Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Sam S. Chang, MD, MBA, discusses the critical role that BCG has played in managing bladder cancer, and how the BCG shortage continues to evolve. Chang is the Patricia and Rodes Hart Professor of Urologic Surgery and the Chief Surgical Officer at Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
BCG stands for Bacillus Calmette-Guerin. It was a treatment first against tuberculosis [(TB)], developed from 2 men who were working in France at the time. [With possible benefits shown against other cancers, like] leukemias [or] even soft tissue tumors, a pattern began to emerge for soft tissue tumors: if the tumors were small [and] if the BCG contacted the tumors [directly,] an immune response was elicited. Alvaro Morales[, MD, FRCSC,] in Canada, had a small cohort of patients where he was the first to use BCG for bladder cancer and placed it into the bladder once a week for 6 weeks— the classic instillation schedule—and found a positive response to BCG in these patients. From that point on, further studies were developed to realize [that] this is an effective treatment that decreases recurrence and can help prevent progression.
We know that the majority of bladder cancers are non-invasive, and we know the treatment really [hasn't] been any different over the past 100-plus years of using an antiquated telescope [to] try to remove the tumor. What has been so revolutionary with higher risk disease is that a medicine placed in the bladder effectively decreases the chance of tumor recurrence and likely also decreases the chance that these tumors become invasive, perhaps even metastasize. So, you've gone from something that inevitably would have come back within the bladder, and perhaps even metastasized outside the bladder, to having an agent that very effectively—for the vast majority of patients—prevents the tumors from occurring and also from progressing.
Merck is the solitary manufacturer of the US FDA makes the approved BCG strain. Merck has had issues with production capability and quality of production and shortages have resulted. the unfortunate part is it's somewhat random in terms of who can get BCG and who cannot get BCG. It depends upon distribution of pharmaceuticals. There are individuals within the same city [who] may have access to BCG, and [who] may not. So, it has affected patients in a sporadic fashion, where there hasn't been a clear source of, "Okay, everybody's going to have a shortage." In fact, it is somewhat haphazard.
In areas where there has been a shortage, patient treatment regimens have required change with an emphasis of proper use and rationing. So, that includes making it quite clear that lower risk patients should, in fact, not get BCG. The [American Urological Association (AUA)] developed with the [Society of Urologic Oncology (SUO)] a white paper giving recommendations regarding lower risk disease, high-risk disease, the limiting of maintenance therapies, [and] the use of dose reduction. These are all different strategies that people are taking into account when there's a BCG shortage. It's gotten to the point where there are individuals [who] we think would benefit from BCG, who in fact, simply cannot get BCG. There are plans to build another production plant to make more BCG, but that's years down the line. And so, this sporadic intermittent BCG shortage is going to continue to affect practices, and unfortunately, it's going to affect patient care. We have had patients actually travel long distances to get BCG, we've had patients who are unable to get BCG, and we've had patients who've had limited dosing, decreased concentrations, or shortened their courses of BCG.
For the first time in decades, we have an FDA-approved medication for non-invasive bladder cancer, but it’s a totally different type of treatment that we haven't had in the past. That medication is pembrolizumab [(Keytruda)], a type of immunotherapy. As opposed to intravesical therapy, treatments are actually given intravenously once every 3 weeks or once every 6 weeks. About 40% [of patients] had a complete response at the 3-month mark, and these are for carcinoma in situ cancers unresponsive to BCG. But, over time, there's a diminution effect. We've never had any systemic treatments for non-muscle invasive disease.
I think also exciting is combination therapies [and] understanding that immunotherapies are effective systemically. There have been combinations, now in trial, looking at [how] we can augment this response, [how] we can give BCG [in] a smaller amount or shorter amount for a period of time and we can add the systemic immunotherapy agents and perhaps even get a better response. Also, we have intravesical therapies that show promise that, unfortunately, have had FDA hurdles and have not been approved. That includes nadofaragene as well as vicineum. These are agents that have been studied in larger trials, that have shown a benefit in terms of recurrence and, again, significant improvement in complete responses as well as disease free states, but they've not been FDA approved. So, we still are quite lacking in this space. We have exciting medications that have shown a benefit but haven't been able to get through FDA approval hurdles. And now, we have lots of studies on the horizon looking at different types of agents, molecules, and treatments that are intravesical and systemic.
BCG is the standard that other new treatments need to be compared against—but this hasn’t happened.I believe this is true because the BCG bar of efficacy is very high.New trials are coming out rapidly, with many incorporating BCG; we need to have comparative trials with BCG as a comparator arm.