Michael O'Donnell: Hello, good morning. This is Dr. Michael O'Donnell, I'm the Director of Urologic Oncology at the University of Iowa. Today, we're going to be covering what to do about the current BCG shortage. Just a few of my disclosures here.

There is a crisis in this country with regard to BCG, and this is not the first time it's happened. Right now, Merck is the only supplier of BCG in the US and is the main supplier for the entire world. You may remember a prior BCG shortage that was in 2014 through '15, this occurred when the other company that made BCG, Sanofi, stopped the Connaught strain production due to some factory issues. The second major shortage occurred in early 2019, and it's predicted to end sometime later this year, although we haven't gotten the complete details on that.

Today, we're going to talk about the strategies to deal with this crisis. First of all, making the most out of the current BCG supply, and second, taking a look at alternative intravesical agents that could be used in place of BCG.

In terms of the current BCG supply and making the best use of it, the most important thing is to prioritize your patients from the highest to lowest risk. For instance, a T1 high-grade cancer with CIS clearly takes precedent over multi-focal TA low-grade. Since the low grades rarely progress, but the high grades have the greatest potential for that. They are even subdivisions of high risks that can be considered.

So, let me show you how do you assess the risk in order to do this most intelligently. Go to the AUA guidelines. They list three categories of risk, low-risk, intermediate-risk, and high-risk. The low-risk is simple. It's the small, non-recurring low-grade disease that's not invasive. The high-risk is also pretty easy to remember since it's any high-grade Ta, T1 one, or CIS. The intermediate-risk is the one most people have trouble with. It's always low-grade, but it's usually with some of the confounding factors such as multifocality, high recurrence rate, large size, etc.

Now, according to the guidelines, you should never use BCG for low-risk tumors. So, if you're using BCG now get rid of it, it's a waste of the precious resource. The intermediate-risk, we're lucky that there are actually two options available. There's either a chemotherapy option, and most people choose an optimized form of mitomycin C, usually, a six-week course, followed by monthly maintenance for one to two years. BCG is also an option here, but when you're looking at the intermediate-risk group, there's really no big advantage of BCG over-optimized mitomycin with maintenance. And so you can feel reassured this is a safe and effective therapy. The trouble is with the high-risk group where a BCG is noted and affirmed to be the most successful agent. So, we'll explore some options there too.

Now here's an easy way to determine the relative risk to your patients. And this is a six-component table, and there's even an algorithm for it you can download from the EORTC that takes into account the primary recurrence rate, number of tumors, the size of the tumor, whether it's Ta or T1, the grain, it uses the old system of G1, two and three, but you can more or less take the low-grade G1, G2s and put them together, and the high-grade G2, G3s. And finally income and CIS, and as you can see in this example, it will give you a five-year probability of recurrence and progression that you can use in estimating if this patient is at higher risk for a limited supply or not.

Here's an example of how the risk calculator works for what would seem to be a relatively straightforward situation, that is T1 grade 3 or high grade. And here is, here you can see that the risk for the two- and five-year recurrences vary from 34 and 46% respectively, to up to 71 and 78%. Likewise, the two- to five-year progression rate goes from eight and 17% respectively to 26 and 45%. And it's all dependent on the details. In fact, that devil's in the details. So, as soon as you start getting large size recurrences, multifocality, a coincidence CIS, and then all three together is when you get the worst-case scenario. Clearly those in the bottom here would be the ones you would want to use your limited BCG resources for.

How do we make most of the current BCG supply? Well, another way is by reducing the BCG dose and by grouping patients by threes for each BCG vial. For instance, a one-third dose means that you reconstitute the standard vial, and then you take a third of it for each of the 50 cc increments that you're going to use for patient instillation. And this is especially useful for maintenance therapy or reinduction where the patients are pre-immunized. And it's also useful for the intermediate-risk patients where the risk of a progression is reduced.

Here's an example of what was a large study that was performed by the EORTC in 2012, which looked at four categories of treatment based on BCG dose, which was full dose or one-third dose, and length of maintenance, one year versus three years. As you can see on the chart on the left, the recurrence rate was not very high between even the most extremes.

We're looking at about a 7-8% difference between the full dose at three years, the green line, versus the low dose at one year. In fact, these were the only two differences that were statistically significant. Everything in the middle, that is one third dose for three years or full dose for one year, were essentially equivalent and not statistically significant. Now there's a little caveat here, because among these groups of four equally defined patients, patient groups for the study, there were both intermediate-risk and high-risk patients included in both. If you segregate that out, and that's what you see on the far right? You can see that the biggest difference is for the full dose high-risk group, where there was a statistically significant improvement over any of the other categories when you use the full dose for three years. So, that's really going to be the point for rationing as well, is for those that really need it the most, you should probably give a higher and longer dose if possible.

But let's explore that even a little bit more. There is a way to make the current BCG that you're using more effective. And that's by considering the addition of interferon-alpha, another immuno-stimulant. The dose is 50 mu, and it allows for both a lower maintenance dose and a truncated schedule, instead of going with the SWOG schedule of every three months for years one, three, six, maybe nine, 12, 18, 24, 30 and 36. One can get by with just three doses. And the results are very similar to the complete SWOG protocol, which is about a 60% two-year disease-free rate. Let me show you the data for that.

So, this is the original BCG plus interferon national study that I ran. As you can see on the larger chart, the naïve group did pretty well. And in fact, it was about 60% at two years, they got full dose BCG plus Interferon for just induction therapy. And the maintenance schedule was three sets at three months later, nine months later, and 15 months later, at a dose that varied from one third to one-tenth. In fact, each cycle of the maintenance, A, B, and C were one third, one-tenth, one-tenth, one third, one-tenth, one-tenth, etc. You can see on the smaller left panel graph, the results are similar for CIS. So, this adjustment, in fact, does allow for you to use lower doses of BCG with a compensating agent, interferon.

Now, there was a second trial in a very similar group of patients that looked at whether Interferon actually improved the total results versus BCG. And in this case, the full SWOG regiment, full-dose BCG, for full three years was used in all of the four different subgroups. One subgroup had megavitamins, another one had RDA vitamins, but then the other ones were BCG Interferon or BCG alone.

The bottom line here is at the 24 month time point the results were very similar to what I just showed you. Namely, a 60% two-year disease-free rate, indicating that while the SWOG regimen is very well-tested and tried and true, an alternative regimen will give you results very similar and allow you to save BCG.

Finally, don't give up on maintenance for your high-risk patients. And if you have to give a limited maintenance supply, maintenance treatment, please give the first maintenance cycle in all high-risk patients. Let me show you why. This is a meta-analysis of studies that support BCG maintenance. There are four of them and they show a decrease in progression only with maintenance, an improvement over mitomycin C, only with maintenance, an improvement over mitomycin C for recurrence and progression, and also improvement in CIS. So, the important point again here is that maintenance is extremely important.

Now, if we look at the CIS subgroup, the original SWOG studies show that if you don't give maintenance, your result in six months was about 61%. But if you did get even one cycle of maintenance, it was up to 84%, indicating that it's that first maintenance cycle that is critical for getting the best bang for your buck for that limited amount of BCG.

Let's look at alternative intravesical agents. I'm going to talk about mitomycin and enhanced mitomycin strategies. There are at least three ways you can enhance mitomycin. Probably the easiest is a relatively simple technique of, it involves concentrating the mitomycin dose 40 milligrams in 20 ccs instead of 40 milligrams in 40 or 50 ccs, giving the patient oral bicarbonate the night before in the morning of, it's usually 1300 milligrams, making sure that they are not taking any coffee or high fluid load beforehand and draining the bladder completely.

But one of the important things is when you use gel to place a catheter to aspirate the first few ccs to let the flow go through, otherwise, you'll think the bladder is empty when it really isn't. There are other ways to enhance mitomycin, but they remain investigational. For instance, hyperthermic mitomycin and a delayed-release via gel. As you may know, this was recently approved for upper tract disease for low grade, but it's still investigational for bladder work. I'll talk about some new drugs, gemcitabine, and docetaxel, either alone or in combination.

So, if we look at what we know from past experience with the use of intravesical agents, we can see that BCG clearly was the dominant agent with a complete response rate of 60 to 70% for CIS, and a reduction of progression by about 27%. If we look at the other forms for chemotherapy via TEPA and adriamycin, they basically drop out.

They're not very strong. mitomycin is acknowledged as the strongest one, but the complete response rate for mitomycin for CIS is 40 to 50%. That means it works in over close to half the time. However, it's not as good as BCG, but still it's better than nothing. I should mention that an optimized regimen that I spoke to you about, nearly doubles the durable remission with mitomycin C. And so these numbers may be even better if we used an optimized formula. Unfortunately, mitomycin C has not had any effect on reducing progression. That's where the rub comes in.

Now here's an interesting trial that compared gemcitabine, which we're using all the time now as single-dose therapy, versus mitomycin C in a group of patients who had failed BCG. Most of them had failed once. They were intermediate- to high-risk. There was no CIS and what you see here is gemcitabine outperformed mitomycin. Again, it wasn't the optimized mitomycin, but one could say that if you have gemcitabine available, it's probably going to be better than mitomycin, at least in the standard format. So, consider that as an alternative on your BCG naive patients, for which you don't have BCG. Now, remember there has been no trial looking at gemcitabine alone as upfront therapy. So, this is a bit of a conjecture.

I also want to show you some interesting new activity of a combination approach. You may have seen the May Journal of Urology article talking about patients who had failed BCG and had entered the BCG unresponsive category. And for which there have been very poor alternatives. In that trial we showed a 52%, two-year disease-free rate for high-risk disease for patients who are totally BCG unresponsive in terms of high-grade recurrence. Fortunately, this treatment also works for BCG-naïve patients. Now, this is a limited number of patients. It was 30 patients at the University of Iowa, but as you can see, the results are frankly outstanding. Our three-month disease-free rate was 96%. And at one and two years, 89% of the patients remained disease-free. They were receiving maintenance therapy during these two years. It's not clear what happens much after that because the numbers are too small, but I can show you what the individual risk groups did. So, in seven patients with intermediate-risk, a hundred percent were disease-free two years. In 10 of 11 patients with carcinoma in situ, a very difficult to treat disease, 92% were free of that disease. And even in Ta, T1, high grade, 75% of the patients were free. Now we are putting together a multi-institutional study of BCG-naïve patients, and we hope that will be published soon. The spoiler on that is that it's better than BCG, but very similar, certainly not worse. And it should be something to consider.

In summary, the best way to weather the current BCG shortage is to make use of the current BCG supply by prioritizing patients, reducing the BCG dose, considering adding Interferon-alpha and truncating or spreading out the BCG maintenance to include at least the first maintenance cycle. And then probably another one at six months later, another one six months after that, if you have the adequate supply. Alternative intravesical agents would include optimized mitomycins with maintenance, usually one or two years, single-agent gemcitabine with maintenance, also one to two years, and the sequential gemcitabine-docetaxel with maintenance. This is the preferred approach, this latter one that we are using at the University of Iowa and have actually switched our patients over to gem-doce most of the time. Thank you very much.