Addressing the BCG Shortage: New Strains and Alternative Treatment Options on the Horizon for Bladder Cancer - Janet Kukreja

May 11, 2021

Ashish Kamat hosts Janet Kukreja to discuss intravesical therapy for bladder cancer, providing a comprehensive overview of treatments such as BCG, gemcitabine, and mitomycin C. Dr. Kukreja emphasizes the importance of understanding patient risk categories and adhering to guidelines for treatment decisions. She addresses the ongoing BCG shortage in the U.S., discussing its impact on both treatment availability and surgical choices. The conversation also delves into emerging therapies like nadofaragene and vicinium awaiting FDA approval. Dr. Kukreja highlights her collaboration with medical oncologists in administering treatments like gemcitabine/docetaxel, underscoring the multidisciplinary nature of bladder cancer care. She concludes by expressing optimism about potential FDA approval of another BCG strain, which could alleviate concerns about its shortage.


Janet Kukreja, MD, Assistant Professor, Surgery-Urology, Urologic Oncologist, UCHealth Tony Grampsas Urologic Cancer Care Clinic, Anschutz Medical Campus, Aurora, CO

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, TX

Read the Full Video Transcript

Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston. And it's my pleasure to introduce Dr. Janet Kukreja, who's Assistant Professor of Urologic Oncology in Colorado at the university, to join us today and present her take on what patients need to know about intravesical therapy for bladder cancer. Janet has quickly established herself as a true expert in bladder cancer. I had the privilege of being part of our training journey when she was with us at MD Anderson. And I can clearly say that her insight into things that have to do with patients and their journey through bladder cancer is clearly reflective of the years of thought process she's put into the disease.

Janet, if you could present to us your talk that you gave at BCAN, which was obviously directed towards patients. But keeping in mind that our audience listening in is going to be a lot of our contemporaries, that would be great.

Janet Kukreja: Thank you so much for that kind introduction, Dr. Kamat. So we talked about what patients need to know about intravesical therapy to treat bladder cancer. So briefly we talked about how the medications are administered, the staging of bladder cancer, the risk categories, how we determine who gets BCG and who does not. I'm just kind of skipping through these slides because these are really directed towards helping patients understand why we say what we say.

So importantly, intravesical therapy is not the only treatment for bladder cancer. There's much more to the treatment of bladder cancer, which includes cystoscopy, cytology, CT scans. And I also talked a little bit about sequencing treatments, and the discussion of after the initial TURBT, doing gemcitabine is different than doing gemcitabine afterward, and different than BCG afterward.

And we talked a little bit about BCG usually starts about two to six weeks after the last TURBT. And this nice induction and maintenance schedule that's available on the BCAN website, which is very helpful to patients and frankly trainees, too, to understand the BCG schedule and how it proceeds for, depending on the patient, one to three years.

So intravesical treatments we discussed. We discussed BCG and then different chemotherapies. So first of all, BCG, the original immunotherapy. It causes an immune reaction in the bladder and activates the immune system to treat the cancer cells. Right now we're using this for patients that have high-grade tumors, or CIS, which has always high-grade, or T1 disease. Common side effects, low-grade fever usually, lower urinary tract side effects, and some BCG cystitis can be seen.

Induction and maintenance are important when doing BCG treatments. So the induction that we just looked at, it's usually six weeks and then maintenance at least for a year right now. And if there's a recurrence, the timing really matters. So specifically for carcinoma in situ and T1 high-grade, the recurrence of the tumor, if it's within a year or it never went away, makes a big difference. So usually the AUA/SUO/NCCN guidelines are super helpful in determining what the correct treatment path for a patient is.

So we talked a little bit also about the update on BCG shortage. It's always a huge quandary to patients and residents, what is this BCG shortage about? Why is it? So we talked, Merck is the only supplier in the United States. We have a global shortage of BCG. They did announce that they are going to be making a new facility, however, that takes years to build. So we do expect the shortage to continue. There are some clinical trials available, but our biggest clinical trial in this space that was helping provide the BCG to patients is now closed to accrual.

So in general for patients, the way we're trying to manage BCG, not give BCG to anyone that has low-risk disease and reserve it for those that have the highest risk disease and limit it to one year of maintenance and split dosing if necessary.

The next medication, intravesical anti-cancer drugs, or gemcitabine. There's a lower risk of chemical cystitis with this compared to other agents. The side effects, in general, lower urinary tract symptoms. And occasionally it can be absorbed into the bloodstream, but pretty a low likelihood. Very few patients have the systemic side effects that they have that are consistent with intravenous chemotherapy. So nausea, vomiting, hair loss, low blood counts can all happen, but rarely.

Mitomycin C is also used in the bladder and it's similar to gemcitabine in that it's an anti-cancer drug. The side effects are very similar. However, it is more common to see mitomycin cystitis. Cystitis is more of a sustained problem rather than something that goes away after the treatments discontinue. And occasionally you'll see a patient that just has really severe side effects from having mitomycin.

And heated mitomycin is something that you have seen a lot of clinical trials about. These patients tend to have severe hypersensitivity. So they do respond better to the heated mitomycin C, but the bladder also is more likely to have mitomycin cystitis with the heated treatments.

Gemcitabine and docetaxel is the new combination that has been gaining ground in the last couple of years. The clinical studies that have been put out are in patients who had BCG failures or could not receive BCG. And this is a sequence of medications used on the same day, also done with an induction period and a maintenance period. Side effects are also lower urinary tract symptoms. Often, we can use medications to get patients through, though. The majority of patients will complete an induction course.

So valrubicin is used in patients that have CIS after BCG that did not respond to BCG. However, I'll show you in a few minutes a table as to why this is usually a last resort. It's very well tolerated, but the response rate tends to be very low.

And then pembrolizumab, this is actually intravenous. It's not intravesical right now. It is FDA approved for patients that have CIS after BCG treatments. The side effect profile is vastly different than other intervenous drugs that are given for cancer. They're auto-immune side effects. So we think more about thyroiditis, colitis, pneumonitis, and that type of stuff as side effects.

So I think that this would be what I would call the money chart. So this has all of the agents listed here and their response rates at three months and two years. So you can see from this that BCG, by far, has the best response rate for three months, two years, and up to five years.

The medications at the bottom, we're going to touch on in a second, but are pending FDA approval.

So in the future, what's to come with intravesical treatment? So as I mentioned before, the SWOG study that was being performed for BCG, the BCG PRIME trial, looked at a couple of different things, so the Tokyo BCG strain. And hopefully with that trial, we'll be able get the Tokyo BCG strain into the United States. In addition, it looked at PRIME the immune system with BCG vaccination. So that part of it could increase the efficacy of BCG. So really excited to see those trial results when it comes out.

Also in the future, so vicinium has picked up some ground. It is being used at some clinical practices around the country. It's currently not FDA approved yet, but it's pending FDA approval. It is for patients that have bladder cancer recurrence after BCG. It's a new compound that's been developed. It does have an intense dosing schedule though. So it starts with twice a week, goes down to once a week, and then it's every other week for three years. So it is quite intense for patients.

And then the last thing I want to mention is nadofaragene, also for patients that have a recurrence of CIS after BCG, and this is using a viral vector. And similar lower urinary tract side effects. Also waiting for FDA approval, but really actually some of the better response rates that we've seen from these newer things that are coming out.

Ashish Kamat: That was great, Janet. So thanks so much for doing that and representing what you presented at the Think Tank meeting. For the patients that are listening in, and also for the providers that are listening in to this presentation, what would you say, in your opinion, are the agents that you're most excited about as far as this broad space is concerned?

Janet Kukreja: I mean, I'd be very excited to get another BCG strain approved in the United States. I think that would really just open up the treatment space for patients. I think patients that are getting BCG often get really preoccupied with is BCG going to be available to me? Am I going to end up losing my bladder because I couldn't get BCG? So I think that would just really provide a lot of peace of mind to patients. And I'm really excited to see nadofaragene in the office. I think the dosing schedule is really reasonable for patients. So my understanding, it's once every three months, and I think that, combined with a high three-month response rate, would be really great to have to offer to patients.

Ashish Kamat: I agree. And it's kind of strange because if you look at different parts of the world, and we did a podcast on BCAN, actually, recently about this. There is sufficient BCG in other parts of the world. So there are places, including Germany, for example, when we talk to our colleagues, are like, well, "We have no shortage." Talk to people in other places, they're like, "We have no shortage. There's plenty of BCG." It just that there's not approved BCG available in North America and Australia and some other places.

So getting BCG that's already approved, and very similar to the Thai strain approved in the US would be a huge win for our patients. But obviously, we have to go through the regulatory process. And I'm glad you recognize that because again, you'll hear many people say, "Well, we have these other drugs. They're so novel and they're unique." But as you pointed out in your table, which was very informative, BCG still has a very, very high response rate. And it is very, very inexpensive, almost a log-fold, if not two log-folds less expensive than a lot of these newer agents.

So when you're counseling your patient, for example, that's coming and talking to you and hypothetically says, "I really want to get BCG, but I don't have access to it where I live and I can't come and keep seeing you at the university because it's a four-hour drive for me," what are some of the recommendations you're making to your patients?

Janet Kukreja: So that's a really great question because we absolutely see that patient. And the chemotherapy regimens are also often limited in that situation in the more rural areas. I think there are some rural urologists that have access to BCG. So we kind of have created a network, if you will, of BCG places where patients can go. So that if they do have to travel, it's closer to home. I think something that I talked about in the BCAN presentation is that intravesical therapy is great if you have it, if you have access to it. But occasionally intravesical therapy is not the answer. So for those patients that are the highest risks, if they have a large T1 high-grade with CIS, upfront radical cystectomy is usually something that's really reasonable for them.

Ashish Kamat: I agree. The patient that would be better served with having his or her bladder taken out early, rather than trying intravesical therapy that's suboptimal, clearly should be guided in that direction. But it's interesting if you look at the incidence of radical cystectomy globally, as it parallels the BCG shortage, it's too much of a coincidence to note that there was a 300% increase in radical cystectomies that coincided with the BCG shortage. So clearly there are patients who are undergoing radical cystectomy who normally would have had the opportunity to save their bladder.

I like what you're doing, which is creating this network of potential referral centers where patients could get BCG and not necessarily have to come to you. Are there other little snippets like that, that you could share with our audiences as to ways in which you've helped patients overcome either shortage issues with BCG, or if you're recommending that they get, say, pembrolizumab? Do you guide them towards the medical oncologist? Or do you do it yourself? There are just some practical tips for our audience to consider.

Janet Kukreja: So that's a great question. So we actually have some really awesome medical oncologists that we work with here at the University of Colorado. And they introduced me to some of their local medical oncologists. So pembrolizumab, that's always great. But I have actually found a few medical oncologists who are willing to do gemcitabine/docetaxel treatments in their treatment centers through catheters for patients. So that was actually a really cool thing that we were able to do. And the medical oncologists actually were very supportive of it. The side effects that they see with the IV gemcitabine and docetaxel just are not really seen with intravesical. So they were actually pretty happy to do it.

Ashish Kamat: That's interesting. I think this might be the first instance that I've heard of a urologist having the medical oncologist do the gemcitabine/docetaxel intravesically. Was it more born out of necessity because you didn't have urologists that were able or willing to do it and the medical oncologists were?

Janet Kukreja: Exactly. So the fume hoods and all that stuff that's required to mix the gemcitabine and docetaxel are available at the smaller community oncology practices, but not necessarily the urology practices.

Ashish Kamat: I love it. And again, I think that's a great way to show by example to our patients and our colleagues that bladder cancer is truly a multi-disciplinary disease. And even in the early stages, there is room for collaboration across all disciplines. So that's a great little message there. Janet, I could chat with you forever, but in the interest of time, we're going to wrap it up. And I'd like to give you the final moments to kind of leave us with your closing thoughts.

Janet Kukreja: Well, thank you so much for having me today. I think that this is just a snippet of what's to come in the future. I think that a lot of people are focusing on non-muscle-invasive bladder cancer in translational research. And so I'm really excited to see what the next many years bring in this space.

Ashish Kamat: Great. Once again, thank you so much for taking the time. Stay safe, stay well, and hopefully, we'll actually see each other in person this year.

Janet Kukreja: Sounds good. Thank you.