Transcript of New Discoveries in Bladder Cancer

April 12, 2023

Diane Quale, BCAN Co-Founder:

Well, it is my great honor to welcome our three guests here today. And I want to thank you all for joining us. It’s such an important part of the Summit and to have you hear really means everything. So, thank you so much. I’m just going to dive right into this because I know we’re all anxious to hear from our experts. And first I would like to introduce them directly. To my left is Dr. Donald Lamb, who’s a urologist with more than 47 years of experience treating genital urinary cancers, especially bladder cancer. Although he’s recently retired, Dr. Lamb is still engaged in research. And for those of you who’ve had BCG treatments, this is the man. He’s been a pioneer in the field of immunotherapy since the early 1980s, having done the trials for BCG and getting BCG approval. He’s established the well-known Lamb protocol for the induction and maintenance of BCG. And it’s wonderful to have you here, Don.

Next to Dr. Lamb, we have Dr. Parminder Singh, who I think many of you in the audience already know. He’s a GU medical oncologist at Mayo Clinic, Arizona. He’s a national leader for multiple registration trials, evaluating new strategies to preserve bladders in bladder cancer patients, something we all are very interested in. Welcome Dr. Singh.

Dr. Parminder Singh:

Thank you.

Diane Quale:

And you’ve already met Dr. Jennifer Linehan, who we now is know an Arizona native, although now a resident of California. She’s a board-certified urologist and is Associate Professor of Urology and Urologic Oncology at the St. John’s Cancer Institute in Santa Monica, California. Welcome.

So I thought I would start just by asking each of you, and I’ll start with you, Dr. Lamb. I can say from my experience, having been in the bladder cancer field now for 23 years, that especially in the last 10 years and certainly in the last six to 10 years, there have been a tremendous number of changes. And we talked earlier this morning about hope and everybody having a reason for hope because of the advances. But given that we have a limited amount of time today, can you tell me, and I’m going to ask each of you, what do you see as one of the most exciting advances in bladder cancer or bladder cancer treatment over the past five years. And one.

Dr. Donald Lamb:

Oh, that’s the hard part. The one part because there really are so many things, and part of the upside of the BCG shortage is there’s now an opportunity to study many new drugs in bladder cancer that we didn’t have before. But I have to say that in my opinion, and you’re probably going to want to say this one too but I got it first, the big step forward is in what? Immunotherapy, of course. And it’s a combination of the immune checkpoint blockers, the pembrolizumab, and the durvalumab, and the other drugs. And often, and I think generally very significantly, improving the response is combination with other agents, primarily BCG but many other agents.

Diane Quale:

Great. Thank you. Dr. Linehan, your turn.

Dr. Jennifer Linehan:

So one of the things that I think, well, two, okay, I only get one. I’m a technology person so I think there’s better technology at finding bladder cancers. I think there’s better urine tests at finding bladder cancers, and I think robotics to take out the bladder that is also improved. And then, of course, some of the trials that we talked about, too.

Diane Quale:

Great. And Dr. Singh.

Dr. Parminder Singh:

First of all, I would like to thank all my patients who came over. We sent a flyer and I see folks from Colorado. Laura is here from Colorado. We have Kester here. We have Kesters from Tucson. And Sheryl, and John, and Jack, and so many folks from local Arizona taking our time today on a Saturday. You could have gone to the Tempe Arts Festival but you decided to come here. Thank you so much for doing that. But I think, personally, in the last 10 years, the biggest advancement in bladder in US is actually BCAN. It is not pointed out so much the role of advocacy in bladder cancer research, which Diane and her group has led. And I’ll allude to the development of the largest clinical trial in bladder preservation, which I outrightly, I said Rick Bangs my partner patient advocate who took charge and helped me push through NCI because nobody was ready to fund that trial. And this is all because of the advocacy, which in the last 10 years have changed the way bladder cancer is funded and the field is moving. I think this is the biggest change in bladder cancer in last 10 years.

Diane Quale:

So recognizing that bladder cancer really represents a whole spectrum of diseases from non-muscle invasive to muscle invasive to advance, we’re going to kind of do our discussion through those phases just to keep it simple. But the first question I have really has nothing to do with research advances. It might be why there hasn’t been an advance. And Dr. Lamb, I’ll start with you. And then Dr. Linehan. Why isn’t there a screening test for bladder cancer? We have PSA for prostate, we have mammograms for breasts, we have colonoscopies. Why isn’t there a screening test for bladder cancer?

Dr. Donald Lamb:

Well, we do have screening tests, but they are not terribly good. And there is progress. There is an accelerated approval of a new urinary marker system, multiple markers from simple urine test. And that’s being developed and I think you’ll see it before long. One of the big needs is a system, something that will tell us if all the cancer is gone. In which case, you don’t need more chemotherapy. And that would have to be a blood test because when the cancer’s actually in contact with the urine, you’d expect to find something in the urine that would tip you off. But the real problem is not having a ESA-type test. And there’s a lot of research being done and the genetics and the cellular markers that, that DNA, that can identify minute amounts of cancer. But it hasn’t really come to fruition in bladder cancer yet.

Diane Quale:

So there’s nothing that’s widely accepted and available so that when I go in for my annual checkup that there would be a screening.

Dr. Donald Lamb:

But we need to acknowledge that the importance of what you’re doing, and that is letting people know that if you have frequency without an infection or if you have microscopic or certainly visible blood in the urine, you need to see your doctor. And typically you need to see a urologist. And just the good old-fashioned cytology is very good for diagnosing the dangerous, the high-grade type of tumors, not so good for the low-grade at all.

Diane Quale:

Dr. Linehan, anything to add?

Dr. Jennifer Linehan:

I think you have to think about it as in comparisons. Let’s just take prostate cancer, pancreatic cancer. So the pancreas and the prostate release this enzyme into the bloodstream that you can measure in the bloodstream. And there’s nothing really like that that’s emanated from the bladder. The bladder’s not making any enzymes or things that you can actually check. So we have urine to easy and free tests that you can get. Everybody’s got pee.

So the problem is what’s important in the cells and on the cells that we need to be measuring. Is it the DNA? Is it the mutations of the genes? Is it the receptors on the cell and the markers and the things that the cell may be pushing out to show itself? So we’re trying to understand which of all those markers is important to pick up cancers in the urine. And that’s why the tests have been so difficult to formulate.

There’s eight different urine tests on the market right now looking at all different things. You have the cytology that Dr. Lamb was talking about where the pathologist puts it under the microscope and says, “Is there a cancer cell there?” But then there’s tests that look for DNA markers and mutation markers. Then there’s tests that look for things that are on the cell that are called keratin. So there’s all these different things and we’re all trying to figure out which one is most important and what’s going to give us the best result. Because if you’re going to do these tests, you want to make sure the test is actually very specific for bladder cancer and sensitive to bladder cancer, or you’re going to have a lot of false positive, then that’s going to create a lot of anxiety for patients.

Diane Quale:

And so talking about biomarker tests, is it different for screening, trying initially diagnosing a patient with bladder cancer than having a patient who’s been treated for the disease and now they are under surveillance? Are there biomarkers that are more precise in that instance?

Dr. Jennifer Linehan:

Yeah, absolutely. And one of the reasons that they are more precise is because we have tests that now you could take the patient’s cancer and check for their mutations, check for the things that are part of the cellular makeup of their cancer, and then kind of screen for those things even personally on them. And we understand that certain mutations show up in more aggressive cancers than in low-grade cancers. And so the tests become more specific, which makes them better at finding. So if you know someone has cancer, you sort of know what you’re looking for. Whereas if you’re just randomly screening the population, it’s harder to pinpoint.

Diane Quale:

So what are some of those tests for patients who are under surveillance for recurrence?

Dr. Jennifer Linehan:

So there’s Cxbladder, there’s Oncuria, there’s NMP22, there’s UroVysion, and then there’s the cytology. And a lot of us as urologists, depending on the type of cancer where the patient has low-grade or high-grade, I will use some combination of those tests. I probably use Cxbladder in my practice the most. But like I said, I tend to vary it up and change depending on what type of cancer it is. But those tests in themselves are individually based on whether you’re trying to screen, whether you’re trying to survey, meaning you’re following a patient with bladder cancer or trying to detect if a patient has bladder cancer and the company changes the assay for all of those different classifications because they’re looking for different markers.

Diane Quale:

And do any of those markers hold the promise of reducing the number of cystoscopies that patients need as part of the follow-up??

Dr. Jennifer Linehan:

Yes, absolutely. I think as we continue to gather research on these urine tests, we will understand if you will test positive with this test, that we know that something may be there. And if you test negative, well maybe you don’t need your cystoscopy. And I think as far as screening, using the tests for patients that come into your office with microscopic hematuria, if that test is negative, we may know that, “Okay, you really don’t need a cystoscopy. The urine test was negative.” Like I said, urine is a very easy specimen to get from patients.

Dr. Parminder Singh:

So Dr. Linehan, how is the coverage of these tests? Will insurance pay for this or patients have to pay for this test?

So now most of the tests are covered. If insurance doesn’t cover them, most of the companies will help the patients either get the test covered through their insurance or they’ll just cover the cost of the test for the patients. But to be honest, I can’t remember in a while the last time that a patient said, “Hey, I got a bill for this test.”

So you would be doing these tests every three months, six months, every year, or just once?

Dr. Jennifer Linehan:

No. So I’m repeating these tests when they’re coming in every three months or every six months, depending on where they are in their course.

Diane Quale:

And are you doing these tests in lieu of cystoscopy or in addition to?

Dr. Jennifer Linehan:

I am doing the tests for screening, sometimes in lieu of cystoscopy in patients that I know have high-grade bladder cancer. I’m not yet comfortable just doing the tests.

Diane Quale:

Okay. So talking about cystoscopy, so one of the great advances I think in my time in bladder cancer field is blue light cystoscopy. And I know we have a slide if you wanted to share. And can you talk to us about blue light and the advances there?

Dr. Jennifer Linehan:

Yeah. So the benefit of this type of cystoscopy called ‘blue light’ is that you can find lesions that are very, very small that you would not see with your naked eye or white light cystoscopy, probably what the urologist has been doing in the office. So this uses a dye of what we call a ‘photosensitizer’. And you put it in the bladder for an hour before your cystoscopy. And you can either do this in the office or you can do this in the operating room before you’re going to take a patient back that you know has a tumor inside the bladder. And the actual scope itself is what the blue light is, and when you click the blue light on, tiny little lesions will show up bright pink like this. And you can see the picture right next door. I would have never seen that lesion with the white light. It would’ve been a very soft call for me. I would’ve had to look really close or maybe I would’ve had spent extra time looking.

But you can see these small lesions, which means that you can get them earlier, which means maybe not as many cystoscopies and definitely avoiding the operating room more. So it’s been an incredible technology to have. And so if you can see, I have some numbers up there, that it improves the detection of the smaller lesions 95% versus 68% with just looking with your eyeball.

And this was just some more other pictures of what that looks like. So I know it’s called ‘blue light’, it’s very confusing to patients. So the blue light’s in the scope, but the lesions actually come up pink.

Diane Quale:

Has anybody here, how many people here have had a blue light cystoscopy? Great. Has anybody wanted one and not been able to get it? Okay. There’s the other problem.

Okay. Well hopefully, isn’t there now a flexible blue light so you can do it in the office? It doesn’t require going into the operating room?

Dr. Jennifer Linehan:

No. We do it in the office and then we do it in the operating room.

Diane Quale:

Right.

Dr. Jennifer Linehan:

I’ve had a patient with a bigger tumor who I know I’m going to take to the operating room, right?

When I’ve had a patient with a bigger tumor, who I know I’m going to take to the operating room anyways, then I use it so I can see all the little stuff. And then I have some patients with low-grade bladder cancer, and those tend to recur quite often. And then you can see it in the office with the [inaudible 00:27:15].

Dr. Don Lamb:

There is something between regular white light and blue light, and that’s the narrowband imaging, which is what I use, because we didn’t have blue light. And it is significantly expensive, but once you have it, it doesn’t cost that much more than a regular scope, and it’s flexible, you just push the button and you flip from white light to narrowband imaging. Compared to just white light, you do see more, and you can do a better cystoscopy. Not perfect, but better.

Diane Quale

But you can also do that in the office setting?

Dr. Don Lamb:

Yeah, in the office. It’s quick and it doesn’t cost any more.

Dr. Jen Linehan:

And most urologists have the narrowband that he’s already talking about, which is another…

Diane Quale

Right. Is the blue light being covered by all insurance companies?

Dr. Jen Linehan:

Yes.

Diane Quale

I should have mentioned at the outset, we’re going to have our conversation up here, and then we’re going to have at least a half hour for your questions. So if things come up as we’re talking, just write them down so you can remember so you can ask questions at the end.

Dr. Parminder Singh:

From patient’s point of view, does blue light cause any more radiation risk, or is it just a light color blue?

Dr. Jen Linehan:

Oh, it’s just a color blue. Then we have a fluorescent light, and it just fluoresces, but it’s very safe. It’s not harmful. It’s not really a dye, even though it sounds like it would be, and patients have usually zero issues with it.

Dr. Parminder Singh:

No dye related kidney issues?

Dr. Jen Linehan:

Yeah, because it’s going to go in your bladder and then we’re going to drain it right out.

Diane Quale

Let’s turn to BCG.

Dr. Don Lamb:

All right.

Diane Quale

Let’s turn to BCG. We’re all excited about the new immunotherapies for bladder cancer, but it is an immunotherapy that’s been around for quite some time, and we have you to thank for it. Don, tell us a little bit about any concerns you have with the ongoing shortage of BCG and how you think that might be impacting patient care.

Dr. Don Lamb:

I haven’t looked up the numbers, but we know that patients are having compromised care because of the unavailability of BCG. I think there are more bladders that are being removed that might well have been saved if there were sufficient BCG to go around, so everybody could have the optimal treatment. There should be BCG for everybody to get six. It took forever for us to prove that maintenance was better than just induction. They looked at monthly maintenance, they looked at quarterly maintenance, and it was not until we started with an intensive three-week, three-year maintenance program that we’re able to really show a big difference in prevention of recurrence.

It’s the study that the schedule that has been shown not only to almost double the benefit of BCG, but to significantly reduce metastasis and mortality from bladder cancer. We need more BCG because the guidelines for BCG in the shortage say that you use BCG as a last resort for intermediate risk bladder cancer. But the European study 30911 looked at intermediate and high risk patients, comparing the three-week maintenance BCG with three-week maintenance epirubicin, and-

Diane Quale

Epirubicin is a chemotherapy, correct?

Dr. Don Lamb:

Is a chemotherapy, yes. It’s like a doxorubicin type of drug. It’s a good drug. There were over 900 patients in the study, 500 of whom had intermediate risk. They excluded carcinoma in situ because everybody accepted that BCG’s best for carcinoma in situ. It’s ideal. It’s superficial. The medicine comes right in contact with the cancer. But they found that the group that had the greatest protection was actually not what we expected. It was intermediate risk group. So intermediate, even low grade tumors that continue to come back, tend to get worse and are dangerous. So we definitely need more BCG. I’m working with three different companies trying to develop a way to get more BCG. There will be a new manufacturing site in Durham that Merck hopes to have online in 2026. But still, it’s a long time, and there’s a lot of patients that are going to miss optimal care until that time, so we’re trying to get it. And there is promise with Dr. Robert Faytec’s SWOG study looking at Tokyo-172 BCG.

Diane Quale

Which is a different strain of BCG than what’s approved here?

Dr. Don Lamb:

Yeah. It all came from Pasteur in July of 1921, and this makes me feel so good to be a BCG advocate. Doctors Calmette and Guérin developed this. It took them over 10 years to develop it. They develop it and it’s saved the life of a newborn whose mother died and was going to be raised by the grandmother who had active tuberculosis. Chances of that child making it were slim, so they said, “It’s time to do it.” They gave him oral BCG and lived happily ever after. But that was such a horrendous disease, tuberculosis, at that time that, without patenting, without anything, they sent it to countries all over the globe for free. Unfortunately, it took a while for us to figure out that you needed to have a seed lot and preserve the original. So with serial passages around the world, there are some differences in the strains of BCG, but I have not seen one yet that is not effective in bladder cancer looking at carcinoma in situ response rate.

Diane Quale

You had mentioned at the beginning that one of the upsides of the BCG shortage is all the trials that are going on now, because there’s an obvious need for alternatives to BCG. Dr. Jen Linehan, I know you have this wonderful visual for us. Can you talk to us about what’s going on in the non-muscle invasive space?

Dr. Jen Linehan:

Absolutely. First of all, I am very honored to be sitting on stage with Dr. Lamb. There’s no one in this world, I’m pretty sure in this world, that knows more about BCG or intravesical therapy. He definitely is the father of that, so if I say anything wrong, just tell them right away. There’s no way we could go through all these trials, but the point I wanted to make, this is a slide by another really great urologist named Max Kates, and he presented this at ASCO. It’s showing you the different types of cancer, and then what trials are available and when those trials started. You don’t have to worry about reading this, because on the Beacon website there is a clinical trial finder. You can put in your cancer and it will show you all these different studies. It’ll show you what they’re doing and it’ll show you what you have to do to be included in those studies.

But my point of this is, because of the BCD shortage, a lot of this came to be. A lot of this came to be because of Beacon, because they worked very hard at getting these trials pushed through. If you’ve had BCG, there’s patients that have cancer that have not had BCG yet, so those are BCG-naive, meaning they’ve never had it. So those patients can have those trials. There are patients that are what we call “unresponsive” meaning they’ve had six weeks of BCG and probably another one after that, but the cancer keeps coming back at some point in time, either right away, it never left, or it comes back. Those are the trials they’re candidates for, right there, the BCG-unresponsive, and then up at the top, the intermediate risk. There actually is a urine test called Oncuria that you can get that will tell you if the patient will respond to BCG, so we are getting better about figuring that out as well.

Diane Quale

Really important. I know that one of the trials that Azimax is doing, but there’s also been work done on this, in terms of alternative therapies, is chemotherapy and using the combination of the docetaxel and gemcitabine.

Dr. Don Lamb:

Gem/Doce.

Dr. Jen Linehan:

Gem/Doce.

Diane Quale

Yes, I never get that right, Gem/Doce. How does that compare to BCG, and do we know who it might work better for than others?

Dr. Jen Linehan:

Do you want to take it first?

Dr. Don Lamb:

Okay. This is a very effective combination. As an example, we had a patient who had a huge tumor, two very difficult large resections at Memorial Sloan Kettering. He absolutely refused to have his bladder out. He came to see me, two huge resections, and initially it was so big you couldn’t get it all out in one setting, but even when you could get it out, it was growing so fast that you couldn’t keep up with it. We had BCG at the time, but it takes three months, sometimes even six months for BCG to stimulate the effective immune response. It’s going to get rid of the tumor, so we gave him gemcitabine-docetaxel and he did just fine. And then, knowing that he was going to remain at risk for recurrence, we gave him BCG.

That’s been 10 years ago and he’s still fine. So very rapidly recurring tumors, gemcitabine-docetaxel has an advantage over BCG. I think, in the long run, had we been able to do three-week maintenance BCG and so on and so forth, I think BCG is better than the combination. The reason being that it stimulates an immune response that persists. Not forever, I don’t know that but we don’t think it lasts forever, but it is long-lasting. So when you develop a new tumor, your immune system can recognize it and eradicate the tumor. Chemotherapies are actually carcinogenic, and I shouldn’t have said that, but there was so much disparagement of BCG when it first started. I got to get back a little bit. It’s great for killing tumor, but oftentimes the DNA that have the mutations that produce the tumor in the first place will eventually break through and cohost new tumors. So I prefer BCG as an ideal option, but the numbers are very comparable.

Diane Quale

So the Gem/Doce goes into the bladder? It’s an intravesical therapy, right?

Dr. Jen Linehan:

Right.

Diane Quale

And when you do that, how often do you get installations?

Dr. Jen Linehan:

If we’re going to do a chemotherapy into the bladder with the Gem/Doce, which Dr. Lamb is right, I just looked at the data recently again, it is very comparable to the response rate, the cancer going away, that you get with BCG. It’s not as good, but it’s pretty darn close. And so, in that setting, you have to give… There’s two drugs. You got to give the docetaxel first and then the gemcitabine, and they each have to stay in the bladder for an hour. And so the patients are spending a little bit more time in clinic, but they’re doing that once a week for six weeks.

Diane Quale

For people for whom BCG does not work, and they are not ready to have their bladders removed, before we get into bladder preservation, is there a good other treatment for them to try?

Dr. Don Lamb:

As many as 80% will responded in Gem/Doce.

Diane Quale

Oh, so the people who are non-responsive to the BCG, Gem/Doce will work up to 80%.

Dr. Don Lamb:

Right. It can work.

Dr. Jen Linehan:

I think, what we’re still trying to… If you think about the different types of non-muscle invasive bladder cancer, because remember, once it gets into the muscle that’s changing the treatments that we need to do and you need to see this guy over here, but if it’s non-muscle invasive, we can put the treatments into the bladder. That’s intravesical therapy. There’s many ways to do that. You have the immunotherapy, which is BCG and BCG plus other immune agents like Pembro, OPDIVO®, or those kinds of drugs. We were talking about that earlier. And then you have the chemo section.

There’s multiple variations of chemotherapies, combinations of chemotherapies, and heating chemotherapies, like Dr. Lamb taught us to do, you can put in the bladder. And then there’s what we call target therapies. That’s where we test your cancer and it says that it has this mutation and we have a drug that targets that mutation. Then you can put those drugs into the bladder. So there’s lots of different ways to go depending on what might be best for the patients. And a lot of these things that we’re learning are still in clinical trial because we don’t know. We might know they work as well as the BCG, but do you have to give the patients maintenance, or how long is that going to work for? Those kinds of things we’re all still figuring out.

Dr. Jen Linehan:

Yeah. There is another intravesical chemotherapy that is approved that’s based on if you have a certain mutation in your cancer. So if you’ve had a mutation, then that would be the best drug for you, and that’s the FGFR mutation.

Dr. Parminder Singh:

There are two drugs which I think should be available. One, FDA is reviewing their data, which is an interleukin-based immunotherapy, and one is going is already approved, but having some production challenges. What should be available by middle or end of the year is Adstilladrin. It’s based on a virus vector, which can help induce your immune response to kill the cancer. And so I think the options for bladder cancer in non-muscle invasive setting now, the portfolio has expanded dramatically and there is hope for a lot of patients now beyond BCG and traditional chemotherapy like Gem/Doce.

Diane Quale

Let’s move on now to muscle invasive disease. I know, Dr. Sigma, you also had a slide for us on some of the trials that are available in that space.

Dr. Parminder Singh:

Sure. I think, from the medicine point of view, certainly the field has changed in last five, six years with so many options as we talked about immunotherapy. Many of the patients here in the room had exposure to immunotherapy in my clinic, and also newer drugs which are more like delivery systems. These are, think of it as, smart bombs. They are antibodies which are looking for special targets on the cancer cell, and behind, on their tail, we have attached chemotherapy molecule. This delivery system, or this antibody, looks for a cancer cell in your body, wherever it is, it will go and attach to the cancer cell, and inject the chemotherapy into the cancer cell, and kill the cancer cells. So very smart delivery system. And they have revolutionized the way advanced disease patients are now responding, even far and beyond than what I saw with immunotherapy by itself.

And they’re changing the whole treatment paradigm for bladder cancer. Now they’re moving up into early stage disease. We have John here, who is on a clinical trial in early stage disease, where we are going to investigate this new antibody chemotherapy molecule. But I would encourage patients to enroll in clinical trials, as these help move disease treatment options forward, like all the trials which Dr. Jen Linehan showed regarding bladder cancer. In an early stage, you should ask your oncologist or urologist to get you access to trials so then you can get new access to new drugs, one. And it also helps move the field forward. Just to point out here on the screen, I’ve just put in the stripes, they reflect when the new treatment came on. You see here, since 2016, ’17, so many new drugs came up. Above the blue line are the new combinations, which are now very close to finishing of those trials, and maybe they’ll get approved. So the field for advanced bladder cancer is exploding in a good way for our patients.

Diane Quale:

A question, I think, for all of you, because we’ve talked about targeted therapies, even in the immunotherapy and the different mutations that a particular tumor might harbor. Do you think that genetic testing should be standard of care for all bladder cancer patients?

Dr. Parminder Singh:

Certainly. I was thinking about it. I knew this question is going to come up in this meeting, and how to address this? Because, a lot of patients come in and they ask about genetic testing, but one, it is an expensive test, and second is the applicability in my patients who I am seeing. There is a new drug which is listed here on the list now, the yellow strip. The erdafitinib is a drug which targets a special mutation or DNA alteration called FGFR. So, some patients whose tumor has FGFR3 alterations, then we can give this drug, but the problem is that there are very few patients who have this. Even though that test is available and now Medicare pays for that test, and we can get it done on each patient costing close to $3,000, but then in terms of care planning, we are still lacking drugs which will target mutations.

Even though that information is critical to understand how the disease is progressing or to do clinical research, it hasn’t boiled down to the actual ground level for our patients. None of my patients here in the room have had this mutation, except I think John, you have this and we had talked about this. So one patient in the room has it. I think I have 20 patients here. Very few patients will have this mutation and so the drug applicability is limited, even though that test is critical to understand the disease. But on the flip side, I had always believed that this cancer is chemo sensitive. It responds to chemotherapy, and whenever we throw some chemotherapy, it works. So Dr. Lamb, through Gem/Doce, it works. We would throw paclitaxel, it would work. And so the moment we figured out there is a better way to deliver the drug… Daniel, you had Enfortumab EV and Stage 4 disease now in remission. I think there are few more patients who had Stage 4 disease cancer just melt away, because we can deliver the chemotherapy to the target. And these cancers, they respond.

Diane Quale

Was this personalized therapy, so you knew what you were targeting and you had a specific drug for that target?

Dr. Parminder Singh:

That’s the beauty of this, there is no personalization. It has a wider applicability. 85% of the patients who have bladder cancer express that protein, which this antibody’s looking for. So I don’t even care about testing. Why would I spend $2,000 to test? 85% patients will have this anyway, so we just give the patient the drug. And if the tumor is shrinking, then it’s working. If in some patients it doesn’t shrink, which we would know in six weeks on a CT, we stop the medication. But if it is working for you… I have patients, Stage 4 disease in the room, which were in remission. I’m going to tell you a story. When we did the original clinical trials at Neo Clinic, I had a gentleman who came from hospice and he’s like, “Doc, I want to try anything,” and we had just opened the trial for Enfortumab.

He had over 25 liver metastases. I was like, “I don’t even know if the sponsor will approve you as a candidate,” but his liver function was normal. Otherwise, liver was healthy. I gave him Enfortumab. Six weeks, everything gone. He lived for another two years and he died of UTI, not from his cancer. So I think there is a lot of promise for bladder cancer coming. Petros Grivas brought about Sacituzumab, which is another similar antibody drug conjugate, and now we are combining them with immunotherapy. If you see the orange line just above the blue line, the Enfortumab and pembrolizumab trial, FDA is reviewing that and we may get it approved as a combination, where immunotherapy is going to go with this smart chemotherapy and well then open up… 7/10 patients are responding to these combinations. Never seen before the kind of responses I’m seeing with these drugs.

Diane Quale:

That’s wonderful. Very hopeful and promising. Going back from advanced disease to muscle invasive, because we’ve also had this conversation while we’re here, because it’s very important for many people to keep their bladders. When you have muscle invasive disease, the standard of care has been chemotherapy plus bladder removal, is that the only option?

Dr. Parminder Singh:

I knew Diana’s going to ask me this, so she asked me to put this next slide on to show folks what she’s talking about, is bladder preservation. What is bladder preservation? My interest has always been to preserve the bladder, and so, when the BCG stopped working, we opened a clinical trial, 1605, which was looking at immunotherapy in BCG-unresponsive. Unfortunately, it did hit the statistical threshold, but Keytruda’s statistical design was such that it hit the benchmark. So it was approved even though the results were comparable. But then, similarly, in advanced disease patients, which is more patients who have muscle invasive disease, but it is still limited to the bladder, can we preserve the bladder?

Believe it or not, in US, this was not considered a good option for bladder cancer even though, across the pond in Europe and UK, people were getting it all the time. Even in Canada, this is very prevalent, but USA folks are not interested in studying this. That’s where patient advocates pushed for this trial. I couldn’t find anybody to support this idea in 2016, ’17 when we proposed this, but then patient advocates pushed it so hard. When we proposed this, but then patient advocates pushed so hard that NCI, FDA, everybody agreed that, okay, we’ll push, we’ll let you move with this trial. And this is looking at combination of chemotherapy, radiation, and immunotherapy to see if we can put all that together and kill the cancer and prevent it from coming back. Now it is not a good option for everyone, and there are folks in this room who I have told that this is not a good option and I have folks in the room who are told this is a good option, but they decided not to take this. So John and Jack, we will ask them to comment on why they didn’t opt for radiation when we talk about it because there is something which comes after the treatment, which is the follow-up. Because once you go through this treatment, your bladder is saved, but you have to follow, every three months have a cystoscopy, which could be painful, discomfort.

So that’s where Dr. Lamm’s research comes in. If we can find out the recurrence without doing a cytoscopy, they may have to undergo repeated biopsies. And then in future, if the cancer comes back, then you will have to have your bladder removed at that time. And what if it comes more advanced at that time? So that’s the risk that is always there. So some people don’t like that and they want their cancer to be out of the body and that’s okay. But then at the same time there are folks who may not be a good candidate. So I have a gentleman here who wanted it and I said, “No, you are not a good candidate” because in men, as we grow mature, not older-“

Participant:

Our prostate gets bigger and invariably many patients will require their prostate to be scraped with age to help alleviate difficulty in urination. And if the radiation is done in that area, then those problems will become aggravated and your quality of life may go down after preserving your bladder. And so you don’t want to actually decrease the quality of life by keeping your bladder in because if you have to pee every hour post-radiation, then it doesn’t make sense. Why would we preserve that bladder? So you have to select the patient right. Patient has to be motivated to follow up so that we don’t miss the cancer coming back. Bernadette is here, she can talk about her experience with radiation, and she’s doing fine, but you have to be strict with your follow-up and it can certainly be done. It’s an option, which is a great option and we are trying to improve the outcomes even better with these clinical trials.

Speaker 3:

One other kind of bladder preservation that I’m aware of is, and I know they’re doing this at Sloan Kettering, so I’d like your thoughts about this too, that the patients undergo the chemotherapy and then they are scoped again. And if the bladders look clear, meaning the neoadjuvant chemotherapy works, then there’s watchable waiting. Can you speak as to your thoughts about that and who is… it really a viable option? Is it a safe way to go?

Speaker 6:

Yeah, there are some patients who will have a complete response to combination chemotherapy with muscle invasive disease, but we don’t just look, we got to do a deep biopsy and multiple biopsies to be sure that there’s no cancer remaining in the bladder. Now that’s the ideal situation where you wish you had a blood test or a more sensitive urine test to tell you if there’s any cancer anywhere. But you can do that. And we have patients who’ve gone for… that’s been it for them. They don’t needed any other therapy other than watchful wait.

Speaker 3:

Dr. Laman, your [inaudible 00:57:59].

Speaker 4:

And I’ve definitely seen those patients in my practice and how things have gotten started is that you were supposed to get the chemotherapy and then we take your bladder out and that was the standard of care. And then you’d have patients where they got the chemotherapy and then you took your bladder, their bladder out and there was nothing left.

Speaker 3:

And okay, the good news is the bladder is [inaudible 00:58:20] cancer.

Speaker 4:

Right. So then if there’s patients that if I look in their bladder and the tumors are small, and I think I can get it all by carving it out through the scope. Those might be good candidates for just having chemotherapy and then following them along and see if it worked. And also seeing the same results with the immunotherapy. They just had immunotherapy, that’s all they had, and we’ve watched them very closely to see if the tumors come back. So I think there’s more and more options that are going to be coming available. We just have to study them.

Speaker 3:

And when somebody does that, is the surveillance, is the watching after the chemotherapy and any other reception, is that more often than you would do otherwise? Is it like more than every three months or-

Speaker 2:

One out of three. So close to 30% patients will recur and that’s risky versus doing something definitive either a radiation or surgery after chemo. I’m the one who give chemotherapy, and I’m not undermining its value by saying that, but chemotherapy can potentially leave cancer behind, and it may be very difficult for urologists to find that cancer because they can’t just scoop out all your bladder to confirm that it’s gone. On this trial itself, because I have to review all charts, I’m seeing patients undergoing radiation, chemotherapy, the surgeon goes in, they don’t see anything, and they call and ask do we really need to biopsy? And I say yes. And so they do a deep biopsy and they find cancer deeper layers of the bladder still persisting. So not removing the bladder is still, in early investigation, where we are figuring out which is the right candidate to do that.

But I would not use this as a general advice at this time because the data shows that it is risky to leave the bladder post chemotherapy. Maybe we need to figure out a better combination, maybe the newer delivery systems and the immunotherapy combination which are showing remarkable response in advanced disease may take us to a point where we will consistently see that patients are having no cancer in the bladder. So John, the trial he’s on right now is looking at that combination before we remove the bladder. So the trial mandate us to remove the bladder because we are going to find out if once we give them that chemotherapy, how many of them truly has no cancer? If nearly seven, eight or 10 or nine out of them are having no cancer, then it may make sense. Why would we need to remove that?

But I think it is still early, and it has to be Dr. Lamm done on a clinical trial, not as in the general advice. Now besides that, what we truly do and like, I also have patients who have just put their foot down, “No, I’m not removing my bladder.” So there is actually now a test, which is a blood marker approved by Medicare, which can take your biopsy specimen, your tumor and then look for and do the DNA testing on your tumor and then try to match that into your blood to see if you have any of those similar mutations in the blood circulating.

And that test can pick up very, very small amount of cancer if it still exists in your body somewhere. It was approved last year. So we are still learning how to use or interpret results in context of clinical situation. But I have done a gentleman from Flagstaff who was like, “Doctor, I don’t want surgery, no matter what. I accept all the risks.” We gave him chemotherapy, we did the biopsies, they were all negative and he decided not to go for it. But I’m doing that test, but again it’s very risky and it should only be done under a clinical trial context, not as a general advisement.

Diane Quale:

I want to give enough time for questions, but I also want to have one more area, which is not as common but I also want to recognize it. Upper tract disease. Are there new treatments or new trials looking at upper tract disease? Anybody?

Speaker 4:

So one of the newest treatments, so this is where I was actually explaining this to my mom. So the cells that line the bladder and the kidney are the same type of cells. So you can get bladder cancer or urothelial carcinoma up in your kidney. That’s upper tract disease. And so you can have low grade and high grade just like in bladder cancer, and there is a new therapy for low grade upper tract and it’s basically a hydrogel that’s liquid when it’s cold and when you shoot the gel either through the back through the kidney or up through the bladder into the kidney, as soon as it gets to body temperature, it turns into a gel and it stays wherever you put it, because if you could imagine if you put a liquid up into the kidney, it would just trickle out and you’d pee it just out.

So it would never stay in there long enough to actually interact with the cancer and treat the cancer. That’s called Jelmyto, and that’s currently approved for low grade cancers right now. And there will be more intra-kidney therapies and cavitary therapies that you can use. You can also use BCG in some of these cases and you have to instill it through a tiny tube called a nephrostomy tube into the kidney as well. And there are more, I think a lot of the immunotherapies are the same that work for bladder cancer, can also be applied to upper tract as well.

Diane Quale:

So if somebody’s had high grade upper tract and had their kidney removed and so they’re being watched, is there anything you can do proactively because we know that oftentimes upper tract, the tumors can then show up later in the bladder. Is there anything you can do or is there any research being done looking at being more proactive than?

Speaker 6:

Oh my, that’s a very important field. It’s very hard to do studies to determine that something is effective.

Diane Quale:

Yeah, because you don’t really have target, you’re shooting.

Dr. Lamm:

Yeah, 40 years ago, we looked at high dose vitamins Oncovite and we found a huge advantage and then we did a larger study and it didn’t turn out to be any better than the three-week maintenance BCG. Well you can’t protect something if it is not there to protect. But your vegetarian plant-based diet, your exercise, staying out of… quitting smoking obviously are some things that may help. When we remove bladders for muscle invasive disease, we find that 17% of the time the distal ureters that also come out with that operation, 17% of the time there will be carcinoma in situ there. So it is always a concern that especially with medications, these are just topically effective like intravesical therapy, the medicine is not getting to where it needs to be. So you do see delayed failures in the upper tracts, and it’s something that we have to be aware of and continue to watch out for.

Speaker 4:

Well, I just think in all my patients that if they’ve had high grade upper tract urothelial carcinoma, they still need cystoscopies, urine tests looking for upper tract disease. We’re still figuring that out but there’s better ones coming out and the, of course, imaging following them closely with scans as well.

Speaker 3:

Great. Well so now we’ve got 30 minutes left so I’d love to open it up for questions.

Stephanie:

I have the first question and then I’ll come around with the microphones.

Speaker 3:

Yes, Stephanie.

Stephanie:

So give us a second. The first question, what are the clinical outcomes that you are seeing with a reduced dose of BCG due to the shortage, Dr. Laman?

Speaker 6:

Well, the AUA has a guideline, and it says that just give full-strength BCG for one year. And the study that one of the study that’s based on is the [inaudible 01:08:08] study where they looked at one year and one third dose double randomized to three years and full dose mixing that up so it’s balanced. And for the intermediate risk patients they said that, well one of your full dose is enough.

And actually if you look at the curves, the group that got one third dose for three years did better, not statistically significant, but their line was above the group that got a full dose for one year and it’s less BCG, it’s enough BCG to give several other people there, another induction. So if you can extend it out for the three years, it is not, it is probably, and there was almost a thousand patients in that study, that would be my preference if I was getting.

Speaker 2:

But I think, maybe, Stephanie’s question was in context to one-third dose of BCG because of the shortage, folks are using one-third of the BCG, what they would put in the bladder if the BCG shortage was not there, right Stephanie? Is that the question, right?

Stephanie:

Right.

Speaker 2:

Yes, absolutely. Absolutely, absolutely. Now-

Stephanie:

Giving it in over year, as [inaudible 01:09:57] said a one-third dose over three years. Yeah.

Speaker 3:

Yeah, yeah. Next question.

Speaker 6:

Can I say one other thing? It is clear with intravesical chemotherapy that what counts is not the dose of chemotherapy, not how much you put in, but the concentration, it gets into the bladder down a concentration gradient. So the more highly concentrated is, the more effective the penetration is. And I didn’t get a chance to talk about that yet, but we were involved in a study looking at nanoparticle docetaxel, which in animal models goes all the way through to the muscle layer of the bladder and it’s a very encouraging results with that. So it is, I don’t like to confuse chemotherapy with immunotherapy, but there’s no reason, there’s nothing magic about 50 cc. People sometimes will draw picture of bladder and they’ll, it’s half full, well you see half and there’s air in the rest. There is a bubble that goes in, which is the air that was in the catheter.

So you need to get up off the table really is all you have to do to displace that bubble. But you can put a third dose in a third volume and have the same concentration. And that hasn’t been done in the studies. That’s what I’ve always done. Also, you can warm the solution with chemo again and chemotherapy analogy, as a chemical reaction, what speeds chemical reaction, that’s chem one, increase temperature. So just warm it, and we wrote a paper and we said, it’s 43 to 44 degrees centigrade. Well that’s too much. We did that for a while. That’s too much trouble, just baby bottle warm. And you all know what baby bottle warm to the inner arm is and you know have a heating pad, you put your water or saline in, whichever depending whether you’re giving chemotherapy or BCG. And it’s right there. And it doesn’t take any longer, it doesn’t cost anymore, and it hasn’t been proven, but logic says it should be a whole heck of a lot better and take them all of the [inaudible 01:12:40].

Speaker 3:

How induction courses can you give?

Speaker 6:

Pardon?

Speaker 3:

How many induction courses can you give a BCG?

Speaker 2:

Well, the famous Catalonia study was if you give three it’s too high a risk of disease progression. But it depends on the interval between courses. And I much prefer, rather than if somebody’s been off for a while, I must prefer to give three and then three months, three more rather than continuous six. Some people have such a mild reaction that it’s, they may well need six or if they had no symptoms with the first three, you could carry on to the fourth drift and six treatment. We can’t go by, don’t worry if you haven’t had symptoms because some people have never had symptoms and never had a tumor back.

Speaker 3:

Next question.

Speaker 5:

Okay, thank you. Two quick things. If you talk about the CXbladder treatment in lieu of a cystoscopy and also is there… is CAR T-cell therapy, in other words T-cell transfer therapy, is that on the horizon for bladder cancer?

Speaker 3:

You want to talk about Cx?

Speaker 4:

Yeah, so for the Cxbladder, there’s been good evidence showing that you can use it to hold off on cystoscopy in screening patients. I think the data’s coming out of whether we can hold off on doing it in patients we know have bladder cancer where you’re using it to monitor them. Again, I’m making that decision very individually based on the type of cancer the patient had, how often they’re recurring, so whether it’s high grade, low grade, and how often they’re recurring. But I think that’s the hope as we gather the data on these urine tests that we’ll be able to say, “Okay, you could push cytoscopy off to three… from three months to six months if the CXbladder test is negative.” And again, I’m doing that in patients that I’m screening in, so the patients come in with microscopic hematuria and if the CXbladder test is negative, then I might hold off on doing cystoscopy and just follow them for a quick, the patients that we knew have bladder cancer, that’s still a little different.

Speaker 3:

Did you also ask about blue light?

Speaker 4:

Oh, no. He asked about [inaudible 01:15:10]-

Speaker 2:

CAR T-cell.

Speaker 4:

Yeah.

Speaker 2:

Yeah. So actually CAR T-cell that’s yeah, it’s a very good question because a lot of patients ask for, because of the media attention on CAR-T. So I’m just going to give you a very simplistic explanation of why CAR T-cell is complicated option for blogger is any immunotherapy, which is targeted immunotherapy where you’re training an immune cell to go after cancer cell or you’re developing a targeted immunotherapy, then you have to have that defined target on the cancer cell, which is not seen on other cells. Otherwise, your immune cell is going to go and hurt both the cancer cell and the normal cells. Now we spoke about that antibody drug conjugate, which I was so fascinated about. It goes after a target which is there in 85% of bladder cancer cells, but unfortunately that target is also expressed on the skin. And so as the chemotherapy goes into the bladder, it also goes into your skin.

So I have folks who will get bad skin reactions in the beginning when we were just new with this and we didn’t know what was happening and we had some patients who had really, really bad reactions and they died from the skin reactions too. So it’s risky, but now we know how to deal with all this. So we don’t see that kind of bad outcome now. But for any kind of immune therapy you have to have a define target, which is expressed only on the cancer cells.

So for lymphomas and leukemias, which are characterized by a certain protein or sometimes, different leukemias have different targets, which are very specific for that type of leukemic cell, it is easy to make CART therapy or lymphomas, but for bladder or any solid tumor per se, it is difficult to create such treatment options. But now, we have just started to go into the solid tumor field by first taking prostate cancer because there are certain things which are peculiar about prostate cancer that we may have a particular target for prostate cancer, and we, Mayo Clinic is going to open those trials shortly, but I don’t have anything coming up in bladder yet because we haven’t figured out the right target in the bladder.

But otherwise the other options which are, the field is moving in a way that I think we will be able to have a good handle even in advance in these patients with the other new options, which we have.

Speaker 3:

Next question from Beck, oh-

Speaker 7:

And Peggy. And a test was mentioned to see if the patient will respond to the BCG treatment. What is the test and where is it available?

Stephanie:

So the test is the Oncuria test. It’s a test-

Speaker 7:

Oncuria?.

Stephanie:

Oncuria. Yeah. Oncuria test. It should be widespread available. I mean it’s FDA approved, they should be able to get it in the institutions. We do have it… it’s actually originated out of Cedars and in Los Angeles, so we have it, but that test does look at characteristics of the urine that will say this patient has a higher likelihood to respond to BCG. Now, should you not use BBG based on just that, I’m not saying that for certain, but it might give you a better idea of how this patient might do, or maybe you’re saying, “Okay, we’re going to try BCG and if it doesn’t work, we’re going to move on to something else right away instead of doing a second course of BCG.” So I mean, we have a lot of information that’s coming down the pipeline and how we use that is always going to be very individual right now to each patient.

Speaker 4:

Stephanie, we also have questions up here.

Stephanie:

Okay.

Speaker 2:

All right.

Alan:

Hello, my name’s Alan. And my question is that if a patient becomes septic to BCG after going into maintenance, is there new procedures that they could get back on BCG? Because it was effective, but because I’m being told by my doctors that they won’t do BCG anymore. Okay?

Speaker 6:

Yes. Well, a bit of good news first, the patients who have a very serious reaction to BCG often don’t do well without further BCG. That’s a very strong immune reaction that can last a long time. But we have had patients who were very BCG intolerant, one woman whose father died of bladder cancer had very long-lasting severe irritated symptoms that eventually responded to antibiotic therapy. And because of her high risk, we put her on heat inactivated BCG. Actually, my first animal study in bladder cancer in 1973 was with a cell wall preparation of BCG. It wasn’t the live organism. There’s advantages to the live organism, one of which is, it persists, can persist for a long time so you get a long stimulation of-

PART 3 OF 4 ENDS [01:21:04]

Speaker 8:

… so you get a long stimulation of the immune system. But once you have been exposed, a second exposure using heat-killed, or inactivated, or there are cell wall preparations, of course, not commercially available, but there are preparations that can be used. But simply autoclaving the BCG and giving a reduced dose can be done and it seems to be quite effective. We don’t have good comparison studies to say that.

Speaker 9:

Okay. Can you hear me? Yeah. Okay. I had a question. If you have T1 high-grade CIS and you’ve got six weeks of BCG at half dosage and you didn’t respond, is that long enough to know if you could respond or not?

Speaker 8:

It depends on when you say didn’t respond. It will often take more than the six weeks after you finish the BCG for the immune response to completely get rid of the carcinoma in situ. If it’s increasing, it shouldn’t be increasing, it should be decreasing. So, if you go from multiple sites of carcinoma in situ, I assume that the T1 disease was resected, or if the T1 recurs, then it’s getting a little too risky perhaps to continue.

But sometimes it takes six months for the BCG to completely respond and we give three installations, not a second, six. But three at three months and then it will typically respond by six months. I have had patients go as long as nine months, but that’s kind of pushing it.

Speaker 9:

Okay. But if it’s reoccurred with multiple tumors, then it probably got-

Speaker 8:

Yeah, it’s time to go to something else.

Speaker 9:

… to go to chemotherapy. Okay. Thank you.

Speaker 10:

I know of an integrative doctor that does immune therapy like ozone therapy, high dose, IV, vitamin C and other things. What is your opinion of those types of therapies?

Speaker 11:

In context with advanced disease or localized disease? In context to advanced bladder cancer or localized bladder cancer?

Speaker 10:

To cancer.

Speaker 11:

Just in cancer?

Speaker 10:

Yeah.

Speaker 11:

So, it’s a tricky question to answer for us because there is no strong data behind all this. Whatever trials have been done in cancer, even by NCF, there was a large trial, select trial in prostate cancer looking at selenium and Vitamin E [inaudible 01:24:13] and it showed poor outcomes in patients who got supplementation. I generally tell my patients that, “You think about it in this way. Because there is lack of data, it is quite possible that taking high dose supplements may actually be helping your cancer cells also because these are your own cells. They are not aliens or foreigners jumping into in situ or they’re not viruses or bacteria. These are cells which have become rogue and they have similar mechanisms inside them as your normal cells. If you think your high dose vitamin C is going to help your immune system, it’s also going to help the cancer cell in some way or form.” And so my suggestion usually to patients when they ask me about all these therapies is, to avoid this because there is lack of data.

Now, in context with radiation therapy, our radiation oncologist, they always tell patients not to take supplements, because there is higher oxidative stress in the tissue when they’re radiating and that can lead to more adverse effects. So, certainly, with radiation we tell them not to take it, but in conjunction with other therapies, I usually tell patients to avoid it and that’s the reason behind it.

But there are folks, there are clinics here in Scottsdale, unfortunately, who claim to offer low dose insulin, Vitamin C and other supplements, infusions, ozone therapy to cure cancer. But again, the data, there’s no true data, randomized data to support all that.

Janet:

Another question about that?

Speaker 17:

Yeah.

Janet:

Okay. [inaudible 01:25:54].

Speaker 17:

First of all, I want to thank you all for being here to share your expertise with us. It’s very much appreciated. I have a question. I think you kind of circled around this a little bit. For patients who’ve had radical cystectomy, one of the things that we all worry about is upper tract recurrence. And my understanding is the current protocols for screening are periodic CT urography, which can miss very small tumors, or CIS, and urine cytology, which kind of lacks the sensitivity that I think most of us would like. There are other tests like CX bladder, but I believe you have to have your native bladder in place for that. How do you screen for upper tract in post-RC patients these days?

Janet:

I mean, the best and safest way at this point is going to be imaging. And I still look into the neobladder to make sure that there’s no cancer recurrence in the neobladder, because that would also tip me off, and or in the ileal conduit, too. But I mean-

Speaker 16:

Do you scope them on a routine basis?

Janet:

Yeah, in the very beginning, yeah, I do. But the imaging is going to be the best test for this, because at some point, it will be large enough that you will see it in the ureter. And if you’re suspicious of something else in the bladder then you may want to investigate more in the conduit or in the pouch, whatever diversion the patient might have.

I also think the test that he was talking about, which was the blood test that matches your cancer, I think that will become another good helpful watch test. And if that’s positive, you’re like, “Okay, well where is it then? I got to start looking.”

Speaker 16:

But would that require having a fresh sample of the tumor? I mean something from years ago, could you still match it?

Speaker 11:

Good question, sir. Just to explain to the audience again is, what we are talking about here is a test where we take your tumor sample, we check your DNA, and then we look for those changes in the DNA in your blood because then you are not looking… it’s essentially looking for a needle in a haystack, but because you now have a magnet which can pick up the metal, so then it is easy to find that needle in the haystack versus you just scrambling the haystack.

So, the question is, if the bladder was removed many years ago, will that test hold good now if we try to do this? This is an unanswered question because that test was just approved last year. And as I said, we are also learning how to use that in context.

At this point, the Medicare has approved it in patients who had bladder removed and when they removed the bladder, there was still a lot of cancer so there is a risk that the cancer is floating already in your blood. And so those patients, we can do that test to look for if there’s any cancer left, which is not being seen on the imaging.

But not in context with somebody who had had cystectomy many years ago. Because it is possible that now the cancer you are going to show up in your upper tract may be a new cancer and may not harbor the same mutation as your previous cancer. Again, the field is moving very fast.

With AI coming in, at Mayo Clinic, we are using AI platforms to read your scans. We are feeding in data from like 20,000 scans with various changes in patients who then had their bladder removed or kidney removed and they found cancer. So then AI is going to help radiologists localize that, “Oh, this is something which is suspicious.” So then the chance of us missing a small lesion will go down.

Similarly, I think in bladder space also, Mayo is looking at a AI platform where the urologist will put a camera inside the bladder, the AI will read the images in real time and put a circle around a spot where AI thinks there is cancer, even if it is not seen by the urologist. Like the white light you saw, there was no lesion there from the naked eye, but there are still some changes there which the AI can pick up, and then the AI will circle that area, so then the surgeon can go in and take a biopsy even if nothing is seen there. And then if the biopsy’s positive then we will find cancer. Again, the field is moving very fast, things are going to change in the next two years at a very fast speed.

Speaker 16:

Thank you.

Speaker 11:

Absolutely.

Speaker 13:

I had a question about, for those people who it’s not clear that they are a candidate for cystectomy, because they’re not stage two, I’ve seen some studies saying that perhaps some people at maybe a stage one could get a benefit from considering a radical cystectomy earlier on. What studies are being done in that area and when exactly should that be at least discussed?

Speaker 11:

Could you repeat that question? Yes. Thank you.

Speaker 18:

So were you asking about patients who don’t have high grade?

Speaker 13:

So if I had a high grade cancer, but it was like a state zero. When should a radical cystectomy be considered? I think I’ve seen some studies where maybe it became clear based on some results that there was some muscle invasion that was not detected.

Speaker 12:

So high grade, low stage cancer, would you ever consider cystectomy earlier [inaudible 01:31:30]?

Janet:

Yeah, I mean there are cases where I would consider cystectomy in those patients, but that’s pretty rare. With all the intravesical therapies that we have now, I have patients where they have so much pain from their cancers, from the resection of their cancers, they’re having high rates of recurrence and recurrence are multiple tumors all around the bladder. And we’re having to do more and more cystoscopy, more and more procedures to try to keep up. We’re doing intravesical therapy, but they’re still recurring. Those are the people that I’m really going to talk, sit down and say, “Okay, look, we’ve done two rounds of BCG and three clinical trials of different drugs intravesical, and you’re still recurring. Do we have to have a talk about that?” But I think that that situation is really rare. I don’t know any of my other urologic oncologists that would push patients into that unless it was an extreme situation.

Speaker 12:

A related question, Janet, because we’ve had this question before. So if you’re diagnosed with say a TA high grade and you’ve resected it and I’m watching it, what’s the chances of recurrence of it being like T1 or T2, because it started as high grade?

Janet:

So the chance of becoming T1 or the chance of recurring, period, remember is about 65% in general. The chance of it coming T1 is about 30 and the chance of it becoming T2 is about maybe 10.

Speaker 12:

Okay.

Janet:

I mean in patients that don’t have any intravesical treatment.

Speaker 12:

Right. Right.

Speaker 11:

But again, there will be patients who are outliers, and I’m pointing out to you Dan again. But Dan was T1 and then when I saw him with T1, we were thinking about giving immunotherapy, but then he ended up having stage four disease now in remission. But there are patients who we may miss. I think that’s what Maggie your concern is, that in an early disease patient, are we missing somebody who has advanced disease? Those patients are outliers, but they happen in our practice. Sometimes we are fortunate or lucky that we end up doing some extra testing. We may pick up the disease, but most of the patients we can follow them. And the idea here is to preserve the bladder, native bladder function as long as possible and then remove it when we think now the cancer has become too risky and go after it.

Speaker 8:

That’s why we call it the art of medicine.

Speaker 11:

Of medicine. Yeah.

Speaker 12:

Yeah. I think in the 23 years I’ve been doing this, I mean the number one lesson I’ve learned is that medicine is an art, not a science. Yeah.

Speaker 19:

A question. Do any of you know or aware of any…

Speaker 8:

It’s on. Just hold.

Speaker 12:

It’s on. Yeah, there we go.

Speaker 8:

There we go. Okay.

Speaker 19:

Would any of you know or be…

Speaker X:

Okay now [inaudible 01:34:41].

Speaker 19:

Okay, thank you.

Speaker 8:

She got you covered.

Speaker 19:

All right. Are you all aware of any non FDA-approved treatments or procedures that have been successful for bladder cancer?

Speaker 11:

Yeah, there are a lot of procedures which are not FDA-approved and FDA is reviewing that data-

Speaker 12:

Gem [inaudible 01:35:03].

Speaker 11:

… because we have done clinical trials. So you see the list of the clinical trials, many of them are either ongoing, they’re not approved, but they’re in clinical trials and or their clinical trials have completed and the FDA is reviewing the data to see if data merits approval of their drug. So those medicines come under the purview of unapproved strategies or you can say drugs.

Now, [inaudible 01:35:31] is in clinical trial right now, but we can still give it to our patients. We are trying to, because there is no clinical trial data showing in a randomized way that [inaudible 01:35:43] is as good as BCG or maybe even better so the trial, the confirmatory trial is ongoing, but F FDA allow us to give [inaudible 01:35:51] to our patients because of the lack of BCG if we want to give it in our clinics.

Similarly, immunotherapy in combination with chemotherapy is not approved, but we can make cases, because there is indirect evidence that they may be beneficial that we are able to get the insurance or Medicare to pay or sometimes even get the pharma company to just give it to us for free to our patients. That’s where the art comes in, where we think that this patient may truly benefit with this combination, we may ask for an off-label drug use. We do that all the time in our practice.

Speaker 12:

And it’s my understanding gemcitabine-cisplatin was never approved for bladder cancer and it was the standard of care for [inaudible 01:36:34] disease.

Speaker 11:

Muscle disease, yeah. Yeah.

Speaker 8:

There are a lot of disapproved drugs that are also quite effective. I was going to give the example of one of my patients who had low grade tumors, low grade tumors, not huge, multiple, multiple, but frequent low-grade tumors. And we tried everything. I finally, “Well, I’m going to give you some KLH,” keyhole limpet haemocyanin, which is an immunotherapy from a Pacific Sea slug that’s approved in Argentina and Austria and other places, but failed in the United States, because while a previous study comparing it with mitomycin in Germany found it to be better, they approved the mitomycin treatment subsequently and it turned out it was not as good as mitomycin, which of course is a good drug. So, it’s disapproved, but it’s available so we gave it to her. And after having tumors multiple times a year for years and years and year, a decade, she’d never had a tumor yet. And so, we miss her, we see her once a year.

Speaker 12:

Carlos, I think the last question.

Speaker 14:

Yes. I was just wondering if anyone on the panel can comment on FDA’s recent approval of Adstiladrin.

Speaker 11:

Yeah. So yeah, I’m going to… You answered that, yeah?

Janet:

Yeah.

Speaker 11:

Janet.

Janet:

You can go in. You can go ahead.

Speaker 11:

No, no, no. Go in. That’s your space. I’m not muscle-invasive bladder cancer.

Janet:

So this is another intravesical therapy that has been approved. Like we were talking about earlier, there has been some production issues with it so it’s not become as mainstream, but it is approved as another intravesical therapy that we can use.

Is it a replacement for BCG? I don’t think it’s there yet, but it’s definitely along the lines of different strategies that we can use for patients with high grade and TIS disease in that setting.

Speaker 15:

I think it’s coming this fall. That’s the-

Speaker 11:

Yeah, that’s what… yeah.

Speaker 15:

But I think-

Speaker X:

It was last fall. So they’re in the production.

Speaker 19:

You didn’t want to add anything to [inaudible 01:39:07]?

Speaker 11:

No, the same thing he said that, again, FDA looks at not just the drug activity but also, and I’m learning all this because I’m part, big, important part of being all these clinical trials is, that they even go and inspect the facilities where these drugs are manufactured and if those facilities have all the benchmarks standards met.

I don’t know, don’t quote me for this, but they found in one of the swabs, some fungus in that factory, so then they had to shut that factory down and they’re have to rebuild all that. So that’s why the delay is happening, and that’s what I heard. But again, I don’t know, did you hear the same thing?

Speaker 8:

Well, no, but that’s the same thing that got [inaudible 01:39:52] BCG in Toronto.

Janet:

BCG [inaudible 01:39:55].

Speaker 11:

[inaudible 01:39:55]. Oh, yeah.

Speaker 8:

They found some fungus somewhere and they-

Janet:

They shut the manufacturing.

Speaker 8:

… they shut it down and they built another one and then they had a hundred year flood.

Janet:

But to Dr. Lamb’s point, I think the more drugs that we have that we can use, you never know what’s going to work in a patient. And I think eventually we will get to figuring what’s going to work out best intravesical in patients, but the more options we have available, it’s better for patients. Period.

Speaker 12:

Well, I want to thank you all again so much for your time and expertise and sharing your Saturday with us. So thank you very much.

Speaker 11:

Thank you.

Speaker 15:

This is wonderful.

Speaker 20:

Thank you.

Speaker 21:

Keep up the good research and if… Lego, will you put on the last slide deck?

Speaker 22:

Yeah. This is wonderful. Thank you guys so much. This has really been enlightening. I love to see what gets you excited. And the things you’ve been able to talk about now, we didn’t have even at the very first patient summit that we did eight years ago, so this is really an exciting time. Never a good time to have bladder cancer, but comparing to eight years ago, it’s a much better time if you have.

Speaker X:

I’m quite excited about… Oh, picture?

Speaker 22:

Yeah. Picture. Picture. Come next.

Speaker X:

Thank you so much.

Speaker 22:

Excellent, excellent. Okay, super. Now where’s the… Can I have the clicker?

Speaker X:

Jen’s got the clicker.

Speaker 22:

Jen’s got the clicker. Okay.

Speaker X:

Thank you so much for everything.

Speaker 22:

So wrapping it up, we talked about nutrition and taste. We gave you some samples, we gave you some recipes. Lymphedema was a hot topic, yeah? Doesn’t happen to everybody, but now you know about it and you know more about rehabilitation before treatment, during treatment, after treatment, all of those things. I hope you have a better sense of addressing anxiety and fear. I will be sending out an evaluation and it’s going to have some follow up links in it because so many things that we’ve done and talked about, we also have more resources. So it’ll be a long email, but it’ll have a lot of good information in it.

We talked about strategies for dealing with sexuality issues. I think that was a great program this morning. I hope you got a lot out of thriving and surviving and the new research patient advocate groups that we are trying to keep going. So I will add all that in an evaluation email. So I want to find out, just raise your hand. Are you better informed than before you got here? Yay. Okay.

Are you better connected to other people that know? Good. How many of you got your sheets all filled out? I see a lot of blank pages on the tables.

Okay, so are you still confused if you’re a patient, a survivor, a family friend of one, a carer, a caregiver? All of the above. And it’s really hard to just pick the right term to describe. I tried the best I can to try to be encompassing, but I do want to say that you all now have a bladder cancer PHD. You’ve all been touched in some way by the sixth most common cancer in America that nobody talks about.

What’s a bladder cancer PhD? It’s a personal history with the disease. So you are all better educated. So you can say, “I have a bladder cancer PhD.” Whether you are a loved one, family member or the person who was diagnosed who’s now a long-term survivor, or about to go through treatment, you got this. Okay?

Thank you again to the sponsors that made this possible and free of charge. This is what we really appreciate is being able to do what we love to do, which is connect with you.

And remember, I had you guys take out your phones before. I’m going to, I promise I will hound you until you get this done, but I am giving you a first crack at the survey right now and I’m letting you know, if you get it done before Friday, you will be eligible to win this, very nice, it is very nice and stylish, Beacon jacket that you can rock on any walk anywhere in the country. So make sure you get it done.

The email will come tomorrow. I have to finish it and it will come tomorrow. Thank you. Safe travels to wherever it is you have to go.

PART 4 OF 4 ENDS [01:45:43]