Good evening and welcome to tonight's Platinum webinar. I'm I'm excited about tonight's speaker, but before I get on to choosing tonight's speaker, he'll be talking about bladder and prostate tumours, more than just NSAIDs, just a little bit of housekeeping. For many of you, I'm sure you've joined us previously, but if you haven't joined us in a while or you're new to us, because I know we have taken on a large number of new members in the last couple of months, which is absolutely fantastic to see us growing and er spreading the word.

How to get involved. We want this, our live webinars to be interactive. We want to give you the opportunity to post questions to the speaker.

So what we'll do, we, at the end of the webinar, we give a bit of time over to, ask your questions directly to the speaker. So throughout the presentation, if you do come up with a question, please just pop it in the Q&A box, which you'll find at the bottom of the screen. All you need to do is open, click on the Q&A, type in your question, and then afterwards at the end of the presentation, I will come back to that and answer any of your questions.

So please do take some time to put them in. If you have any problems throughout the webinar, my colleague Lewis is on hand to deal with your technical queries. So you can contact Lewis either by, writing a message in the chat box or sending an email to office at the webinar vet.com.

That noise in the background was my noisy cat, so I do apologise for that, but just adding a bit of authenticity to the whole proceeding. What else was I gonna say, sorry, yeah, we'll see, you know, put in the questions, and then at the end there will be a short survey that will pop up. So please do take time to complete that because we do value your feedback.

So please do take time to complete that. So, on to tonight's speaker. I'm delighted that we're joined this evening by Doctor Douglas Tham.

Doug, Doctor Tham is also a is a director of clinical research at Colorado State University, Flint Animal Cancer centre. He's also a member of the Development Therapeutic section of the University of Colorado Comprehensive Cancer centre. Up to date, he has authored over 140 peer-reviewed publications, 20 book chapters in veterinary and basic cancer research, and is co-editor in chief of the journal Veterinary and Comparative Oncology.

His clinical and research interests include novel targeted therapies for animal and human cancer and ways to integrate these therapies with existing treatment. So once again, I'm delighted to welcome to you Doctor Douglasham. Over to you, Douglas.

All right. Well, thanks very much for that introduction, Rich. It's great to be here, everyone.

I've done quite a few of these, webinars and I always find them really, really enjoyable. So just in case some of you might not recognise, I did my best to really sort of accommodate the British audience by, using the King's English, whenever possible, as far as my spellings go, especially in words like tumours, but you may find through the pro the proceedings that, I do sort of go back and forth between, the US and the King's English version, so please forgive me for that. I'll just say one other additional things.

So it's about 1:30 in the afternoon here right now and it's about 40 degrees. So it's a really wonderful day to be, inside in my office with, with air conditioning instead of being out, in the field. So, so today's talk is gonna be about bladder and prostate tumours.

And really, I think the title says something that's very important that, really, there, there is more to, dealing with these and more options for management of these than simply the use of non-steroidal anti-inflammatory drugs, although that is a topic that we'll, we'll discuss because they can be very useful, but it really can be just the tip of the iceberg. . So this is my conflict of interest, and for this particular hour, actually, I don't have any relevant conflicts, so I won't be talking of any about any therapies or, or diagnostics for which I have any conflict of interest.

So here's some of the topics that we'll try and touch on. Today. So some generic and general information about, bladder tumours and their incidence and presentation, both in dogs and in cats.

And unfortunately, we will sort of bias this toward dogs where we have a lot more information. Risk factors for tumour development, sort of diagnostic and staging procedures, and then a variety of different treatment procedures including surgical kinds of treatments, interventional radiology, which is a really new interesting up and coming, field of, of therapy. NSAIDs, as the title, we're talking about, chemotherapy, a little bit about kinase inhibitors that might be useful, what we know about those and and then radiation therapy as well.

And then we'll, of course, along the way be talking about how well all these different things work so that you can inform your clients appropriately and help them make an educated decision about how to proceed. So, just a bit of background information from an epidemiologic perspective, as I think most of us know. Transitional cell carcinoma really constitutes the large majority of the tumours that we see in the bladders of dogs.

As, so, and again, this particular survey, it was about 3/5 of all the bladder tumours that we see with another 10% falling into a category called undifferentiated carcinoma. So these probably were transitional cell carcinomas that have just sort of de-differentiated or become some so plastic that they no longer have that classic histological appearance. So if you actually add these two together, about 85% of the bladder tumours that we see in dogs are actually probably derived from the transitional epithelium.

We do see a few squamous cell carcinomas, very small number. And another kind of odd tumour that we can see, are occasionally liomyomas, so tumours derived from the small muscle of the bladder and, quite uncommon. Another kind of tumour called a rhabdomyosarcoma, which is actually a, a skeletal muscle tumour.

These can often occur in young dogs. And they're often preceded by the the adjective botryoid, which refers to an appearance that's very much like a a bundle or a cluster of grapes. So once you see one, you'll definitely know what it looks like, but again, they are quite uncommon.

In cats, it's, slightly less, of transitional cell carcinoma, so about 3/4, slightly less than 3/4 versus 85% in the dogs, are transitional cell carcinoma. And then we do see a few, other kinds of carcinomas, again, adenocarcinomas and squamous cell carcinomas, and some smooth muscle tumours again. Lymphoma, primary lymphoma has been reported in the bladder of cats, but it's so rare that it doesn't even make this list.

So are tumours the only things that can actually cause mass-like lesions, in the bladder? And, and the answer there is certainly not. So, either polyploid or granulomatous cystitis can certainly have a mass-like effect in the bladder that you would see on, imaging, for example.

Again, there are these, there's other condition called inflammatory pseudo tumour, which again is another one of these, kind of inflammatory cystitis type conditions. And then we actually can see polyp-like lesions as well in the bladder of dogs. So, again, so those are somewhere on the neoplastic spectrum, but essentially hyperplasia versus being overtly cancerous.

So all of these are actually feasible and possible to see. But again, unfortunately, I think those are comparatively rare versus transitional cell carcinoma, especially if you have a breed that we know is at increased risk for that particular disease and we'll get to that in just a second. So, again, most of, of the talk today is really going to be focused on transitional cell carcinoma.

And that's because, again, depending on the species, 75 to 85% of all the cases that we see are probably transitional cell carcinoma. And actually, in my experience, the majority of the prostate tumours that we see in dogs. Are probably also actually transitional cell carcinoma of the prosthetic urethra, rather than being true prostate adenocarcinomas like like men get.

And one of the things that's interesting is that really, a very large amount of the, of the urinary tract is lined by transitional epithelium. So you can see what's, what's histologically defined as TCC is high up in the urinary tract is the renal pelvis. It can occur in the ureters, although that's quite uncommon.

Bladder is certainly the area that we talk about the most, but we can see it in the very, very distal urethra as well. So even in the urethral papilla or, or vaginal vault. So anywhere within the urinary tract is really a place where we could theoretically see transitional cell carcinoma.

The most common location in dog is in the trigonal region. But in cats, interestingly, it's not, although the overall incidence is much less in cats. In cats, actually an apical or or body location is, is, statistically more common than the trigonal location that we see in dogs, and we actually don't have any good understanding about why that might be.

As I mentioned earlier, there, certainly appears to be a very strong genetic component, in dictating risk of transitional cell carcinoma. And there's some dog breeds that we know, have a, a very significant predisposition to TCC and the one that really rises to the top of the list. Are the Scottish terriers where they appear to have a roughly 18-fold excess risk over normal mixed breed dogs.

So really quite, quite astounding. And the genetics of this, this, enhanced risk have really yet to be, convincingly worked out. So we know they got a lot of them.

But we don't really have a good idea about those genes that predispose them to it. Some other breeds that we commonly associate with an increased risk as well, are the others you see there is your shelties, your beagles, your Westies, and your wire-haired fox terriers. But on the other end of the spectrum, as, as separated by that red line, you can actually see there are some breeds that are at significant decreased risk for the development of transitional cell carcinoma.

And these are the retriever breeds, and, and breeds like the German shepherds. So that certainly does not mean by any stretch of the imagination that, that transition cell carcinoma can't occur in these breeds at lower risk, but certainly the incidence does appear to be less. What are some of the other risk factors that have been associated, at least some studies with the development of transitional cell carcinoma.

So we'll start on the pro side, and by pro, what I mean is these are things that tend to increase the risk for transitional cell carcinoma. So these include being a female, living close to areas where, mosquito, eradication is performed, living in urban, or industrialised centres, prior exposure to the cyclophosphamide, which can cause bladder irritation. Prior exposure to tryptophan metabolites, and certain other kinds of herbicides and insecticides, either topical or systemic, and by systemic, I mean sprayed in the environment.

And obesity is actually a modulating risk factor for several of these, chemical exposures. And the thought there is that many of these chemicals are actually relatively lipophilic. And animals who have a more obese body condition actually store more of these chemicals that they're exposed to in their adipose tissue, and those can serve as a sort of a slow release reserve of these potential carcinogens.

Very interestingly, On the, on the con side of the of the equation, consumption of of leafy green cruciferous vegetables, or orange vegetables like carrots actually appears to be associated with a decreased risk of transitional cell carcinoma, at least in the Scottish terriers. So here are some lifestyle things that if you do happen to be the, the veterinarian for a Scottish terrier owner, you could potentially talk to them about with the intent of trying to, to keep their risk as low as possible. So again, avoid topical insecticides, avoid exposure to other herbicides and insecticides in your environment, keep your animal at a nice lean body weight, and, and again, that goes along with actually feeding the vegetables, so that's pretty good.

And again, obviously, if they live in the city, you can encourage them to move to the countryside, which, may or may not be very feasible. So, again, as we mentioned before, in dogs, trigon is the most common location, but, in the male dogs, about a third of male dogs with transitional cell carcinoma may have prostatic involvement as well. So some of these tumours do start in the trigonal region and then extend.

The proximal urethra into the prostate. We certainly do, as I mentioned before, see our share of true what looks like primary TCC of the prostatic urethra as well. So either of those is, is possible.

But again, overall, about a third of male dogs will have some involvement of the prostate. About 15% or 1 in 7. Of these dogs may have metastasis at the time of presentation, and the most common location for that is gonna be in the regional lymph nodes.

Generally, these are gonna be the sublumbar or median sacral nodes. About 50% of dogs, however, will have evidence of metastatic dissemination at the time of death. However, probably in more than 50%, it's not the cause of those dogs' deaths.

So more than half of the dogs will actually eventually be euthanized as a result of lower urinary tract signs, either worsening clinical signs or or evidence of urinary obstruction. In cats, actually, there's very little information for us to be able to go on. But as I did mention previously, it does appear that there's a, a preponderance of cats who may develop transistence cell carcinoma in regions of the bladder other than the trigone.

And this is actually a beneficial thing for them because that allows us the ability to potentially perform surgery on those patients. So how's an animal with transitional cell carcinoma likely to present at our clinic? So, lower urinary tract signs are generally the, the presenting complaint, and these can include things like hematuria and dysuria, most commonly.

polauria is very common. Overt urinary incontinence occurs in a small percentage, about 1 in 10. And, then some patients may present with signs that are consistent with tenesmus, and this could be an owner reporting, what they think is straining to defecate is actually straining to urinate.

But again, with, with significant prostatic involvement, we can actually see compression of the colon as a result of prostatomegaly that could result in tensmus. And about 50% of dogs with TCC are hematuric, grossly, the, the amount of microscopic hematuria we can see is greater than that. And one of the things that can be a little bit of a red herring is, some owners may certainly elect for empiric Antibiotic, treatment, for example, for a dog who displays signs that are consistent with the urinary tract infection.

And it's actually not all that uncommon for these signs to sometimes improve a bit with antibiotics, even if the primary incited cause for this dog signs is in fact a tumour and not a urinary tract infection. So why is that? So, I think secondary infections, secondary UTI is actually a relatively common finding in these dogs.

If you can imagine, the urothelium in these dogs is incredibly abnormal and really serves as a very, very rich and fertile ground for bacteria to grow. So the incidence of secondary infections in these dogs is actually fairly high, and as a result, some amount of spontaneous or, or some amount of improvement with empiric antibiotic therapy can be seen. And again, especially in those cases where it becomes refractory or the response is partial, a really, that should really trigger us to, I think, think about a search for an underlying cause.

Some dogs, the very first time they present may have signs that are consistent with the urinary tract obstruction. And that can be complicated in some dogs with concurrent urolithiasis. So if they have a urethra that's not quite right, and they have stones.

Obviously, the likelihood of one of those stones resulting in an obstruction can be higher, etc. Rarely, we can see presenting, dogs present with signs related to lameness and this could be most commonly due to bone metastasis. So, not common, but actually urinary tract tumours are one of the tumours that more commonly in veterinary medicine do actually eventually metastasize to bone.

So, on, on a physical exam, unfortunately, in the majority of these dogs, they are gonna be relatively normal. You can see a list of some of the abnormalities that are occasionally seen. So a good rectal exam is always a great thing to do, as part of the workup in, in these dogs with urinary tract signs, it could be TCC because about a quarter of the time, you may be able to feel your urethral thickening, on our rectal exam.

And similarly, especially in these littler dogs, you do have an opportunity to check out at least by palpation. The, the size of the sublumbar lymph nodes as well. In a small percentage, about 1 in 8, you may be able to feel a caudal abdominal mass.

In the boy dogs, again, despite the fact that about a third of them may have prostatic, involvement. You'll only find prostatomegaly and maybe half of those dogs that do have prosthetic involvement. And then a small percent of dogs may have caudal abdominal pain as well.

But again, if you flip that around, that means an awful lot of these dogs may have a relatively normal physical exam and that by no means rules out the possibility of transitional cell carcinoma. The other thing that I'll mention is that actually relatively few of these dogs are gonna be systemically ill. So most of these dogs with the exception of their urinary tract signs, They're gonna be eating OK.

They're gonna be drinking, they're gonna be playing, doing all those normal things. The exception would be again if we have a dog that's, that's developed a secondary post renal exotemia where they certainly could be systemically ill as a result of that. So as far as our staging goes, we do like to start off with some very basic blood work, the, the typical stuff that, that we would do in, you know, in any older patient, that we were worried about cancer or something else.

And actually, in the majority of these patients, they are relatively unremarkable. One of the things that we would want to pay very careful attention to, of course, is the possibility for post renal azotemia as we discussed previously. Urinalysis is obviously gonna be a key component of, of working up any dog that has urinary tract signs.

And unfortunately, with a plain old urinalysis, quite often the results are gonna be a bit confusing or not necessarily diagnostic for transitional cell carcinoma. So, whether we have a dog whose primary signs are related to urinary tract infection, or whether the primary signs are related to a tumour in the, in the urinary tract, the findings on urinalysis can often be actually quite similar. So it's very common for us to find excessive white blood cells.

Red blood cells, protein, plus or minus bacteria which could all be very consistent with the urinary tract infection, and either with a UTI or with a, a primary bladder tumour, we also can see a population of epithelial cells. And sometimes these epithelial cells can actually be fairly odd-looking on cytology, but actually it can be very challenging. Cytologically to be able to diagnose or, or distinguish between reactive and neoplastic epithelial cells in the urine.

However, one of the things that certainly might tip you off, that you're dealing with a neoplastic situation is you, if you see a lot of these epithelial cells, but you don't see a lot of other inflammatory signs. So there's not a lot of red blood cells, a lot of white blood cells, a lot of bacteria, because then one would have to ask themselves, well, these could be reactive epithelial cells, but what are they reacting to if there's no other signs that are consistent with inflammation. So again, rarely will a plain old wet urinalysis be sufficient for a diagnosis, but it certainly could be a, a contributing factor.

So how does one get a urinalysis in a dog with suspected transitional carcinoma? So this is actually an interesting question. We actually do whenever possible like to avoid doing a cystosis in these dogs because for reasons that are not entirely clear, bladder tumours are, are one tumour type where seeding of the needle tract has been actually very, very well documented and it seems to be much more frequent with bladder tumours than with other intraabdominal masses that you might want to sample with a needle.

And there's at least one study that does suggest that dogs who develop this needle track seeding, do have a shorter lifespan, so it does impact their long-term outcomes. So we do like to avoid that, as a, a way to get our urine sample. Theoretically, there is a risk of bladder tear or urethral tear, bladder perforation.

If a urinary catheter is placed, I have to say that I, I do catheterization fairly routinely in these patients, and I don't think that it's, there's a lot of excess risk associated with that, but it is a theoretical risk. But in this particular situation, this might be one situation where a free catch might be better than, for example, a cystocentesis. Which again is something that I think we're all taught in veterinary school is, is probably the opposite, where free catch is not as useful, but this might be an exception to that rule.

Obviously, imaging is a really key component of, of what we do to work up these dogs as well if we have, again, clinical signs that are suspicious in an at-risk breed, and a, and a cytology that may or may not be contributory. So for, you know, many decades, the gold standard was actually contrast radiography. So either positive contrast or dual contrast radiography.

And I still actually consider this to be potentially a very, very useful technique. So this is an example where you can actually see a very obvious filling defect here in sort of the, the ventral bladder wall creeping up into the trigonal region. So it's quite obvious in this case and this can again be a very useful test to perform in a situation where ultrasound might not be readily available.

However, ultrasound is a screening tool if it's available, it's really an incredibly useful test. And one of the reasons for this is that again, it does give us a very, very nice view of what's going on in the bladder itself. And it actually allows us to look at the rest of the abdomen in, in good detail for evidence of metastasis as well as evaluating the prostate.

It can also give us a good look at the kidneys and the ureters. To determine if there may be any evidence of urinary tract obstruction at the level of the ureters as well. However, it is very challenging to image the pelvic urethra, with ultrasound, and again, that's obviously due to the presence of the bones in the region.

So that is one region where, something like, a cystourethrogram, using conventional radiology actually could be superior. And one thing that we'll talk about more, but that we really know is that despite the fact that it's used very commonly for assessing response to therapy, so we measure some things with ultrasound. We do some treatments and then measure again and ask whether things are better, or worse or the same.

There's actually an incredible amount of variability from measurement to measurement in These bladder tumours. And part of that has to do with the operator. Part of that has to do with how full the bladder is at the time of imaging, but it really is something that complicates our ability to use this as a reliable tool for serially assessing bladder tumour size.

Although, again, for want of a better technique, it's something that we all do. So again, a couple of ultrasound images that you can see. So the image on the right there really does suggest a trigonal location for this mass.

The, the image that you see on the left actually demonstrates a location that's sort of more really in the body, of the bladder, not really in the apex, but in the body. So again, trigonal may be the most common location, but it's by no means the only location. So if we do see a tumour, in the apex of the bladder, or in the body of the bladder, it by no means rules out the possibility of transitional cell carcinoma.

Again, in the trigonal region of TCC is a little bit more likely compared to some of the other odd histotypes, but again, it's not 100% confirmed that it's gonna be a TCC either. CT scan is actually a very useful test for these dogs. So, with, catheterization of the urinary bladder and, and, sort of standardisation of the amount of fluid that's in that bladder, the measurements that we can obtain are actually more accurate serially with CT.

And of course, it does do a lovely job of, of allowing us to evaluate the rest of the abdomen thoroughly for evidence of disease elsewhere. That being said, it's a technique that at least the way we practised it here does require general anaesthesia. And it's not particularly inexpensive.

So as a routine staging test or routine test to use for serial measurement of response to therapy, you know, honestly, at least in, in, in, in our practise, there are a few owners who are really have the financial wherewithal to be able to do that. So, great technique, unfortunately, not something that we can use as frequently as we want mostly because of cost constraints. Cystoscopy is actually a very useful test for assessing bladder tumours in a few different ways.

So it's not a particularly useful test for serially measuring response to therapy because obviously, with a little scope like this, there really are no yardsticks. There's no no good ways to say whether things are better, worse or the same. There are no objective measurements that can be taken.

However, there are few situations where we do find it incredibly useful. So one of them, especially in the larger dogs, is if the cystoscope that you're using is large enough that it actually has a biopsy port, you can obtain pieces of tissue via that cystoscope that you can submit for histopathology. And that's one of the ways that we can obtain our definitive diagnosis.

The other situations in which it's actually incredibly useful and actually bordering on mandatory in my mind, one of them is in the situation where we do have an apical or a body transitional cell carcinoma, and we're contemplating surgery. So, here, again, where we have the ability to do cystoscopy quite easily, we'll always try and do cystoscopy on these patients first to make sure that the results that we're seeing with imaging, whether it's CT or ultrasound, suggesting the absence of trigonal involvement are, are borne out with actually visual inspection. So if we do find that there's evidence of tumour creeping down into the trigone region, Then surgery is likely to be of limited benefit.

If the trigone really looks clean and based on the assessment, it looks like we can, we can do a full thickness or section around that tumour, then we'll certainly consider that dog to be a surgical candidate. The other situation again here at CSU where we actually find cystoscopy be very useful is again as a matter of, of trying to determine really the, the physical extent of the tumour, where it begins and ends, if we're contemplating doing radiation therapy, which we'll talk about a little bit later. So, we've actually found that imaging, whether it's ultrasound or CT scan actually does tend to underestimate the extent of the disease, compared to what we see with cystoscopy.

So we actually use the cystoscopy to help us make sure that we're not missing any of the tumour, if we're planning to do radiation therapy. So some of you may be familiar with a, with a test that is still available. It's called the VBTA or veterinary bladder tumour antigen test.

So, I only put this slide up here to tell you that this is a terrible test. And really in, in my mind, it's, it's fairly close to worthless. And the primary reason for this is that while the sensitivity is fairly high, you get false positives with most of the other things that you would want to rule out in a dog that presents with urinary tract signs.

So you get false positives with white blood cells, with red blood cells. With protein. All of those things that would be present in a dog with urinary tract infection or bulithiasis or any of those other things.

So really, again, unfortunately, due to its incredibly high false positive rate, I really do consider this to be as close to a worthless test as I think is available currently. So, as we mentioned previously, really for a definitive, unequivocal diagnosis, histology is, is required. That being said, there certainly are situations where I think cytology is appropriate.

As far as how to collect our histology samples, we'll get back to cytology in a second. So as far as how to collect our histology samples, a cystic scope is one of the ones that I mentioned already. If you do have a tumour that's in the body of the bladder, a surgical biopsy is very, very appropriate as part of a, of a, full thickness resection.

Finally, there's a technique called traumatic catheterization, which actually can be very useful. And in this technique, the dog is sedated or anaesthetized, and a catheter is is passed into the bladder and then with the ultrasound guidance, The tip of the catheter is manipulated into the region where the tumour is and then some fairly vigorous aspiration via via syringe that's attached to the catheter, as well as some moving back and forth, can often actually dislodge pieces of tissue that are substantial enough that they can be submitted for histopathology. Or even if not, often we can get some really, really good impression smears from the, the small pieces of tissue that are received.

So this is actually an incredibly useful technique that doesn't require a lot of specialised equipment, the way, the way a cystoscope might. So cytology, as we mentioned, I talked about this previously, so I'm not gonna belabour the point. But often the, the transitional cells in a TCC case are gonna be really quite abnormal.

Multinucleate cells with very, very prominent nucleoli can be seen, and it's very common for us to even see mitotic figures sometimes. However, again, one of the real complicating factors is that we can see reactive transitional epithelium, which have an appearance that's virtually identical to this. So these kinds of cytlogic findings really need to be taken with an enormous grain of salt with TCC specifically.

But again, if you've got a fairly obvious bladder mass that you can visualise via imaging, a cytlogic picture that looks like this, and a real absence of other profound evidence of inflammation, I think the index of suspicion for transitional cell carcinoma should be very, very high. One of the things that I'll do, which I think is actually quite useful, is rather than sort of submitting a urinalysis for the traditional sort of wet mouth cytology where, you know, you put a you put a drop of something on there and you put a cover slip on it and look at it. A technique that I find actually very useful is to, is to sort of spin down your sample of urine, dip, a cotton swab into it.

Into the pellet after you've poured off the supernatent and actually roll that cotton swab across a few glass slides and then submit those for conventional cytology rather than just the, the wet mount inspection that you get with a routine urinalysis. And that can often really help to get us a good picture, like these pictures of what the, the, the cells in the urine look like. So I am actually relatively comfortable moving forward with definitive therapy and a dog with a bladder mass, especially in the trigone region, and a highly suspicious cytology.

So I do not feel even here in my ivory tower that, and in the United States, which obviously is very litigious, that we need histology on every single case. As we discussed before, we like to avoid, transabdominal aspirates because of, of reasons associated with, seeding of the needle tract. So one thing that's new and actually quite interesting.

It recently, several different groups, actually 3 different groups have identified a recurrent mutation in a gene called BRAF, which appears to be present in about 85% of canine bladder and prostate tumours. So, BRAF is a known oncogene and actually the mutation that's present in the BRAF gene is present in the exact same mutation is present in quite a few human melanomas. So canine melanomas don't appear to have this mutation.

Human bladder tumours don't particularly have this mutation very often. It's about 0.5%.

But again, about 85% of dog, bladder, and prostate tumours actually have a mutation in this gene called BRAF. And this is very interesting and there may be some ways to utilise this therapeutically, but the thing that's really exciting is that there's a diagnostic test that's been developed using a technique called droplet digital PCR that allows the incredibly sensitive detection of again as few as 1 in 10,000 mutated copies of this gene. And this has actually been looked at in a large number of dogs with transitional cell carcinoma or, or prostate carcinoma.

And it's found to be about 85% sensitive and as near to 100% specific as, as, as you can imagine. So there are virtually no false positives with this test. And again, the likelihood of a false negative is about 15%.

So those are the dogs whose tumours simply do not carry this mutation. And this is a test that is commercially available in the United States. It's called the Cadet Assay and it's sold by a company called Sentinel Biomedical, which is a a spin out of North Carolina State University.

So this test is, was developed by the laboratory of Doctor Matthew Breen, who's a, a canine geneticist at North Carolina State. So the last time I checked, Unfortunately, they were only able to accept samples from the United States. But actually right here, it does say, for orders from Alaska, Hawaii, and outside the United States, please contact us.

So it's possible that this is a moving target and actually they're, they're working very hard to be able to, to go through the regulatory paperwork to allow, The acceptance of submissions from outside the US. So actually, we do find this quite a useful test. And again, this a common situation might be, we've got a dog with a bladder mass.

Our cytology is really equivocal. The, the clinical pathologists are not willing to say whether what they're seeing down there is consistent with transitions of carcinoma or not. And again, it's a choice between sort of trying to get a piece of tissue with biopsy or histopathology or surgery or not, or doing something else.

Again, this is a test that's simply done on a 20 mL sample of urine. So the owner can collect up the sample of urine, send it directly to the company themselves. It's about, again, a one pack, it's about $160 or so.

So compared to the cost of anaesthesia and histopathology and cystoscopy, it's a really great deal. So it is something to consider, and again, I'm really hopeful that in the near future, folks in the EU may be able to actually take advantage of this, this really exciting new development. So one of the things that you'll hear oncologists talk about a lot is assigning a clinical stage to dogs with various kinds of cancer.

And this is also something that can be done in dogs with transitional cell carcinoma. And it uses what's called the TNM staging system. So T stands for what's going on with the primary tumour, N is the lymph node status, and then M is the presence or absence of distant metastasis.

So, Unfortunately, in veterinary oncology, and this is one way in which veterinary or or canine bladder cancer is very, very different from the human disease. About 3-quarters of dogs with transitional cell carcinoma are gonna have T2 lesions. So these are muscle invasive bladder cancers, and the rest of them will generally have T3 lesions.

So, the majority of human bladder cancers are actually caught when they're superficial, or even in situ, which is barely malignant at all. And these, actually can be treated quite effectively with a variety of intravesicle treatments. So, therapies that you can actually ins.

Into the bladder. We commonly get the question, hey, you know, my aunt had bladder cancer and they put this drug into her bladder. Why can't you do that for my dog?

The reason is that these lesions are so invasive and so large when they're detected in dogs that they are not amenable to therapy with these intravesicle treatments, unfortunately. So, let's talk about surgery. So, unfortunately, again, the majority of the tumours that we encounter in dogs are in a location that's not amenable to routine, partial cystectomy.

So really the ability to do a full thickness excision is gonna be quite limited unless you have a tumour that's exclusively in the apex of the body of the bladder. Even with histologically complete excision in those tumours where we are able to, to achieve that. Recurrence within the bladder is actually quite common, and we don't know whether that's because there are tumour cells floating around in the bladder, in the urine that actually have the ability to implant in another part of the bladder wall, or do what's called a field or due to what's called the field effect, which means that, hey, that bladder epithelium, that entire bladder epithelium has been exposed to the same amount of whatever carcinogens caused the tumour to form in the first place.

So other little areas of neoplastic change are probably pleasant. However, whenever we think that there is the ability to do a full thickness resection, that is certainly the first order of business as far as treatment goes. There's several studies that do suggest a superior outcome when surgery is performed first.

There's one older study that was published that actually reported an average survival time of about a year with surgery alone, in dogs that, with transitional cell carcinoma. There are a variety of sort of advanced surgical techniques including urinary diversion techniques where the ureters can be hooked up to the urethra or the ureters can be even hooked up to the colon. And yes, I mean, these are procedures that are perceived, performed relatively commonly in humans, but they're associated generally with a an unacceptable, what most owns would find unacceptable occurrence of adverse effects.

There are other procedures. There's a procedure called transurethral resection, that, that has been described but again is associated with a very, very high likelihood of adverse effects. I'm gonna again sort of skip skip a bit about this, but really talk about debulking.

So this is one of the things that we don't know about. So if we have a tumour that's in the trigonal region. Or another region where we really don't think that a full thickness resection is appropriate.

Is there any role for going in there and kind of trying to scrape out as much of this tumour as possible to actually facilitate whatever adjuvant therapy comes next, whether it's chemotherapy or NSAIDs or whatever. The answer to that is really unknown at this point, but there is a very large data set that some of my colleagues here in the United States are Trying to generate, comparing about 60 dogs that did have this kind of cytoreductive surgery followed by medical therapy, combined to about compared to about 60 dogs that didn't, that just had medical therapy to really try and determine if this sort of cytoreductive or debulking surgery could play a role in in management of this disease. So if you're capable of doing full thickness resection, it's fairly unequivocal, that's a great thing to do.

Do you buy anything from debulking? It's really not clear. Stay tuned for that.

We have a recent paper that just came out, last year that actually looked at a combination of partial cystectomy plus medical therapy for dogs with transistor cell carcinoma. And in those dogs that had full thickness or section, so not like a submucosal carveout or anything else like that, and were followed with an NSAID plus or minus chemotherapy, their median survival time was about 2 years. And again, if you compare that to chemotherapy alone, it's a little bit more than double what you would expect from only chemotherapy and about 4 times better than what you would expect with a simple NSAID.

So, again, just really hammering home just like with most oncologic tumours that we deal with, if there's a possibility to do surgery, it really does appear to be valuable. And I'm very briefly gonna talk about interventional radiology. So this is something that does require quite a bit of specialised techniques and, and specialised experience but can be very useful for managing malignant obstructions.

So, the images that you're seeing here, are of the placement of a stent in the urinary tract in the urethra to actually alleviate a urethral obstruction caused by a tumour. And what happens in this situation is using, in this case, fluoroscopy actually, this stent is placed by a urinary catheter and then it's expanded very much like an umbrella expands to basically push the tumour tissue away from the lumen and actually create a space that the dog can urinate through. The same procedure can be performed in the ureters as well, although it's even more technically challenging.

And there are some side effects associated with this procedure. So about 2/3 of dogs will experience some amount of incontinence postoperatively. In 1/3 of dogs, it's permanent.

And in another 1/3 of dogs, it's transient. It lasts for a week or two and then it resolves. So, permanent urinary incontinence is a very serious risk, but again, as far as, as far as survival goes, it certainly is preferable to not being able to urinate at all.

So this is a procedure that can be performed. It's not cheap, and it is associated with side effects, but it's incredibly useful for managing malignant obstructions. Laser ablation is another technique that's been described, but it usually does require multiple treatment courses.

And again, a single treatment, at least here in the United States is about $4000. So if you have to do that multiple times, it quickly really becomes out of the reach of the, of the average pet owner. How about radiation therapy?

So this is an interesting one. So, historically, radiation therapy has been challenging to do because of so many tissues in the region of this tumour that don't tolerate radiation particularly well. So the guts and the kidneys and things like that.

So in the older literature when it was tried, actually there was a pretty high likelihood of unacceptable adverse effects either to the, to the intestinal tract or to the bladder itself. Palliative radiation therapy, so once weekly radiation therapy, all outpatient, can be done in a very indiscriminate way using radiation doses that are low enough that they're not gonna cause any side effects. Actually can be a very useful palliative measure in those animals whose signs aren't adequately controlled with an NSAID.

So that is the main way that we use this kind of once weekly radiation therapy and that, again, the likelihood of seeing improvement in clinical signs is actually very high. Over the past 5 to 8 years or so, we at CSU and a few other places have started to use, intensity modulated radiation therapy. So this is a curative intent form of radiation therapy that uses some very sophisticated imaging and planning software to deliver extremely high doses of radiation in a very precise method.

To the urinary tract and the tumour specifically while avoiding damage to the normal tissues in the area. So generally, these are daily treatments Monday through Friday for about 3.5 to 4 weeks.

And the 1st 21 dogs treated with this were actually written up and published a couple of years ago. And actually, in this group of patients, again, about 90% of dogs have improved quality of life. The objective response rate is about 60%, and the overall survival time is about 22 months.

So, to my knowledge, these are the best survival times that have been recorded. With a non-surgical therapy for bladder tumours in dogs. So again, this requires very sophisticated equipment that not every radiation facility will have.

It does require multiple daily anesthesias, although most dogs will do just fine with that. And again, our cost here for a full course of therapy is generally between 700 and $8000. So that includes the anaesthesia and the time in the hospital and all those other things, but it's not something that every owner will be able to afford.

How about medical therapy? So really the mainstay of treatment, despite the title of my, of my talk here, is, is the NSAIDs. And if an owner is really only willing to do one thing for their dog with a bladder tumour, I certainly am gonna recommend an NSAID.

And the NSAID that's been studied the most is paroxicam. So going back as far as 1994, paroxicam has actually been studied for dogs with transitional cell carcinoma. And the likelihood of seeing meaningful tumour shrinkage is about 20% or so.

About another half of the dogs will have their tumours stop growing for a while. About 75% of dogs will have improvement in their clinical signs, less straining, less bleeding, less accidents in the house, etc. And the median survival time in dogs who receive proxyam alone is about 6 months.

That's roughly twice as long as what was reported in the older literature without a non-steroidal anti-inflammatory drug. So not only does this actually palliate clinical signs, but it does appear to increase lifespan as well. One of the questions that we get quite commonly is, are the other NSAIDs or some of the other NSAIDs equivalent?

Do they have equivalent activity? So there is some now information available to suggest that both Dayoxib and ferrooxib may be associated with relatively equivalent anti-tumor activity. So despite the fact that there are more studies out there looking at peroxicam and it's incredibly cheap.

It does appear that if we have an animal with a sensitive stomach or an owner who's worried about the, the GI adverse effects that could be associated with paroxicam, that Dacoccib or ferrococcib could be reasonable substitutes. How about chemotherapy? So there's a large number of drugs that have been looked at over the years for the treatment of, of TCC and some of the drugs that appear to have activity include doxorubicin, viblastin, and chlorambusil when administered on a metronomic schedule.

Interestingly, a very early report suggested that carboplatin as a single agent had no activity, but when it's combined with an NSAID, actually, the activity appears to be relatively adequate. So I would put that on the list as well. There's some studies that have looked at combinations of an NSAID with cisplatin.

And in these studies, nephrotoxicity is a huge issue. So response rates are quite high, but really unacceptable and in many cases, fatal azotemia can be associated with these protocols. So we do not recommend combinations of an NSAID with cisplatin.

There's a paper that came out in 2005 looking at a combination of peroxicam and carboplatin. And again, they did see a, a decent response rate, a reasonably OK survival time. But their comment actually was that this was extremely toxic to the GI tract and extremely myelosuppressive.

And I have to say that I've used this protocol for years and years and years. And this has not been my experience whatsoever. This generally is a, is a quite well tolerated protocol.

So somewhere in, in the, in the line of different drugs that we'll try for this disease, I certainly think that a combination of an NSAID and, and carboplatin is appropriate. What many of us consider to be the, the first line standard of care from a medical therapy perspective is a combination of paroxicam and midazantrone. And that's thanks to actually a very nicely performed study that was published in 2003, looking at this, this protocol prospectively in dogs.

And the response rate is about 35%. It's about twice as high as dogs that get an NSAID alone, and the reported median survival time is about 10.5 months.

Again, more than half again as long as with an NSAID alone. So this is the protocol that we generally start with. Midazantron is very well tolerated.

It's only once every 3 weeks. It's not tremendously expensive. And again, it appears to be something that's quite useful.

A more recent paper actually, looked at carbo versus mio when peroxicam was added and, and reported response rates that were not as high. However, the way they went about their response assessment was not as systematised. And as a result, that may be responsible for some of the differences that we're seeing.

So this remains sort of my first line treatment. And generally, when I'm trying to, to determine whether this is working or not, I'll start with two treatments. So I'll get some measurements with ultrasound.

I'll do treatments, excuse me, 2 treatments with my dazantro as well as continuous NSAID. And then go back and take another look at the bladder and ask if things are better, worse, or the same. And if the signs are well controlled and the tumour is the same or better, I'll keep doing what we're doing.

If it looks like things are heading in the wrong direction, we'll certainly quit or try something different. And it's quite common for us to roll through a succession of agents over time, when we're managing these dogs. So one will work for a while, then we'll try something else, and then we'll try a third one.

And we're usually willing to continue to try different things as long as it's something that the owner is interested in. So the, the bottom line here is that really there is no one protocol that's head and shoulders better than all the others. Again, I'm a fan of proxyam and midazantrone really purely because, because of its, cost, its side effect profile, and the fact that it's only once every 3 weeks.

But it is by no means the only choice. And some of the others, that we, that we went through very briefly, Vlastin, chlorambuil, etc. Are also quite reasonable choices.

Well what about palladia? So, palladia is the, the mast cell tumour drug that's sold by Zoettas, but it may have activity in a variety of other kinds of cancer as well. And actually, in the initial study that was performed with palladia back in 2003, there were a few dogs with transitional cell carcinoma that did appear to experience long term disease stabilisation with palladia as a single agent.

But very recently, there was a paper that was published looking at a combination with palladia and Vinblastin. And there was actually no obvious improvement in outcome versus blastin alone. So today, other than a couple of anecdotes in a very early study, we really don't have a clear understanding of the value of palladia for the treatment of transitional cell carcinoma in dogs, unfortunately.

So how are we gonna tell if an individual dog is likely to do better or worse than average? So, there, there's not necessarily a 12 3 grading scheme for these tumours, the way there is for mast cell tumours, for example, but tumours that appear to be very undifferentiated or anaplastic do appear to have a worse outcome. Tumours, involving the urethra or prostate as a group may have an outcome that's not as good as tumours that are arising from the bladder itself, and dogs who present with metastasis as a group tend to also be on the short side of the average mark.

So these are things that you can use to sort of modulate what you're gonna tell an owner about outcome for an individual patient. What are some of the unanswered questions? I think this is one that we talked about already.

Would I treat a dog for bladder cancer without a definitive diagnosis? And again, here in the United States, I love to have a piece of paper in the medical record that actually says that the dog has cancer for liability reasons. That's gonna be different in every practise and in every, in every part of the world.

But, and now that we have this cadet test, which is non-invasive that can be just on off a sample of urine. I love to be able to put a piece of paper on the chart that says the dog has cancer unequivocally. I'm usually very comfortable, prescribing an NSAID for a dog whose owners may decline additional diagnostics to confirm a diagnosis.

But if we get into using cytotoxic drugs or God forbid, radiation, I really feel like from a liability perspective and an ethical perspective that, that having as close to a definitive diagnosis as possible is, is really quite important. We covered this already too, so does debulking provide a survival benefit in those dogs with triadonal disease? If we go in there and scrape out everything we can, does that make our chemotherapy work better?

We don't know the answer to that, but that is the subject of an ongoing study, so stay tuned for that. Should we be using an NSAID other than piroxicam? I think we covered that pretty well.

So there is now accumulating data that Daricoib and ferrococcib have some evidence of anti-tumor activity in dogs with transitional cell carcinoma. And as a result, I do think that those are reasonable alternatives to consider, especially in a dog who may not tolerate paroxicam. I honestly still like peroxicam as my first line treatment.

It's only once a day. It's actually incredibly inexpensive, and the majority of dogs tolerate it well if it's dosed properly, if it's given with food, and if it's not given with any other anti-inflammatory drugs concurrently. Is abdominal ultrasound, an adequate method for assessing response in these patients?

You know, honestly, the answer is the way it's routinely done, it's really not that great. It's what we all do because of absence of a really practical alternative, but it is not nearly as, as useful as we would like. I think especially when it comes to saying, hey, Look, the tumor's a lot smaller.

That can really vary quite a bit. I think if there's obvious evidence of progressive disease, if the tumour is bigger, if it's occupying more of the bladder, if there's evidence of metastasis, you can feel very comfortable that the ultrasound is giving you useful information. And I do think it's quite useful for measuring prostatic disease.

That tends to be much more objective than what we see in the bladder. If we really wanna be a purist, there are formulas for instilling saline into the bladder. So emptying the bladder with a catheter and then instilling a fixed volume of saline based on the, on the weight of the patient that actually allows the bladder to be expanded exactly the same amount every time an ultrasound is performed.

And if we're doing a prospective clinical trial or something else like that, that is actually the way that we choose to do this. But in a busy practise that really becomes problematic because it requires sedation, it requires passing of the catheter, etc. Etc.

So it is challenging and we still are really in want of a great objective way to be able to serially measure these tumours. So if anybody out there has any ideas, we'd love to hear them. What about radiation therapy?

Again, so we have this one study that really, is quite encouraging, suggesting that radiation could be quite useful. We'd love to see some additional work done to confirm those findings. I think it's, it's quite obvious and my experience has been similar that it can be a very useful palliative measure in those animals whose clinical signs are not adequately controlled with, with an NSAID or with chemotherapy, for example.

How about interventional radiology? Again, we do, do urinary stenting here at Colorado State University, but it is a, an expensive procedure and it is a procedure with complications, and again, there's a very steep learning curve to its use as well. So it's not for the faint of heart, it's certainly not for every client to consider, but it is something that we are finding useful in certain cases.

So, very quickly, sort of the big take homes at the end of this. So transitional cell carcinoma is going to be the most common bladder tumour that we see both in cats and in dogs. We really do like to get a handle on exactly where their disease begins and ends whenever possible before committing to a line of therapy because again, it allows us to get the best idea about all the different things that we should be measuring.

And as I mentioned, the presence of metastasis is a significant negative prognostic factor and that's information that may choose how someone choose to treat. We talked about the different methods of diagnosis. So the pros and cons about cytology, different ways to obtain a histologic sample, and we did talk about the cadet BRAF test that's offered by Sentinel Biomedical as well.

And then we covered some treatment things. An NSAID, and again, are all NSAIDs created equal or are they different, as well as a variety of different chemotherapy drugs that can be combined with NSAIDs that do appear to result in potentially superior outcomes. And then we also did discuss the roles of surgery in those cases where it's possible, interventional radiology, and radiation therapy.

So the big prognostic factors, presence or absence of metastasis. And tumour location, so is there urethral involvement or not. And again, we're very excited with the, with the development of this BREF test that a simple test that can be done on a sample of urine that the owner sends in at home might actually allow us to diagnose these dogs at an earlier stage.

And is it possible that that early diagnosis could result in superior outcomes? We're certainly hopeful that that could be the situation. So there are some breeders of Scotty's, for example, or owners of Scotty's who are starting to use this cadet test as a screening test.

So actually, every 6 months, they'll send a sample of urine into the thing and if it comes up positive, they'll go on a tumour hunt looking for a very early transitional cell carcinoma. So this test has not been around long enough for us to be able to really have any data about whether that screening type approach is appropriate or effective, but it is a very interesting concept and something that I'm, that I'm quite looking forward to seeing some data about in the future. So again, lots of my colleagues who I'd like to thank who actually contributed slides, for this presentation, and whose work has really helped to sort of forward this field along.

And with that information, I'd be very happy to take a few questions, assuming there's time left. Yes, fantastic. Thank you very much, Doug.

And perfect timing, it's, as if you've timed it to the second there, so fantastic. Thank you very much and . I'm sure there's been lots of food for thought there for many of the people attending today.

So, please, as Doug says, there is time for questions. We have had one in so fast, but please do post a couple of other questions. As head of sales for the webinar vet with no veterinary background, I, I am able to ask the questions, but, in terms of coming up with them, it's not in my field, so please do contribute any questions you may have.

While you're having a quick think about any questions you want to pose to Doug, I would like to point out we are currently, conducting our annual survey. You should all have received at least one email, maybe two, encouraging you to complete, the survey. It takes about 5 to 10 minutes, but there is a, really good incentive.

There is a prize of 1000 pounds. Yes, you heard me, 1000 pounds, and it's not one of these, bet online betting things where you get it back in free bets or anything like that. It's generally 1000 pounds to one lucky person, for all those who completed the webinar, you've got to be in it to win it, so please do.

Route out that email and complete the survey. We've already had over 2000 responses, but we'd love to get closer to 3000, so please do take time to complete that. Well, can I take the survey?

Yeah, I'll get the link sent over to you, doc. So first of all, I've got a question from Lawrence. Welcome, Lawrence, one of our relatively new members.

In the UK we have thyroic, copsip sorry, as a licenced medication otherwise known as Pri Privat, oh sorry. Privacock, sorry, would you consider that as a suitable first line NSAID over piroxicam, would you have, which would have to be used as an unlicensed medication? Do you have any opinion on other licenced NSAIDs such as meloxicam?

So, basically, would you consider Previcox as a suitable first line over Piroxicam, because obviously it'd have to be used as an unlicensed medication. Yeah, great question. And that's, that's one of the things that, that we always need to keep in mind is here in the United States, we're not subject to the cascade rules that that folks practising in the UK and the EU are.

So we're not obligated to pick a licenced medication first. And there are no head to head studies comparing ferrocoa with paroxicam or, or proxyam with any other non-steroidal anti-inflammatory drugs. But based on these small, single-arm non-randomized studies that have been performed.

So one old study from 1994, looking at paroxicam, and a study from around 2012 or so looking at furooxib as a single agent. Actually, they do appear to have a relatively equivalent efficacy in terms of management of clinical signs and potentially in terms of, of, helping to slow down the tumour as well. So in a situation where one is sort of legally obligated to start with a a licenced NSAID.

I do think that errocoib would be an appropriate choice. Again, here in the States, we also have Daracoib or Daramax. I'm not certain if that's available in the UK, but, that's another one where again, we, we actually do have at least some data from a retrospective study suggesting some activity.

Meloxicam has not been looked at, at least to the extent that it's resulted in a pure few publication. So, can't really comment about the potential efficacy of meloxicam. So, for one reason or another paroxicam wasn't a good choice, but errococcib or Pravacox was available, I do think that that would be an appropriate alternative.

Fantastic, thank you. Jill asks, what sort of stents do you favour and how difficult to place and what are the side effects? And then she follows that up with, do you know of anyone in the UK that is working with this?

Yeah, so, so the, the types of stents, honestly, I can't tell you their brand name, I can't tell you the, the manufacturer, that's . Something that's, that's well out of my wheelhouse. So I'm a medical oncologist.

I don't actually do these stenting procedures. I can find that information out quite easily if you wanted to email me offline, however, so happy to, to track that down for you as far as brand names and suppliers and things like that. But again, we do utilise these stents both for for urethral obstruction and for ureteral obstruction as well.

It does require quite a bit of training and quite a bit of expertise to be able to utilise these successfully. And again, it does require a fluoroscopy as well, so it can't really be adequately done with with static radiography. As far as adverse effects goes, the, the one I mentioned is the most common.

So urinary incontinence is the one that we do, prepare owners for. About 2/3 of dogs will experience some amount of postoperative urinary incontinence. And in half of those dogs who start out incontinent, they will remain incontinent.

So about, if you do the math, that means about a third of dogs undergoing this procedure for the urethral stent will experience permanent urinary incontinence to some degree. Other adverse effects that we can see, so especially immediately after the stent is placed, it can be quite irritating to the urethra. So some increase in strangura and, and hematuria and things like that is quite common.

And honestly, because the function of the urethral sphincters has been compromised, the incidence of ascending, infection is also increased in these dogs who undergo a stenting procedure. So we'll often actually empirically culture the urine periodically of these dogs with a stent in place to make sure that they don't have an occult urinary tract infection. So those are the big adverse events that we can see.

As far as is there anyone in the UK who's currently doing the stenting procedure? I don't know the answer to that. If you had to ask me to guess who might be doing it, Nick Bacon, is probably the guy who's the most likely to be offering that procedure.

OK, fantastic. So Jill, if you want to send an email to office at the webinar vet regarding stents, then obviously. I following Doug's kind offer, we can then forward that email on to Doug, for him to come back to you about the stents, but hopefully that has answered your question, .

Fully, on to another question now. We've had quite a few coming through, so, got a little bit, got a couple more minutes, so just a couple more questions. Oh, that's great.

Yeah, I've got one from Mark here. OK, so Mark, I wrote a couple of these just started another question. So start again, he says.

I have a case that was doing well on Blastine and piroxicam, but blastine is now unavailable, so it was going to change to. Mitozantrone, is it? Which is much, much, which, which is much more expensive here in the UK.

How many doses do you give of the Mitoxone? Yeah, so, so that's a really, really great question. And, and for any of these drugs, when we're treating a measurable tumour in the bladder, we will generally continue treatment indefinitely as long as the tumour is stable or better.

So, when we're using some of these drugs postoperatively, we might say, oh, we're gonna do 4 treatments and then stop, etc. But really for transitional cell carcinoma or bladder or prostate tumours in general, it's a matter of continual reassessment. So I get some measurements.

I do 2 treatments. I take another look. If things are the same or better, I keep going and after another 2 treatments, I'll take another look.

And if things are the same or better, I'll continue. And with most of these drugs, there, there are no cumulative adverse effects that we need to concern ourselves with. So with vimblastin, with midazantrone, with carboplatin, with chlorambucil, really, most of the time these drugs can be given indefinitely as long as we're deriving clinical benefit.

The exception will be doxorubicin, where we do have to stop after about 6 doses due to the potential for damage to the heart. But yeah, so it's very, very common for us to sort of treat these dogs indefinitely. Now that being said, for a drug like midazantrone, if we get through let's say 5 treatments and it looks like things are, are doing very well, we may start to decrease the frequency.

Of administration. So instead of staying with that Q3 week schedule, we might say, well, for the next 2 treatments, let's try going every 4 weeks and see if we're able to still maintain that. And if things are still going well, let's push our luck and try to go every 5 weeks.

So see if we can extend that interval so the cost per unit time actually drops and the, and the dog has to make fewer trips in to see us. So the exceptions as far as the duration of treatment do have to do with those situations where we're doing surgery. So if I'm fortunate enough to have a case where I am able to do a, a complete resection, down to the point where there's no visible disease left, that is the situation when, for example, with my dazantro, I'd probably do 5 treatments.

Then quit the chemotherapy but continue the NSAID indefinitely. Similarly, when we're doing intensity modulated radiation therapy, we'll generally do 5 doses of midazantrone, then quit the midazantrone and continue the non-steroidal anti-inflammatory drug with frequent rechecks. So if treating gross disease, just to recap, we continue as long as it's working.

Microscopic disease or radiation therapy will generally do approximately 3 months of treatment and then continue the NSAID but quit the chemo. Fantastic, thank you very much for that. I'm sure that has answered Mark's question fully.

Question here from Terry. Terry's one of our regular attendees. He says, how do you obtain suitable formulations for Piroxicam as dose rate is so fixed?

Do you have your own pharmacy? Aha, that's a great question. So, so here in, so here at Colorado State University, actually our, we, so we have an in-house pharmacy.

And our pharmacist will compound, really any size capsule that we desire. The, the number of sizes that we routinely carry are, are about 5 or 6, ranging from 1.25 milligramme all the way up to 10, which is the standard size.

Again, out in the, out in the, the practise community here in the United States, one of the things that we have ready access to are what are called compounding pharmacies. So we can call or email a compounding pharmacy and say, I would like you to compound a specially sized paroxicam capsule for my patient. .

And, and there are some caveats to the use of, of compounding pharmacies here in the state. So the quality control is incredibly variable and it's variable how accurate their, their doses actually are. And again, it varies from pharmacy to pharmacy.

So there's some due diligence that has to take place. But that's something that's, at least as it stands right now, quite ubiquitous in the United States and it does facilitate sort of patient-specific dosing. But again, if you're really restricted to utilising commercial sized capsules, that is a major problem and is another, really complicating factor that makes paroxicam perhaps not the ideal choice for use in the UK as the first line I said.

No problem, fantastic. Thank you very much for that. I think that is it for, questions for you, there, though.

Andrew does, just comment though that, in response to Jill, apparently Jerry Poulton does stunts in the UK. Oh great, if you're listening, Jill, let's say you might want to look up Jerry Poulton, I don't know whether you've, come across him, Doug. Absolutely, yeah, yeah.

So you know, Joe, good, good, good. So, yeah, so that's just a little point there. So thanks for contributing that, Andrew.

And that's what it's all about these webinars, especially the live ones, being able to contribute and share information that, you know, your colleagues don't, maybe aren't aware of. So that's a really good example of that. So thank you very much.

So, I think if that is everyone done, all it leads me to do is a few thank yous. Thank you to Lewis for being on hand this evening to support on the technical side, making sure everything goes smoothly. Thank you to yourselves for attending.

I hope you found it interesting, and we will be doing another platinum webinar again next Thursday at 8:30, so I hope you can join us then. And, last but not least, thank you to Doctor Douglas Tham for this tonight's webinar. It has been very interesting.

It will be available in our online library in 48 hours' time. So if you want to refer back to it, it's there for you to do so in your own time. So thank you very much, Doug.

I really appreciate it and you can obviously continue with the rest of the day while the rest of us are getting ready to wind down and go to bed. So thank you very much and good evening, everyone. Thanks very much, everybody.

Cheers. Good night.