical gemcitabine as a good alternative to BCG.

"Usually, BCG has been tested against mitomycin," he explained.

Indeed, mitomycin has earned a spot for use in intravesical therapy administered as a single dose following transurethral resection of the tumor in an effort to prevent implantation of tumor cells that may be floating in the urine after the surgery.

"In this space, gemcitabine appears to have similar efficacy to mitomycin," Kutikov noted.

He also noted that in the United States, gemcitabine is much less expensive than mitomycin.

"I suspect this is why the Brazilian group suggested the use of gemcitabine and not mitomycin, because of cost considerations," he observed.

Regarding radical cystectomy as a treatment option during periods of BCG shortage, Kutikov had major reservations about the use of this "life-changing" operation for all but the most select patients. In addition, he emphasized that this surgery "has to be done at experienced centers by experienced surgeons, as the mortality rate from the procedure alone is not trivial," he said.

"But otherwise, the suggested recommendations made by this group [from Brazil] are very reasonable, especially in these times of BCG shortage," Kutikov concluded.

Soares has received honoraria from Janssen, Pfizer, Bayer, Novartis, AstraZeneca, Astellas Pharma, Pierre Fabre, Merck Serono, Sanofi, and Roche, has served as a consultant for Astellas Pharma, Janssen, Roche, Bayer, Lilly, AstraZeneca, Novartis, MSD, Bristol-Myers Squibb, and has received travel expenses from AstraZeneca, Pfizer, Astellas Pharma, Bristol-Myers Squibb, Bayer, Roche, Janssen, Merck Serono, Sanofi, and Ipsen. Kutikov has disclosed no relevant financial relationships.

J Glob Oncol. Published online August 27, 2019. Full text

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