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Webinar: Navigating Bladder Cancer Recurrence, Surveillance and Beyond

Dealing with low-grade non-muscle invasive bladder cancer (NMIBC) can be a journey filled with uncertainties. While some patients undergo successful tumor removal with no recurrence, many face the challenge of managing reappearances. In this BCAN webinar, urologists, Yair Lotan, MD and Eila Skinner, MD, shed light on crucial aspects of bladder cancer recurrence, surveillance, and the steps beyond.

Year: 2024

Navigating Bladder Cancer Recurrence (Part 1)

Transcript (PDF)

Navigating Bladder Cancer Surveillance (Part 2)

Transcript (PDF)

Navigating Bladder Cancer Recurrence & Surveillance: Q&A (Part 3)

Transcript (PDF)

Full Transcript on Navigating Bladder Cancer Recurrence: Surveillance and Beyond

Stephanie Chisolm:

Welcome to Navigating Bladder Cancer Recurrence, Surveillance and Beyond.

We know that dealing with low grade, non-muscle invasive bladder cancer can be a journey that’s filled with uncertainties. You never know what’s going to pop up next, and some patients undergo successful tumor removal with no recurrence and many face some challenges of managing the reappearance of a tumor sometimes when you least expect it. And so we’re really delighted to have both Dr. Yair Lotan and Eila Skinner with a wealth of experience in the management of non-muscle invasive bladder cancer. Dr. Lotan is professor of urology, the chief of urologic oncology and holder of the Jane and John Justin Distinguished Chair in Urology in honor of Klaus G. Roehborn at the Southwestern Medical Center of the University of Texas. He’s also the medical director of the urology clinic at the UT Southwestern and Parkland Health and Hospital System. Dr. Skinner is the Thomas A. Stamey research professor of urology at Stanford Medical Center and chair of the Department of Urology at Stanford Medical Center. They have so much to share. I’m going to advance their slides, but I’m going to go off camera now. Welcome to both of you. It’s a delight to have you here, and let’s start the program.

Dr. Yair Lotan:

Great. Thank you so much. And I appreciate BCAN and the sponsors for having this webinar and hopefully you’ll find it informative. So we all know that non-muscle invasive bladder cancer represents a heterogeneous disease with a wide range of disease recurrence and progression. Patients with bladder cancer, as you know, usually show up because of blood in the urine, or other urinary complaints. It’s very rare to have it in younger patients. Average age is around 74 and the risk increases with age. And so, most patients are over the age of 50. And the biggest risk factor for bladder cancer is the history of smoking.

So how do we diagnose bladder cancer? As many patients realize when we look for the source of blood in the urine, we look for either blood coming from the kidney, which can be associated with kidney cancer, kidney stone. So most patients will have an imaging study like a CT scan first, and then because bladder cancer is such a common cause, we look in the bladder with a cystoscopy in.

So you can see on the left side of the screen here, image of a CT scan, a cystoscope, and then a typical appearance for a bladder tumor. And if we find a bladder tumor in office cystoscopy, then the next step is to remove it. Usually this is done transurethrally at the time of surgery under anesthesia and the main goal is to remove the tumor and also, which will allow us to find out what stage and grade it is.

The most important factors in terms of prognosis are the stage in the grade of the cancer and stage of cancer really depends on the depth of invasion. So bladder cancers start in the lining of the bladder and if it’s confined to the lining, which is the best case scenario, it can either be a flat tumor called the carcinoma in situ or a papillary tumor, which is actually more common, and that’s a TA tumor and that’s the lowest stage cancer you can get. If it starts invading into the bladder, then it can go into the lamina propria, which is here in blue, and those are stage one tumors.

If it goes into the muscle, it’s a stage two tumor and if it’s at least a pathologic T stage, and if it goes into the fat it’s a T3 tumor. Usually when we resect a tumor endoscopically, we do not know if it’s going into the fat because we don’t want to make a hole in the bladder. And that’s sometimes we find out if we remove the bladder later. Or sometimes you can tell from imaging studies that there’s invasion through the wall of the bladder.

So the goal of the initial resection is to find out what this subtype is.

Is it a typical urothelial cancer? There are other rarer subtypes like squamous cell carcinoma or adenocarcinoma, which are much less common than the typical urothelial cancer and we want to know the grade, high grade or low grade. And then as mentioned, the depth of invasion. We want to remove all visible tumor and the quality of the initial resection really affects the ability to have a correct diagnosis and staging and that will dictate the need for additional therapies and let us know what the likelihood of the cancer coming back will be.

The TURBT procedure, even though it’s endoscopic, shouldn’t be taken lightly. And some patients who have occurrences undergo multiple of these resections and we recognize that there’s a risk that they get readmitted because of delayed bleeding, less so commonly for pain. The rates are not high, but approximately 3% to 5% of patients will have significant complications. There’s a small risk of perforating the bladder, which we’re always concerned about. There’s a risk of infection. And then of course there’s a cost. You can’t work that day, maybe your family can’t work, you have to travel to the hospital, you might miss work afterwards. So we recognize that. And finally, there’s more and more recognition that repeated anesthetic procedures can lead to cognitive decline in older adults. And as I mentioned, the average age for bladder cancer is 74, and so that means half of the patients are over 74. And if you do multiple surgeries because of recurrences, that means multiple times that the patient has to undergo anesthesia.

So what are the causes of early recurrence? I often use an analogy of skin cancer or weeds for bladder cancer because as long as we keep the bladder in place, the other parts of the lining of the urinary tract has been exposed to the same carcinogens or cancer causing agents that the first tumor was. So what happens when we initially resect, we remove everything that looks suspicious, but maybe at the margin of what we resected, an area didn’t look completely suspicious, but there was a little bit of cancer or we might’ve missed other cancers. So that’s one thing we always look at. Can we do better in terms of visualization of cancer at the time of surgery. After we remove a tumor, there’s a lot of times particulate particles floating around and some of those are cancer cells and some of those cancer cells can go and find another spot to land in the bladder. And so for some cancers we will put some chemotherapy immediately after surgery.

It seems to help patients with small low grade tumors, mostly as we’re going to talk later for patients with more aggressive disease, we’re going to give six weeks of therapy down the road and so that initial one treatment may not make a difference. Finally, some cancers are just very aggressive and recur rapidly, and that’s the main reason that we think that most patients will need additional treatments if they have high grade cancers or if they already have multiple tumors in their bladder.

So immediately, like I said, for patients especially those who suspect low grade disease, we might put a dose of chemotherapy. It’s usually either gemcitabine or mitomycin. We do it right after surgery, either in the operating room or in the recovery room. Usually sits there for about an hour and then we drain the bladder and then usually let the patient go home. We’re careful not to do it if we’re concerned that we perforated the bladder, we don’t want the chemotherapy to spill outside the bladder. And the goal again is to kill any microscopic cells that are floating around.

As I mentioned earlier, there are two main components for cancer. One is the stage which is the depth of invasion, and the other is the grade. And most of the cancers are characterized as low grade or high grade. There’s some other categorizations for papillomas. Those are actually pretty uncommon and tend to be benign or behave quite… ith rare recurrences, things like that. But I almost never see them at all. Low grade cancers are ones that look very similar to normal bladder cells except that they develop this papillary architecture and they are growing more rapidly. The normal cells another and high grade cancers are very atypical in appearance. A lot of times the cells look very irregular and they’re dividing a lot relative to what a normal bladder would divide.

So some of the questions that we ask ourselves is, after we get the initial pathology from the TURBT, how do we decide do we need to go back and re-scrape? As mentioned, sometimes we’re concerned about maybe having residual cancer behind. I think Dr. Skinner was going to address this.

Dr. Eila Skinner:

Okay, so sometimes nowadays we will recommend a repeat procedure in somebody even though they just had one. And the reason for doing that is that as Dr. Lotan mentioned, sometimes we know that we resected a big tumor and we’re pretty sure we might’ve left some behind or we’re worried about that. But also the tumors that are starting to invade are particularly dangerous and we really need to know for sure that we don’t have muscle invasion. So generally in those situations where we’re worried about tumor coming back or being left behind, we want to go back and do a second procedure. It’s often disappointing for the patient to hear about that, especially if we didn’t mention upfront. But there’s a pretty good pile of data to explain why that’s important.

And you can see here that in one study at least almost half of the patients had some residual disease and more importantly, some actually were upstaged. I want to point out that this acronym, NMIBC, we use for non-muscle invasive bladder cancer. So you’ll see that throughout here. Next.

So now that you know the staging grade, you maybe had to have a repeat resection, then what’s next? What is the risk for recurrence and how can you estimate that, and do we need to do additional therapy? Next.

There’s actually a very nice risk stratification and this is trying to separate patients into groups based on what’s their risk of recurrence having another cancer say in the next three years, and more importantly, what’s their risk of progression, meaning that the cancer came back and is actually more dangerous or is going into the muscle or even spread to the lymph nodes.

So, the low risk patients or the lowest risk are patients with a small, less than three centimeters, first low grade in the mucosa only. So just on the surface, and that’s actually pretty common, those patients have a low risk of recurrence that’s maybe about 50%, but a very low chance of dying of their cancer. So in those patients, we try to minimize the amount of other treatments they have and just that initial resection with that one dose of chemotherapy might be enough for that patient to be followed. Intermediate risk is a mishmash of a lot of different patients. If you’ve had a recurrent low grade tumor, you automatically become intermediate risk. And then there are some high grade tumors that are small and solitary that go into this category as well. And then the highest risk patients are the ones on the right.

So if they have lamina propria invasion with a high grade tumor, if they have high grade tumors on the surface that are recurring frequently, carcinoma in situ automatically puts you in this group. And then there’s some other things down there on the bottom. And basically those are the patients where we’re worried about the cancer spreading and we want to be as aggressive as we can in order to prevent that from happening. Next slide.

So just to divide up in what it means, and you can see the numbers here for the risk of recurrence is high for everybody and that’s why it’s so important to have follow-up cystoscopy. The risk of progression can really change. Sorry, I’m fighting a cold. On the right is a really important concept. So patients I often find think that they had a 70% risk of recurrence at the beginning, that they’re always going to have that risk.

But in fact, the longer you go without a recurrence, the lower the chance it’s going to come back. And for that reason will often spread out the cystoscopy follow up as time goes on if you don’t have any recurrent cancer. Next slide.

And there are a whole bunch of things that we use to try to predict recurrence, not just those risk categories, but this is one of the calculators that’s out there. And you can type in the number of tumors, how big the tumor was, how often they’ve come back, how invasive they are, and so on. And you can actually plug in what your risk of recurrence is. There’s a bunch of these calculators out there, not as perfect, but this just gives you an example. The lowest risk group has a pretty low risk of recurrence, and the higher risk group is much more likely to have the cancer come back next here.

Dr. Yair Lotan:

So as Dr. Skinner was mentioning, the intermediate risk group really has several different components. There are patients who have multiple tumors which are low grade, noninvasive. You can have early recurrences, you can have frequent recurrences, you can have a large tumor, and you can also have some patients who have high grade disease that are small. And this was just a way to try to categorize it to try to help people make decisions about whether or not you should have additional treatment. So for example, if you had no risk factors, so you just had maybe two small low grade tumors, you never had a recurrence, you don’t have any large tumors, you’ve never had prior therapy, your chance of recurrence within a year is only about 20%. It’s not very low, but it’s such that maybe you wait and see whether or not you ever have a recurrence before you decide to have intravesical therapy.

On the other hand, if you had three risk factors, it was over 60% of the year and even with one or two risk factors is about 40%. So it basically tells us that we can categorize you and then try to make a decision should we give you treatments in the bladder? Because the concept of giving treatments in the bladder has some pluses and minuses. Mostly there’s side effects to the treatments and the inconvenience of coming in once a week for treatment and subsequently even once a month. So it’s nice to be able to give a patient some idea of what the expectation is that maybe their cancer will recur. Most important though is that if you start off with a low grade non-invasive tumor, even in the highest risk group, only about 5% of patients will progress to a more aggressive cancer within a year. And patients with zero to two risk factors, it’s quite a bit less than that.

And so the good news is that the cancer usually doesn’t change in its characteristics from low grade to high grade or from noninvasive to invasive. So the most important thing is for us to keep a close eye on your bladder so that we can catch it when it shows back up.

So with this prelude of the frequency of recurrence and progression, we want to talk about what other treatments we give and which treatment will we give.

So what’s the goal? So as mentioned, the rate of recurrence is quite high. It can be, as mentioned there, 20% up to 60% even for low grade tumors. For high grade tumors, it can even be higher. Progression basically means you went from noninvasive to invasive or low grade to high grade. But this is particularly important for patients who already are starting off with high grade disease, because if your cancer becomes muscle invasive or goes to another organ, your chance of dying of cancer dramatically increases.

And so if you start off with noninvasive disease, we very much want to keep you at noninvasive disease, ideally with no disease, but we definitely don’t want you to progress. And as mentioned, if you thought that maybe you have microscopic disease, especially in patients with carcinoma in situ, which are flat tumors, which sometimes look like red patches, we’re not really sure sometimes if your red patch is cancer or not. We don’t always want to burn or cauterize your entire bladder. So sometimes if you have a wide area with a re’ patch, we biopsy it, find out if it is carcinoma in situ, but we hope that medications will get rid of the rest of it and not having us have to cauterize a large area. So primarily we use it in patients with multiple tumors, frequent recurrences, high grade disease or large cancers.

As far as the terminology adjuvant means after resection and intravesical means in bladder. You hear about other types of treatment, systemic treatments which are IV or intravenous treatments. You hear sometimes about pills of course, but intravesical specifically means we’re going to put a catheter in your bladder and pour usually a liquid in there and that’s the way the treatment will work. And there’s two general classes of them. One is a form of immune therapy, which is BCG, which is a vaccine against tuberculosis. This is extremely common, but very old therapy. It’s been used for more than 50 years. Fortuitously, a couple of urologists wanted to stimulate the immune system. They didn’t really have good drugs. They thought, well, vaccines stimulate the immune system and we happen to have liquid vaccines around.

And they poured the BCG, which was a liquid, into the bladder and they did it once a week for six weeks and turned out it worked exceedingly well and still is the standard of care for high risk bladder cancer. It doesn’t kill cancer cells directly. It really relies on the immune system to work. So patients who are immunosuppressed, they’re on steroids, they’re on chemotherapy, maybe they have lymphomas, leukemias where their immune system may not respond well. They really can’t get BCG because it’s just not going to work very well and there might be some slightly higher risk of getting infection. Chemotherapy basically is a drug that kills cells that are trying to divide. And so that’s another class of drug and we’ll go through some examples. We already mentioned some mitomycin and gemcitabine and docetaxel, all various examples of this. Dr. Skinner, do you want back in, or I’m happy to continue.

Dr. Eila Skinner:

Let me see how my lungs hold up.

Dr. Yair Lotan:

I’m ready, I’m ready.

Dr. Eila Skinner:

I think we kind of covered this already, so let me just skip ahead and so make sure we cover everything else. So the BCG, Dr. Lotan talked about the fact that it’s used and it’s kind of crazy because you’re putting a live bacteria in your bladder, but it gets part of your immune system revved up, which is specifically, anticancer so it actually works pretty well. There’s a big problem with a shortage in this country. It’s maybe getting slightly better, but there’s still many practices that are not able to get BCG for you. And we’ll talk a little bit about what to do. I know BCAN is working very hard to lobby to try to get other types of BCG approved and so on. Next.

So as Dr. Lotan mentioned this already, there are contraindications to BCG. There are side effects that you can get as well and we try to minimize those as best we can. Next.

So one of the really nice things about chemotherapy in the bladder is that it’s not absorbed. So I often have patients, I tell them I’m going to give them gemcitabine. They go look up the side effects of gemcitabine and they’re terrified because those are all side effects that happen when you give it intravenously, which we do. We use this drug for example, for bladder cancer that’s spread already and we use it in the IV form, but in the bladder it really doesn’t get absorbed significantly. You can get some cystitis from all these chemotherapy agents, but very little of it is absorbed. And the general toxicity, for example, myelosuppression means it drops your white blood count or your red blood count. Cardiotoxicity is for these drugs that are hard on the heart. Occasionally we see that, but generally they’re really well tolerated.

And one of the nice things is all these are generics now, so they’re all pretty inexpensive as well. We now are starting to combine some of them even.

So the standard course is six weeks. There’s not a really good rationale for that. That’s just the way we’ve always done it. And generally you come in the office, you can drive yourself there, you get the treatment put in your bladder and then you can go home. We try to have you hold the treatment for at least a couple of hours if you can in the bladder. And so you want to make sure you go in a little bit dehydrated. And if somebody has a lot of bladder frequency, it can be a problem sometimes. We now know that for all these drugs that continuing the treatments beyond that first six weeks can be helpful.

There’s specific indications for example, for giving what’s called maintenance BCG, which we do for three weeks at a time at this regimen that you can see at the bottom. For chemotherapy, we generally do it once a month for maybe up to a year or two.

So, BCG is quite effective. So if you have carcinoma in situ, for example, you can expect a 60 or 70% chance that we’ll be able to get it to go away. It doesn’t mean it’s going to stay away forever, but it actually is pretty effective initially and it’s considered the first line treatment. So in the face of a shortage, we try to use BCG when we need it for these high risk patients and sometimes use chemotherapy for patients who are not as high risk. And the BCG with maintenance has also been shown to reduce progression, which is particularly good. Most of the chemotherapy agents have not really been proven to do that. Next slide.

So this is what we call a risk-adapted approach. So these are the same risk groups we showed you earlier.

So in the low risk patient I mentioned you want to minimize the amount of interventions that you have to do because this is not a life-threatening condition. So for example, if somebody comes in with a small recurrence, we may be able to just cauterize it or burn it in the office. We can make that actually quite tolerable. We spread out our cystoscopy. So, many of these patients we’re seeing just once a year after the initial maybe three months cystoscopy. And then as we mentioned, using that one dose of chemotherapy right after the resection is very helpful, reduces recurrence by about a third.

Intermediate risk is where we start using induction therapy. And for these patients, the chemotherapy and BCG are probably equally effective. And so it really just depends on what’s available in your own particular situation. And then the high risk patients, we want to do the treatments absolutely for sure, we try to use BCG if we have it.

And these are patients where sometimes we’ll start talking about surgery to take out the bladder if we think they’re very, very high risk for progression. Next.

I mentioned the BCG shortages. So what can you do if your doctor says he doesn’t have any or she doesn’t have any BCG? So seek out alternative locations, at least in California, the referral centers and academic centers have a little more supply. You can use intravesical chemotherapy instead. Cystectomy, again, for a high risk disease if that’s the only option. And there are now a lot of clinical trials available, although many of the current clinical trials require prior BCG failure before you’re eligible. So your physician can hopefully help guide you about what clinical trials are available. Next.

And what to do if BCG doesn’t work. So the first thing we do, say you have carcinoma in situ, you got six weeks of BCG and you still have what looks like CIS there.

We know that a second course can be effective. So we usually do a second course before we give up on BCG. If you still have disease after that initial six months, then we know that this cancer is not going to respond to more BCG. We do start talking about cystectomy in that situation. If you have high risk disease has a very high cure rate, but of course there’s a big quality of life impact of taking your bladder out. There are so-called salvage intravesical chemotherapies, valrubicin is the one that’s approved. I will say I have never used that drug and it’s because it only has about a 10% success and has a lot of side effects. So we just don’t generally use it. Individual chemotherapy agents only work about 20% of the time and currently what seems to me to be the best option is this what’s called doublet therapy where we put one treatment in, leave it for an hour, drain it out, and then put the second chemotherapy in.

That so far seems to be one of the most effective ways to treat this situation. Then you probably have heard about Keytruda, that’s an intravenous immunotherapy that is approved for this has about a 20% success at one year. So still not great. It’s pretty well-tolerated, but it does have some potentially very serious complications. It’s used routinely for metastatic bladder cancer, but in this setting it really has to be an individual decision about whether it’s worth the risk and the cost for that agent. And then the newest one on the block is Adstiladrin, which is another intravesical sort of, it’s actually almost like a gene therapy, was developed by urologists, which is great. And it’s just now becoming available. It’s one treatment every three months, which is super attractive. It is very, very expensive at this point, but I think we’re still trying to sort out where all these things fit together.

Dr. Yair Lotan:

So as we mentioned earlier, some of the tumors, especially carcinoma in situ can look like red patches or just not be visible with normal view. And one of the problems when you give drugs like BCG, which cause a lot of inflammation, is that you do end up with red patches and then you don’t know if it’s cancer or if it’s just inflammation. And so many people will try to use enhanced cystoscopy. There are a couple of different modalities to do that to try to identify cancers that are not well seen with typical white light cystoscopy. And so there’s two main strategies. One is called blue light cystoscopy, and for blue light cystoscopy you have to put an agent in the bladder. It’s called Cysview, but essentially it’s kind of like a nutrient that cancer cells selectively take into the cell. The normal cells usually are not bringing in. And when this photoactive substance gets into the cell, when you shine a blue light on it looks pink. And this is sort of a classic picture.

It doesn’t always look quite that nicely differentiated in the operating room, but many times in surgery if you use this you can identify some areas that you might’ve missed otherwise. And it seems to improve detection of carcinoma in situ (CIS) by about 30% and sometimes can help you find some additional papillary tumors as well. And there are multiple studies that have looked at it. And so quite a few centers have this in the hospital for surgery and there’s a handful of places that also have it in clinic, but the main manufacturer right now is not really selling the scopes for it. So it’s still pretty limited who can do it in the clinic setting. The other option is narrowband imaging. It’s basically a way of looking at wavelengths of light that will make blood vessels look green. And since cancers attract blood vessels, if you look for the areas that are getting more blood, you might see some additional tumors that you might miss. And so this is kind of an example and you can see the tumors are a little bit more, a little easier to see.

I think you can see two of them quite well. But one of them is a little pale at the bottom left and you can sort of see it better with a narrowband imaging. And there are some studies that have shown that this improves detection. The good news is it comes on a lot of scopes automatically and you don’t have to instill something in the bladder ahead of time, but not every scope has it. Not everybody uses it who has these scopes.

So we have guidelines that kind of help us try to decide on how to best approach patients. And basically there are several settings where if you have blue light and you’re concerned about recurrence or for example, sometimes we don’t see a cancer but we do a urine wash and it shows cancer cells and we don’t know where did we miss it. So then we say, well, we better do a scan of the kidneys to make sure it’s not cancer in the lining of the kidneys, but maybe we should use enhanced cystoscopy in the bladder to see if we can find some abnormal patches that we might’ve missed with white light.

Dr. Yair Lotan:

And so as I mentioned, there’s good data that shows that it will improve detection of carcinoma in situ and can reduce recurrence of cancers in the early phase because if you find them at the time of resection, you get rid of them and then you don’t see them three or six months later. There’s some data that is looking to see if it reduces progression, but these events are really pretty rare, so the data is not very strong as of yet.

So how often should we monitor patients? We mentioned how frequently this recurs, so how quickly should we look in the bladder for patients?

So how do we do it? Well, first of all, we look the same way. We found it in the first place in the office, look around and it’s important. The most important time to look is actually at three months. As Dr. Skinner mentioned earlier, if you’re disease free for several years, you’re much less likely to have a recurrence over time than right off the bat.

And right off the bat, at three months you really need to make sure, especially if you gave somebody six weeks of chemotherapy or BCG, you want to make sure they responded and you want to make sure you’re not missing patients who have a high rate of occurrences. Now, if the patient was low risk and that was a patient who had maybe one small tumor and at three months you don’t see anything, you may not need to look again for nine to 12 months and then once a year afterwards. But for intermediate and high risk patients, we usually look every three months in the first two years and then every six months until year five. For some intermediate risk patients, we might do it every six months in the second year as well, depends on how they became intermediate risk. As I mentioned, there’s a lot of variety. So you could have started off with two small tumors and been intermediate risk and not recur for a long time. So there’s a little bit of subjectivity there, but certainly we look quite a bit more often for those patients.

So cytology is something that we commonly will do at the time we do cystoscopy, which is to collect some urine and send it to the pathologist to look under a microscope. It’s much better for high grade disease than it is for low grade disease because low grade disease, the cells by themselves look very similar to normal bladder cells. And so cytology is really not that useful for patients with low grade disease. Some people will use it because they want to find those rare cases that patients progress to high grade disease, but it’s not uniform. But for high grade disease, it definitely will help catch those patients who might be missed, even though unfortunately it’s still wrong about 20 to 30% of the time. The one downside of it is that we might look in the bladder, tell you everything looks great, we collect urine. Five days later the pathologist sends us a report and says they see something abnormal and now we got to call you back and say, “Hey, we must have missed something and we need to now do a scan and maybe even go do biopsies in the operating room.”

There is a couple of ways though that cytology can be abnormal. In most institutions, if it’s positive for cancer cells or suspicious, then there really is cancer somewhere. We may not be able to always find it right away. Sometimes it can take six months, nine months before we can even find a cancer, but we know that we should be concerned. But oftentimes you might get atypical cytology and most of the time that means there’s no cancer there and the cells just look a little irregular because you’ve had treatments in there like chemotherapy or BCG that makes cells look a little irregular, a little reactive. And so not every time that cytology is not normal doesn’t mean there’s cancer. And really the urologist will let you know if you should be concerned about it or not.

Dr. Yair Lotan:

Now, I could spend an hour talking to you about various tumor markers that are being developed or have been developed to help detect cancer early.

Basically, cancers are abnormal cells and what makes them abnormal is that they’re growing faster than normal cells and they have mutations either in their DNA or their RNA or they’re making a lot of proteins because they’re trying to grow, proteins are the machinery of the cells. And so people have looked for any variety of these abnormalities, whether or not by looking for abnormal DNA RNA abnormal proteins, because the good news is that the bladder cancers are in the lining, which is right next to the urine. So you can look in the urine for some of these substances that you might not find in normal cells. The problem though is that sometimes if you don’t see anything, and these markers are positive, you have the same problem with cytology is that you may not know where exactly the cancer is and maybe it’s too small to even see with our cameras. And so we’re stuck with what do we do next? Should we biopsy patients? And there’s also a risk that there are some abnormal proteins because of the therapies we give so you can get false positive results.

So there’s still a lot of studies being done to figure out how to best use these markers, but definitely there is a role, if you’re already seeing something abnormal, if you see a red patch and the cytology is atypical, then the marker might help you decide should I have a biopsy or not?

So the good news about them is that they’re quite sensitive, even more sensitive than cytology, especially for low grade cancer. But specificity, which means, do you actually have cancer when they’re abnormal, is lower than cytology. And so, as mentioned, it’s really a matter of selecting appropriate markers for the clinical need and it’s not something that we usually recommend to be done routinely.

So let’s talk a little bit about recurrence.

How do we prevent it? Well, a lot of patients ask me, “What can I do?” And the easiest thing for me to do is stay away from smokers or don’t smoke because there’s a lot of evidence that smoking, which is the most common cause of bladder cancer will increase your risk for recurrence.

So it’s not enough that it just causes it, but if you stop, you’ll actually help reduce the risk for recurrence. It also helps prevent other bad diseases, lung cancer or heart attack, stroke. There’s many things that tobacco is not good for, but if you don’t smoke, then it’s really much harder to do. A lot of patients want to take vitamins, they want to eat fruits and vegetables. I have patients that swear by it. Unfortunately, there isn’t very good data to support doing any of these things. And what I tell patients is, “I don’t really want you spending a lot of money on supplements and other things, at least not on my behalf, because there’s no data.” And we are data-driven people. I think that you can get a good… If you have good nutrition, eating fruits, vegetables, a heart-healthy diet. That’s what you want to do. You want to exercise, but taking a lot of extra stuff hasn’t been shown to help you.

Well, good news for everyone. We made it to the end of our presentation and we’re more than happy to answer any questions.

Stephanie Chisolm:

Well, that was great. Thank you both so much.

There were a couple of questions that I was just thinking of as you were talking. And going back to almost the very beginning. What is the percentage of low risk patients, if you just wanted to give a vague idea, that have a recurrence, how often do you have to keep going back on patients?

Dr. Eila Skinner:

So the overall percentage is about 50% at three years. You can reduce that a little bit with that immediate post-op chemotherapy. And most of them, as Dr. Lotan mentioned, stay low grades. So they’re not any more dangerous than the first one was. But once you’ve had a recurrence, you have a higher chance of having another one. The bigger question I think is when can you stop doing cystoscopy? And nobody knows the answer to that. It’s really not been studied very well.

I usually will kind of start suggesting stopping at about five years for a low-grade patient and about 10 years for a higher risk patient, especially if they had high grade disease. It’s really important to get at least an annual urinalysis to make sure there’s no blood in the urine. But honestly, there’s just no data. And often I find I suggest stopping and the patients are like, “No, no, I want to come every year anyway.” But it is an invasive kind of unpleasant procedure to have a cystoscopy. We don’t have a urine test yet that’s quite good enough to use instead of cystoscopy, but I think we will, and probably fairly soon.

Stephanie Chisolm:

I think that most patients are really eager to find out that they don’t have cancer. It’s not that they want to find it again, they just want to make sure that what was working still works. I know you mentioned, Dr. Lotan, you were talking about blue light. You don’t typically use that for the first time you go in for a cystoscopy to find bladder cancer, the blue light. When do you use blue light? Can you just clarify that?

Dr. Yair Lotan:

Yeah, so I think we should start with, first of all, it’s not approved in patients just with blood in the urine. And as I mentioned, how do we find the cancer? We don’t even know if you have cancer. So it’s really hard to justify bringing you in, putting something in your bladder, and then looking with blue light when there’s a good chance you don’t have bladder cancer. Remember, even patients who have visible blood, only about 10% have bladder cancer, so 90% wouldn’t benefit from it, and you can do it in the operating room if you find a tumor.

So you’re not removing the tumor that day anyway, you’re just doing a diagnosis. And so I think it has value for initial resection. I think it’s good for patients who have multiple recurrences or multiple tumors. Do I do it religiously and everybody, no, not in everybody and not in every setting. But if they do have recurrences, I’m going to do it. And I’m fortunate because I do have it in clinic, and so patients with carcinoma in situ that I’m monitoring, I will do it quite routinely because I’m concerned that I’m going to miss recurrences. But I recognize that there is a burden both financial and time. And so it’s certainly not something that is uniform nationwide.

Stephanie Chisolm:

And you make a really good point. You both are at large academic teaching hospitals and you have access to blue light, but the predominant patient in the community is being seen by a community-based urologist, they might have a big practice. That equipment is very expensive, so they may not have it in their office. They may have access to it at the hospital, at the local hospital, but it’s not as easy to…

Dr. Eila Skinner:

There’s even a lot of hospitals that can’t afford that. It’s a little over a hundred thousand dollars equipment.

Stephanie Chisolm:

Just for the machine, right.

Dr. Eila Skinner:

Just for the tower and the scopes and stuff. So you have to have a pretty busy hospital to make that justified.

Stephanie Chisolm:

There’s a good question that was submitted because I think this happens often in light of the current shortage, somebody was currently undergoing six weeks of BCG treatment because of the shortage, there have been three treatments canceled. It’s a problem that the treatments were not done in the six weeks’ time period, or that they only got three treatments.

Dr. Eila Skinner:

I don’t think we really know. Because it’s an immune treatment, I like to try to stick to the schedule. If we can. If somebody has to be gone one week, we don’t panic and we just keep going. But I think most doctors’ offices will try to make sure they have enough available and set it aside for those six treatments so that you don’t get in that situation. The other thing that we’re doing routinely is cutting the dose in half. If we have two patients that are being treated the same day and we can divide the dose up, that means twice as many people are getting treated. And the evidence is not super strong, but suggests that if you have very high risk disease, it’s ideal to get full dose if you can, but even half dose is probably better than nothing. If you have intermediate risk, honestly, probably doesn’t matter that much whether you use half dose or full dose.

Dr. Yair Lotan:

Yeah, I would say that for us, for intermediate risk, we actually prefer to give chemotherapy because for low grade tumors, we routinely reduce the dose for maintenance, but I think it’s important to try to get probably at least five treatments for the induction. And it’s okay if you skip a week because of infection, but we know that you need to get at least three or four weeks just to even stimulate the immune response.

The one thing I would say though is that especially for patients who, for some of the newer agents, they really depend on you having had adequate BCG to find out if BCG even works or not. So if you get an inadequate BCG and then you have a recurrence, is it because you didn’t respond to BCG, or is it because you didn’t get enough? And we have a hard time when we see patients for second opinions. If you didn’t get enough BCG, we really struggle. “Should I start you on BCG?” Again, we don’t want to waste six weeks of your time by giving you an inappropriate therapy, but we have no way of knowing if you will respond to more BCG because it’s still the gold standard for us.

Stephanie Chisolm:

That does make it hard. It is the gold standard. As you mentioned, sometimes even in the clinical trials, they have to have not had any effect or benefit from BCG before they can even enroll in some clinical trials, which does make it a little bit more challenging for patients when they’re considering a clinical trial. And you brought up one important point when you said you could split the dose and have two patients be treated at the same time. From what I understand, BCG comes frozen, so if you defrost it, you need to use it at that same time.

Dr. Eila Skinner:

At least that day, yeah.

Dr. Yair Lotan:

But it’s a powder.

Stephanie Chisolm:

So, what if somebody doesn’t show up?

Dr. Yair Lotan:

It’s a powder.

Stephanie Chisolm:

Right.

Dr. Yair Lotan:

So once you put in a solution, then you can’t take half the powder out, it will aerosolize. So you actually have to put liquid in and then you can divide it. And people, we divide it routinely to three, but you can’t save the powder, can’t use half the powder, and you can’t save the liquid once it’s in liquid. So that’s the challenge.

Stephanie Chisolm:

So let me ask a question about intravesical therapy, then. Do you fill the bladder? I’m remembering what you had on your slides. You hold it for two hours. I know holding your bladder for two hours, when it’s full, is a challenge. Do you fill it or you just put a little bit in there?

Dr. Eila Skinner:

Most of the time it’s a couple of ounces. So we empty the bladder when we first put a catheter in. So you start with an empty bladder, but it is important not to drink a giant Starbucks on the way to the appointment because you don’t want to have a huge amount of urine volume, it will dilute the treatment. And the other thing that’s one of my pet peeves is some people make patients roll around in the clinic while they have the stuff in their bladder, which seems crazy to me because your bladder, it’s not a bowl, it’s more like a balloon. So it’s collapsed around the treatment and the treatment will get all the edges of the bladder.

But I wanted to make a comment. We didn’t include a slide about clinical trials, but there’s actually probably 15 agents currently being studied as new approaches to this type of non-muscle invasive bladder cancer, and they really vary. There are some agents that are new immunotherapies, some more gene therapies, virus type treatments. There’s some that I have no idea what they do. And so there’s a lot, and it’s sometimes tricky to find one that’s close to home that is available, but hopefully your physician can help you find one or if you can go online and try to see what’s out there.

Stephanie Chisolm:

Yeah, remember on our bcan.org website, we have a clinical trials finder.

Dr. Eila Skinner:

That’s right.

Stephanie Chisolm:

You enter your state and then you can find all of the clinical trials for your particular diagnosis. So if you have non-muscle invasive disease, higher low grade, you can find the trials that are out there that you might be eligible for. And it’s a good way to bring that to your doctor and say, “Hey, should I be in a clinical trial if you can’t get me BCG, or if I’m having a recurrence on a regular basis, maybe I should go to a clinical trial and see what else there is.” And it’s a good question to ask. So I think that’s one of those good important things to bring out. Clinical trials are really investigational medicine. They’re trying to find new ways to solve the problem of bladder cancer recurrence. And so it would give you access to additional treatments that you might not get in your regular doctor’s office. But also you get really good monitoring as well in a clinical trial, because they want to make sure they’re checking to see if that new treatment has any kind of an effect. So I’m glad you brought that up. How soon after… I’m sorry.

Dr. Eila Skinner:

I was going to ask Dr. Lotan to comment on, many cancers now you can use sort of personalized medicine to figure out what’s the genetics of your cancer and can we pick our treatment based on that? Yair, can you talk about where we stand now with trying to do that for bladder cancer?

Dr. Yair Lotan:

Sure. So for non-invasive cancer right now, the main mutation that people are interested in is fibroblast growth factor FGFR, and the main one is three. So they have a couple of different receptors and they’re inhibitors of those receptors. And there was one trial, at least preliminarily showed a very good response for patients with intermediate risk disease when taken by mouth, but it has a lot of side effects. It can affect your eyes and your nails. So there’s actually a new drug that’s coming in, a formulation that looks like a little pretzel that will be alluded into the urine, so hopefully avoid some of the systemic side effects.

This is a trial that’s called Moonrise by Janssen, and it’s this pretzel, it’s called TAR-210. And anyway, that’s a very exciting trial for us, and that’s probably the main targeted therapy because immune therapies and chemotherapies are not targeted, which is good and bad. Now, the drugs, some of the systemic agent, which are checkpoint inhibitors, are looking at different receptors in the immune system. But interestingly enough, even though there are tests to look for those receptor status that hasn’t been consistently, the results of the whether or not that marker is abnormal or not hasn’t necessarily correlated with a response to the therapy. So theoretically, that could be a target but hasn’t been proven yet.

Stephanie Chisolm:

Yeah. So you mentioned the FGFR receptor. So with non-muscle invasive disease, do you typically have a lot of patients that want to have that tumor genomic profile done so that you could determine if they would be eligible for something like that? Or is that something you save more for muscle invasive disease or even advanced disease? When do you do the genetic testing on a tumor?

Dr. Yair Lotan:

Oh, it’s an evolving field. So if you have a trial open, we had the trial called THOR2 for these FGFR inhibitors. I did it relatively routinely because I was looking for who might be eligible for the trial. And we’re doing it pretty routinely for high risk disease, but I would’ve to caution that there’s not that much you can do with it. We don’t use it to tell you if the cancer is more likely to recur, and we don’t know that it’s going to predict response to therapy. So we do it in part because it’s a curiosity and also because once these trials do open, then we at least can tell a patient, look, the drug may not be available right now, but maybe in three, six months if you recur, then I know that you have this mutation and we could enroll you.

Stephanie Chisolm:

Yeah. A quick question. How soon after the initial TURBT is it generally appropriate for a follow-up cystoscopy?

Dr. Eila Skinner:

We pretty routinely do it at three months. And there might be a situation where you do it sooner, but generally the three-month cystoscopy is pretty standard.

Dr. Yair Lotan:

Only if we’re resecting do we go back after about four to six weeks, but the reason we wait four to six weeks is because the bladder looks very abnormal right after initial resection, so you wouldn’t know what you’re looking at it. It’s going to look red, it’s going to have some irregular tissue. And that’s just the healing process.

Dr. Eila Skinner:

Correct.

Stephanie Chisolm:

So you’re not normally going right in right away. And I think it’s really important to understand that there’s a reason why all of these things are paced out, it’s based on evidence, iIt’s based on all the data, all the studies that it’s not just you deciding, but the guidelines are crafted by the American Urological Association and other professional medical associations that bring together leading experts and they discuss the evidence and they weigh the best approach for statistically what’s going to be the most beneficial for the patient, and also to make sure that you are doing your job and keeping up with when that tumor might come back. So I think that’s important to remember that guidelines are still out there, and we do have them linked on our website. You can visit bcan.org and look for the guidelines. They are in there. We have time for maybe one other question. I know you mentioned that you have BCG at your facilities because they’re large institutions. Should they change doctors if their doctor says, “I don’t have it,” what should people do?

Dr. Eila Skinner:

That’s a hard one. I think if you happen to live near enough to a medical center, I think it’s worth calling to see if they have BCG available. It’s usually going to require getting established with another doctor. But in our area, I think most of the urologists who don’t have BCG will offer that to their patients as an alternative. Or, as Dr. Lotan mentioned, if you don’t really need BCG and chemotherapy is going to be equally effective, then I think that’s also an option. The caveat is that many urologists in small offices don’t have intravesical chemotherapy available because there’s a lot of regulation that goes with that they may not have in their office. I think if your doctor says there’s nothing I can do, then I think it’s a reasonable thing to say, could I get another opinion? But on the other hand, if they’re busy, and to ask them to call around and figure out who has BCG is probably not appropriate.

Dr. Yair Lotan:

Yeah, I don’t know. That change doctor is really the proper thing. I think it’s really find another one. You can hold your urologist, but you definitely are going to need to see another one to get to get the treatment. And the fact is, unfortunately, bladder cancer, that’s high risk has a lot of significant potential complications to it. And if you don’t get the appropriate treatment, it’s not just 50 to 70% recur, but 10 to 30% will become muscle-invasive.

If you develop muscle invasive disease, about half the patients will die of their disease within five years. And if you only have noninvasive disease, the chance of dying is only about 10 to 20%. So it’s a huge consequence if your disease gets worse. And so unfortunately, I wish everybody had BCG, I wish I could send BCG give you a six-pack and say, “Take it home and have your urologist give it to you.” Because the fact is that we’re not allowed to do that. Right. And it’s unfortunate because I’m in Texas and people drive two hours each way to get BCG with me, and they’re not even seeing me, they’re seeing my nurse. So it’s just access to these medications is just critical and unfortunate that we don’t have it more widely available.

Stephanie Chisolm:

So on the opposite extreme, when you do have it available, is there a maximum amount of doses of BCG that a person should have? Do you cut it off after so many rounds of BCG? What is the usual?

Dr. Eila Skinner:

There’s not a maximum. I’ve had patients who have had 20, 30, 40 installations. It doesn’t kill you. But generally we recommend for high risk patients, six weeks induction, and then the so called SWOG protocol, which is additional three weeks every three, six, 12, and then every six months after that out to maybe three years. Nowadays, we often will shorten that down so that we save more BCG for the rest of the world. But the most important is not to keep doing BCG if it’s not working. So if you’ve had two cycles of BCG and you still have cancer there, there’s very little evidence that more BCG will help. Sometimes we’ll come back to it if it’s been many years since you had BCG, but you just don’t want to take it if it’s not doing anything.

Stephanie Chisolm:

No. Well, I want to thank you both again for taking your time to do this. We’re at time right now. I appreciate everybody joining us. So thank you so much Dr. Skinner and Dr. Lotan, and also thank you to UroGen for supporting the Patient Insight Webinar series. We greatly appreciate it.

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