Ashish Kamat: It gives me great pleasure to welcome a dear friend and colleague, Dr. Sam Chang, who is a Professor and Director of Urologic Oncology at Vanderbilt University. Sam, we could chat about pretty much anything in bladder cancer because you know so much about that topic. But today specifically I'd like to pick your brain on this whole BCG shortage issue. What's going on in the U.S., globally, where are we, what should we as a community and our patients be doing?

Sam Chang: Ashish, I think one of the main reasons why this BCG shortage is so, I think, frustrating and maddening is that it seems somewhat random in terms of who has access to BCG, who doesn't, when you get access, what is your supply chain. And the sense of frustration I think only grows when even within the same city, some institutions can get BCG, some cannot. So the somewhat randomness of it makes it frustrating I think for not only clinicians but especially for patients. With the current environment, with the sole supplier, at least in the U.S. and North America making BCG, we've got to look for alternatives for different things to try to improve our care, realizing, I think at least personally, that this may not be a short term problem. I think it seems to be a longterm problem. You may have some insight on that as well, but clearly we're looking for alternatives. We're looking for other BCG options other than our current strain made by Merck.

So I think a combination of realizing that this may be something that we are in for a long haul and that we need to start making some progress for other options, not only intravesical, perhaps systemic, perhaps technique, lots of different things, I think to improve the care and decrease the chance of recurrence and progression of these patients, I think will be really important.

Ashish Kamat: You raise an important point because when there was enough BCG in the world, urologists were giving 1.2 million doses of BCG every year and Merck can only make about 750 to 780,000 doses. So there's clearly a gap of 400,000 doses-

Sam Chang: Yes, a shortfall for sure.

Ashish Kamat: That can't be met. But there is more BCG in other parts of the world. So there's the Russian strain, the Tokyo strain, the Indian. There's so many other BCGs. And that's of course why SWOG has a study comparing Tokyo BCG to the U.S. 

Sam Chang: Yeah, absolutely. The study out of SWOG, as you know, led by Rob Svatek I think is a very, very important study for a variety of reasons. First, to examine the efficacy of the Tokyo 172 strain in comparison to the Thai strain that we've used for years and years. But secondly, the third arm of that trial gives us the possibility that we may amp up the response by giving an intradermal injection of that same Tokyo strain.

So that study is just an example of how we need to start looking at other options like other strains of BCG to see whether or not that efficacy is as good as or perhaps even better. And then other things that have been mentioned are what about, we know we've got certain chemotherapy agents that we think are effective or haven't historically been effective, but we haven't been really good at optimizing how we give those intravesical therapies.

We'd go back to why did we start at six of BCG and the whole packaging and how that all started. But, well, why did we do six of say, mitomycin C or other chemotherapy agents? And so others have emphasized and I think it's really important going back to Jessie Au study, looking at optimizing how we give mitomycin C. I think over time we kind of forget some of those important principles. That was actually a study looking at regimens of mitomycin C in different ways and showing that just by making certain adjustments we actually improve and decrease recurrences.

So I think we need to do a better job of the agents that we have and obviously explore other agents, combinations of agents to give us an idea of treatments within the bladder. But beyond that, as you know, the importance of a good TURBT and how we do TURBT. That's something that I think we need to explore, different either techniques or enhanced cystoscopy. But then starting to think outside of the box or do we consider immunotherapies or other systemic therapies sooner. We know there's some efficacy in the BCG unresponsive population, but perhaps we even start looking at that upstream.

So I think this is actually, it's almost forced us to focus on other possibilities and other options. A point that I think is underemphasized, you mentioned the number of vials, the million or over a million vials that had been used to treat. That was in a day when we had BCG. And I think there were definitely patients who received BCG who had no reason to get BCG. As you are a huge referral base throughout the country and the world, you see a lot of different patients who have received different regimens and some of them might, I'm sure it leaves your head kind of scratching of why did this patient get this?

So I think one clear message that we need to emphasize is, okay look, certain patients, we may have given them BCG in the past, but we probably should have never given them BCG. And I think that immediately will help somewhat in terms of rationing the supply of BCG and then better focusing on limiting our dose, limiting our maintenance. All those types of things will hopefully get us to a point where patients who really need BCG get BCG, but then we have a better idea of what the other alternatives are.

Ashish Kamat: You raise a very important point. Patient selection is key. So for the purpose of our viewers, would you recommend today that only the high-risk, high-grade patients get BCG and we leave out the intermediate risk?

Sam Chang: Yeah, that's a really good point. And when you say the word ration, you assume that when you ration you're rationing equally and fairly and responsibly. I think that in a perfect world, what you say is exactly right. The high-risk patient should get BCG, the high-risk patient should get induction BCG. If we have a limited supply, honestly I think induction is more important than maintenance for those patients who've already shown a response.

But if we are careful with our supply, induction, high-risk disease, if we have enough for maintenance, maintenance, but for a shortened period of time, more like a year as opposed to our historic SWOG protocol. I think those things are really important. The intermediate-risk patients, I think those patients at this point probably should get chemotherapy and not BCG. And so some of the regimens that are out there, obviously we still have single-agent optimized mitomycin C, but then combinations of chemotherapy agents I think have shown some promise.

And unfortunately in the U.S., we don't have the chemo hyperthermia. I personally am not involved in any of the trials currently in the U.S. I don't know if you are, but they've shown great promise in Europe, but we don't and I don't personally have any experience with it, but I think those types of options clearly should probably be first-line for intermediate-risk patients.

Ashish Kamat: The chemo hyperthermia certainly is very effective in this group of patients. When it's compared to the standard of care or best dealer's choice in the higher-risk patients, it doesn't seem to be as effective as intermediate. Absolutely. Yes. You raised a point in and I want to ask you because you're obviously on the guidelines committee for the nonmuscle-invasive bladder cancer. When we talk about the risk categories, the European association doesn't have any of the high-grade TA patients in the intermediate risk. We're talking about BCG for high-risk. Are you referring to the European classification or do you mean that even for high-grade TA patients?

Sam Chang: Yeah, that's a really good point. I think, the European classification also went one degree more specific when it talks about basically the very high-risk individuals. When you look at high-risk TA and our table, it's a combination of risk in terms of risk of recurrence and risk of progression. And that's kind of the sticking point because as you know, the risk of recurrence is obviously quite high for those high-grade TA, but still, the risk of progression, even though it's there, is still lower obviously than T1 and the CIS patients.

And so for when I say high-risk, I look at that in terms of a combination of understanding risk and progression. And honestly, when I see someone that has a few smaller tumors, they to me are intermediate-risk, although they may be high-risk for others in terms of categorization.

So those patients for high-grade TA, I tend to treat with intravesical chemotherapy these days, as opposed to BCG. A combination of those things will then depend upon response. To me, the tougher situation is, you have that high-grade TA patient, they haven't responded to intravesical chemotherapy. That patient then honestly then I try induction BCG.

Ashish Kamat: Okay. Now at our center, we are doing one-third dose for patients and that way we can treat three patients with one vial. Is that something that you are doing as well? And if so, how do you advise your or the viewers' hospitals to deal with the billing issue of split dosing?

Sam Chang: Yeah, I'll be honest with you, we do split dose. And there are concerns about the billing and who and what actually gets billed and there are concerns that actually patients should not actually be billed, that there should be one bill and that two patients should not be billed in terms of this dosing.

So what we do, and again this comes to the randomness of BCG supply. We have BCG so that we give full dose for induction and we give one-third dose for maintenance and we have the supply for that. If you look at the AUA white paper and similar to the EAU position statement as well. If your supply is so limited so that you cannot provide that, still the first option should be for the induction patients. And if you don't have enough for full dose, then one-half or one-third dose reduction is the next step. If you want to do intravesical therapy and you're wanting to try and save.

The billing, I don't want to get too particular regarding the proper sequences. Many groups are concerned about not only billing but what's the safety, how do you split it up, all those types of things. We're fortunate, I'm sure your institution is fortunate in that we have a large number of patients that come to get installations certain periods of the week, certain days of the week and the pharmacy knows ahead of time and the pharmacy, our pharmacy will actually then prepare the BCG in one-third and will split up the dose to provide that for those patients. So we upfront prior to installation. Sometimes we, I hate to say, but sometimes we may not be able to give it because patients will have a urinary tract infection or their dip will be concerning, those types of things. But we try to plan it ahead of time before each day of BCG therapy. So the intravesical therapy treatments actually start a few days before they actually are given to try to get things prepared.

Ashish Kamat: Those are great points. Once again, I want to thank you for taking the time off your busy schedule.

Sam Chang: Oh my pleasure. My honor.

Ashish Kamat: It's always great chatting with you.

Sam Chang: Okay.

Ashish Kamat: Thank you so much.

Sam Chang: Great. Thank you, Ashish.