Good evening, everyone. My name is Charlotte, and thank you for joining us for tonight's webinar, bladder and prostate tumours. Is there anything more we can do for them presented by Owen Davies.
Bladder and prostate tumours can be some of the most painful tumours in dogs and cats. Historically, they have been underrepresented in advances in veterinary oncology, and they have remains a challenge to manage the welfare of our patients with these terrible malignancies. Recently, however, we have experienced the advent of exciting and accessible diagnostic tests and treatments for urethral tumours, so the prognosis is not quite as bleak as it once was.
This lecture today explores how to diagnose and manage bladder and prostate tumours in 2023. So a bit about our speaker today. Owen is a RCVS American and European recognised specialist in veterinary oncology.
Before his residency at the Royal Veterinary College, he spent 9 years in general practise, including mixed, small animal, private and charity work. He is a member of the Australian and New Zealand College of Veterinary Scientists and holds a master's degrees based on research into canine lymphoma. Owen currently works at Bristol Vet Specialists.
I wish to let you all know that tonight's session will be recorded and available on playback, and you will all receive a ticket for tonight's attendance also. Please use the Q&A box for any questions you may have for Simon, throughout the presentation. And if you run out of any questions submitted, we'll email out any response in the next few days.
So with no further ado, I'd now like to head over to Owen to start this evening's session. Thank you, Owen. That's brilliant.
Thanks ever so much for that introduction, Charlotte, and my thanks again to webinar vets for having me back to do another webinar. Tonight, we're looking at bladder and prostate tumours. And to help us, we have our assistant Jess, a 13 year old female neutered, sort of border collie.
Jess has a one month history of stranguria and polyuria. And those words don't quite do the severity of the situation justice. She has been getting her owner up several times a night to go and urinate, and when she goes and urinates, it's intensely irritating.
She's spinning round and licking her nether regions vigorously after she does it. She wants to urinate all the time, pretty much everywhere she goes, and it's visibly uncomfortable when she does so. Herona thinks, though he's not quite sure that he may have seen a bit of blood in her urine, and actually he's right, that was confirmed as 3 + hematuria on dipstick.
And she's presented to you a few weeks after signs started because she was put on antibiotics, that's Comoxalav, and she did get better, not completely better, but she did make a significant improvement. The thing that prompted referral, however, was when she had her bladder scan, this mass was discovered. So actually, lots of different types of bladder tumour are available as I've listed here.
But when you consider the prevalence of these, the principal tumour we deal with is the transitional cell carcinoma. And in the interest of time this evening, that's what we're gonna focus on. So the canine transitional cell carcinoma, well, it's a dreadful tumour really.
It is characterised by severe and intractable discomfort. And that stems from two things really, it's really, really invasive. It is far more invasive than you could ever possibly imagine.
And it occurs in very awkward and very sensitive location, that is the trigone of the urinary bladder in most cases. To illustrate just how invasive it is, it may well affect a lot of other locations. For example, 56% of trigonal masses will also involve the urethra.
And about a third of male dogs with a TCC will also have involvement of the prostate. The invasion may cause urinary tract obstruction and acute dysuria. Did you know that this is actually a very metastatic tumour?
I could forgive you for not knowing that because I realised that quite late as well. The reason why we often overlook the metastatic tendency of this tumour is because frankly, it doesn't matter. Most dogs will be, will be euthanized or die because of the pain, trying to con and the difficulty controlling the local disease long before the metastatic disease ever has a chance to cause a problem.
Now that's most cases, that's not all of them, etc. So I think that Jess, our assistant for tonight, is a very good example with a history of very, very acute, uncomfortable urinations. To start at the beginning though, let's look at some risk factors for TCC, OK.
Like all cancers, it's partly to do with genetics that you're born with and partly due to the mutations that acquire as you go through life. And we consider some of the environmental influences. It's been shown that exposure to older generations ectoparasiticides and lawn treatments, that's principally herbicides and pesticides, can promote the disease, as can obesity, cyclophosphamide exposure.
And being female, I'm sorry to say. In one study of Scottish terriers, we found that dogs who were fed vegetables at least 3 times a week seemed to have a significantly lower occurrence of the disease. And that was quite useful to know.
The dogs that were fed vegetables were mostly fed just carrots as training treats and got them at least 3 times weekly. And when they were categorised as such, they had a significantly lower occurrence of disease. And then when we consider some of the genetic predispositions, we know this is the case because of a very strong breed tendency.
The Scottish terrier is the most unlucky breed with this disease. When you compare to a mixed breed dog, whatever a mixed breed dog is these days, Scottish terriers are 18 times more likely to get a TCC. And then Shetland Sheepdogs and beagles are also much more likely as well, as well as the Westies.
And when we consider the Labrador, golden retriever and German Shepherds, well, they're pretty much less than half as likely as a mixed breed dog. And as I've tried to illustrate, the principal clinical signs are hematuria, stranguria, and polyuria in an older dog. Particularly if an older dog who's never had waterwork issues before presents with these signs, I'm already very, very concerned that we've got a urothelial carcinoma.
The average age of onset is about 9 to 11. And what can complicate the picture is that many of these guys, over half of these guys, We have bacterial cystitis as well and will make some degree of response to antibiotics. When they come in, the examination may be normal, but on rectal, you can sometimes feel thickening or pain associated with the urethra and the trigone.
You may also identify iliac lymphadenopathy. On rare occasions, you can get secondary signs like lameness due to bone metastasis or hypertrophic osteopathy. Urinary obstruction and acute renal failure or azotemia.
So let's return to Jess. She's had a one month history of very intense lower urinary tract signs. Some differentials I may consider would be bacterial cystitis, urolithiasis, urolithiasis, sorry.
Polypoid cystitis, what we used to call granulomatous cystitis, which is now proliferative cystitis, or neoplasia. Now for those dogs where the signs will disappear with antibiotics, I'm thinking about bacterial cystitis, OK? Either an uncomplicated case where treatment treats it for good, or the complicated cases where the disease recurs after you stop the antibiotics.
And in this latter group, I'd consider polypoid cystitis. The discomfort would typically go away once you treat the infection with polypoid cystitis, but the polyps act as aidis, and so the clinical signs will often recur when you stop the antibiotics. One feature of polyploid cystitis that I have seen, however, is that because the polyp doesn't physically go away, the bleeding and the hematuria may continue, but the discomfort may go away completely.
When you have less improvement with antibiosis, such as GS. I'm thinking there must be a physical irritation to the bladder lining. So calculli would be on this list as well as neoplasia and this proliferative urethritis that I just mentioned.
Now proliferative urethritis is often physically indistinguishable from a TCC of the bladder, but it's actually a granulomatous lesion and it does respond to prednisolone. It is very rare. Most things that look like bladder TCCs will be TCCs.
In one recent report of proliferative arthritis, they had about, I think 20-30 dogs, and that was captured over a 30-year period. They had to have a 30-year period just to get that small number of dogs. So it is, it is a rare disease, but it is, as I say, on imaging and clinical signs often indistinguishable from a TCC and that underlines the importance of trying to get a tissue sample to diagnose the disease.
So going back to Jess and the differentials I'd consider. I wouldn't think polypoid cystitis is likely because the clinical signs didn't resolve completely with antibiotics. I would be thinking of these latter two here.
And I would seek to do, to augment the information we have by doing a full physical exam and a CBC and a biochemistry, if these have not been done already. And I would go to bladder imaging pretty quickly. I note here, in this dog with this signalment, I would be very, very, very careful about doing cystocentesis until the bladder has imaged.
And if the bladder's been imaged, and if I've seen a mass, I wouldn't do cystocentesis at all. I know that cystos are better for culturing urine, but there's a real risk with a carcinoma like this that you could seed the carcinoma into the subcutis and the skin and cause extension of the disease there. And if you think that's something that just turns up in books, well, here's a picture of it.
You know, at least once a year I get a case like this that has been cystoed and sadly, the disease has been dragged into the subcuti and now we've got a much more difficult problem to deal with. But going back to your analysis. Whether, if I see a bladder mass like this on ultrasound, I'm not gonna do a cysto.
Instead, I'll try to get a catheterized urine sample if possible, or second best, a midstream voided free catch. And I'll send urine off for the full urine panel, including culture, sediment, dipsticks specific gravity. I will also send off some urine in EDTA for cytology.
Because neoplastic cells in TCCs will be present in the urine in about 1/3 of the cases. Those odds aren't bad. If you diagnose this disease on cytology, that's a very quick, neat, and non-invasive way of doing it.
And that's exactly what happened in Jess. That part of her case, at least, was easy. We saw the bladder mass.
We got a urine sample, which I believe was voided and midstream, and the clinical pathologist was very happy to call this a carcinoma. In constellation of the clinical picture in the trigonal region, we were happy to call it a transitional cell carcinoma. In a lot of cases though, you won't be so lucky as we were with chess.
So, to confirm the diagnosis, if you don't get one on cytology, I think cystoscopy or biopsy could be considered. And that's really fun and it's great to see, you know, inside the bladder. It's really cool.
The only downside of that is that the biopsy channels in cystoscopes are really small and you tend to get a tiddly little biopsy. Often a better pigment of tissue is obtained through a catheter suction biopsy, and that's a really simple, and useful technique to get to know. If you get a histo sample and they're wondering, is it a TCC or is it not a TCC then you're a plaque in 3, we don't need to know the name.
But we have got an immunohistochemical marker that is available to distinguish a TCC from other neoplasms or even granuloma. So The technique for a catheter suction biopsy, as I said, is very easy. Please use a male dog urinary catheter, regardless of the gender of your patient.
You insert against the side of the mass under ultrasound guidance because remember that the whole of the catheter is on the side. Attach a 20 mL syringe, apply negative pressure. If you're just dragging fluid into the catheter, then rotate the rotate the catheter until the hole is against the tumour and you're getting negative pressure there.
Once you get negative pressure, and you have at least several mLs of negative pressure, withdraw by a few centimetres very swiftly to rip off a bit of tissue. Remove the IV, remove the urinary catheter and see whether you've got any particles. If you've got a particle bigger than about 2 millimetres, then put it in a histopot.
And if you've got a particle bigger, sorry, smaller than 2 millimetres or just a few little floaty bits or even nothing at all, please don't be dismayed. Just show you an image here. Now the the actual bladder lesion is here.
And you can see, I've got some arrows, this is actually the catheter that's visualised under ultrasound. So some tips, . To get good purchase on the mast depends really where it is.
So you might need a bit of jiggery pokery to find the right technique for an individual case. But if we're not getting a good sample, or not able to contact the mass very well, I would consider infusing saline into the bladder to extend it to a predictable amount. You could, if you're very careful, consider cutting the end of the catheter off if you're able to directly abut the catheter straight onto the side of the mass.
In a lot of cases you can't, but that may be useful in some cases. Just be very careful not to traumatise the erythral mucosa as you go through. And as I say, if you get a sample of over 2 millimetres, you're laughing, put it in a histopot.
If you get a tiddly little sample, you could still get a very, very good diagnosis. This is a sample that my resident took a few months ago. She was a bit miffed because she thought she had a nice bite of the tumour, but there was nothing visible in the catheter tip.
We made a few direct smears though, and this is what we got. And what we can see here is evidence of a carcinoma. OK.
What we have is some very, very large cells. If you compare them to red cells, you can see just how big they are. And they're sticking together.
And that suggests carcinoma or epithelial rather. You can also see they're very pleomorphic, lots of different shapes and sizes and morphologies, and that would suggest the malignancy. I think you can see some of them a bit closer up.
There's a huge variation in size and shape and both of the cells themselves and the nuclear nuclei and the nuclear features. This one it seems to be trying to divide. So we've got carcinoma, and to put the icing on the cake.
We identified these because pleomorphic epithelial cells spells carcinoma, it doesn't say anything about transitional. To get the diagnosis of transitional, we're looking for these pink inclusions in the cytoplasm of these pleomorphic epithelial cells, and that's a feature of the transitional cell carcinoma. So from what looked like a rubbish sample, we had a great diagnostic sample.
And then finally on the note to diagnosis, we could use the BA mutation, PCR, OK? Now, cells will always be shared into the urinary tract, whether they're healthy cells or whether they're cancer cells. And this test is looking for, is it a PCR test essentially looking for a very specific mutation in the genes of the cells that have been shed into the urinary tract.
This BAF mutation is very, very well characterised. And it's not been found associated with any non-cancerous diseases. It's present in about 80% of urothelial carcinomas, and as a test, the commercially available PCI is supposed to pick up at least 3 quarters of them, if not more.
And the initial study suggests it's also not gonna miss any, or sorry rather, it's not gonna give you any false positives, it's very specific. I would caution though, it hasn't really been tested, where we'd want to test it. For example, where you've got a bladder mass like a granulomatous cysti urethritis or a polypoid cystitis.
The comparison is not quite real world. It's only been compared to normal urine samples, and we wouldn't often test a lot of these guys for a TCC in the first place. But still, notwithstanding, it can be a very good test, and I think that can provide a lot of good support to the diagnosis of a TCC.
If we have appropriate clinical signs and a trigonal bladder mass and we're BRAF positive, I would accept that as a diagnosis of a TCC. If we have a positive breath test and appropriate clinical signs, but we don't have an obvious mass or any cytology, and we've tried hard to get that, I would still be a bit unsure about the diagnosis and I'd still want to pursue that a little bit further. Let's look at staging of bladder TCCs now.
And as I said earlier, Most of these guys will be put to sleep because of the intractable discomfort associated with the bladder mass. And that may bring a very logical question, well, why should we stage these? It's kind of irrelevant to look if the cancer spread or not.
And I guess in a lot of cases you'd be absolutely right. But if you're gonna treat the case and you've got a committed owner. The gravity of missing cases where the tumour has metastasized is actually huge, as I'll illustrate now.
This is a CT scan of a dog's pelvis, and if you can see where my arrow is, there's a metastatic lesion that's pretty much dissolved all of the sacral area. The dog was walking a bit funny and a bit hunchbacked, but yeah, you could forgive the dog for doing so because there's a horrible bladder tumour. Actually, a key reason why the dog was walking like this was because of this metastasis there, and I would have hated to have missed that.
Can you see the way the bones dissolved? There's another case here where there's no mets in the abdomen or the thorax, but it seems to have muscular mets up here, which again suggests possibly a more aggressive disease if these are present at diagnosis than a lot of them. They could also be the site of bleeding or pain as we move forward.
And here's another case with no disease in the abdomen and a relatively small bladder tumour but huge pulmonary metastatic lesions. So with these 3 cases, if I was to quote the average statistics for prognosis to the owner, I would probably be being a bit too optimistic. On the flip side, if, in terms of pain control and other things we can do, we may have more we could target or more we could look out for in the one with the skeletal nets, at the very least.
And let's return to our friend Jess. Did some staging tests on her after the diagnosis and we have a complication. We're looking at a transverse section of the abdomen.
That's the left kidney and that's the right kidney. Can you guess what's wrong? This is hydronephrosis.
And if we go back we can see the ureter here, not no ureter on the other side that's distended, just this one here. And you can trace it back into the bladder. The distension of the ureter goes all the way into the bladder where the tumour at the trigone around the insertion of the ureters is compressing it.
And you wouldn't guess this from blood, so creatinine was almost normal and other markers of renal function are normal. So let's go on to talk about treatment, TCCs now. The first bit of practical advice I can give you is please treat the urinary tract infections.
Over half of these guys will have at least 1 positive urine culture during treatment, OK? And when you're talking about females, this is 80% of them, presumably because they have a shorter and wider urethra and opportunistic infections, just a bit easier. But it's still a third of males.
And again, urethral involvement, and I presume disruption of the physical barrier between the outside world and the inside of the bladder, it is also a risk factor for developing a UTI. And look for these UTIs please, because you can treat them. And if you're able to treat them, that can often make the dog feel a degree better quite quickly.
Also think about how painful these are and consider multimodal analgesia if possible. And once you've got your UTI under treatments and you've got an analgesic plan, third thing, then start thinking about treating the tumour. For most of these TCCs out there.
The mainstay of treatment is medical. I'm pleased to say things are changing a little bit now, with access to other and more sophisticated treatments, and I'll tell you about these in a minute. But the core treatments described so far are medical chemotherapy drugs, and I'm afraid the response is often a bit disappointing.
Carcinomas as a group of tumours are very unresponsive to chemotherapy drugs. They're diseases that you try to remove if you can, but this is often a location where you often can't. So cisplatin was one of the first drugs described, and only about 20 to 50% of dogs responded.
And the average survival of several months. Cisplatin is also a horrible drug, which can cause severe nephrotoxicity. We tend to use carboplatin a lot more now, and cisplatin's largely been replaced by carbo in veterinary medicine.
Carbo is much less nephrotoxic and overall a very well tolerated drug, but still, a study looking at carbo on its own for a TCC showed that no dogs responded. A survival 4 months. Isn't that depressing?
What about Vin Blastein? Well, happy to say things are getting a bit better now. Average survival only 5 months, but you can see the overall response rate is almost 96%, almost 90%.
That is almost 9 out of 10 dogs benefited from the drug. Now I'm gonna talk more about different types of response, so just as a quick digression. When we talk about complete response, we're talking about the tumour disappearing.
When we're talking about a partial response, we want it to decrease in size by at least 30%. When we're talking about progressive disease, we're talking about where the tumour grows by at least 20%. And if it shrinks by up to 30% or grows by up to 20%, we'd still call it stable disease within the realms of measuring error, OK?
And data for these things are what you see here. So we've been blasting, we mostly get tumour shrinking but not going away, or more likely held at the stable size. And the overall response rate, which I guess as you might have concluded is the sum of the complete, the partial, and the stable.
Now what about clorambuil? OK. Again, there's similar data for loambiil as there is for vimblastine overall.
Some dogs respond. 30% of dogs have disease progression, etc. Again, the average survival is in the order of several months.
So despite loambicillin vimblastine looking possibly a bit rosier, it's still not great, is it? Let's take things in a different direction. Because around 30 years ago, a very interesting anecdote started a lot of interest in the use of non-steroidals for the treatment of cancer in dogs and cats.
And the story goes that a very highly regarded veterinary oncologist in the state owned a dog who developed a TCC of the bladder. And the dog was in acute discomfort, so said oncologist went to their dispensary to get the dog some analgesia. And I understand that the only drug on the shelf was peroxicam, a non-steroidal.
It's very non-selective between the COX 1 and COX-2. So the dog was treated with peroxicam and felt better, and that was good. But the clinical signs resolved quite a lot and stayed resolved for some time, and a subsequent ultrasound showed the tumour to have shrunk.
And this prompted studies like this one which showed that if you just treat the TCC with peroxicam, well, still about 20% of the tumours will shrink, and the average time for which they stay shrunk is in the order of about 5 months, you know, so well possibly 6, sorry, I can't do the maths, it's late in the evening. It's coming up to about 7 months, isn't it? So why not treat with chemo and a nonsteroidal drug?
And that's what the latter studies have done. Remember, the rubbish results of carboplatin on its own, well, at a non-steroidal, then suddenly things get a lot better. From zero responses we get to almost 40% of dogs having tumour shrinkage and an average survival of about 5 months.
Myitoxantron alone again had rubbish results on its own, but when we use peroxicam as well, you get an average survivor of almost a year and about a third of the dogs having no response. This isn't just a piroxicam thing. And this has been shown beyond contention in human medicine.
All kinds of non-steroidals are considered to have the same broad anti-cancer effect in people, and we're starting to see that as we're studying different non-steroidals in dogs. I think piroxicam was a great drug in its time, but it's not licenced in dogs, and it's very good at causing gastrointestinal, as well as renal toxicity. There's many safer and better tolerated and licenced drugs out there.
So we get similar, similar data treating TCCs withdraoxin, as we do with the iroxicam. Just another brief digression here. If you're interested in why non-steroidals may have an anti-cancer effect, then consider the effect on the healing of the wound, OK?
Cancer is sometimes called the wound that never heals, because from a cellular point of view, very similar things are growing going on. Now in a healing wound, you'll have lots of cytokines that are encourage cells, encouraging cells to proliferate and to grow and mature. You'll also have a lot of promotion of angiogenesis to support this cellular activity.
And the encouragement of cell growth and proliferation and angiogenesis are also features of a cancer. Furthermore, as part of the acute inflammatory response, inflammatory cells will elaborate reactive oxygen species designed to damage the DNA of pathogens. And sadly, Your host cells can get caught in the crossfire.
So this genomic damage on the background of promoting cell proliferation can further promote the growth and progression of a cancer. And this is the cyclooxygenase pathway, which is abbreviated. And non-steroidals act here, to stop the To stop the production of prostaglandins involved with either tissue homeostasis or an inflammatory and proliferative effect, or both.
And piroxicam can cause adverse effects because it tends to inhibit both roughly equally, and some of the newer non-steroidal drugs like meloxicam and oxibs are more favouring to COX too. Another way of looking at this is that the hallmarks of cancer described very eloquently by Hannahan and Weinberg, OK. You're using a non-steroidal drug or taking out one of those hallmarks already creating an inflammatory environment.
And this will have knock-on effects on lots of these things here. So potentially the effect of non-steroidals in solid tumours should not be dismissed. Anyway, that was a brief aside.
I'll come back to the story here, we're giving you some practical medical treatment advice for TCCs. I've said, treat those UTIs. And then as part of your analgesic plan, please use a non-steroidal drug if at all possible.
And then you come on to choosing the chemo drugs. With TCCs as opposed to lymphoma and things like that, there's been no benefit shown of using multi-agent protocols. Perhaps they should have been explored a bit more.
I'd like to see that in the future, but from what we know at the moment, the way to go is to choose one chemotherapy drug along with a non-steroidal if possible. To use it, to monitor hard, and when the disease starts coming back at you change to another drug. So we tend to use serial monotherapies rather than combination therapies.
Now, here are some of the most commonly used drugs for TCCs. I've got a question for you to consider. This isn't a vote.
But just consider what you would consider is the most effective treatment for TCC from the data here. Now we've got overall response rate, that's the sum of the complete responses, partial responses or stable disease. Progression free interval, the remission time if you like, before the tumour starts to progress, and then you've got the survival time.
So what are you thinking? What's got the best numbers? I bet you you're thinking about the MO, Myitoxantrone and peroxicam, aren't you?
Because they have the best numbers. But please don't be distracted, or don't try to compare. Studies based on small numbers of dogs done in different institutions and at different times.
That's the recipe for trouble. We can make very kind of broad assumptions based on this, but we don't want to compare things exactly. In this randomised controlled trial, We found that the data for the moxantro and for carboplatin was no different, both in the response rates and also the length progression pre interval.
And if you look at the carboplatin here. It's much less at face value. Another point I wanted to make is that we don't really want to choose a treatment based on overall survival time for this particular cancer, because the reason why the dogs die is people put them to sleep when they're painful.
And that's heavily influenced by people's own views on how painful the dog is, and different people make their PTS decision at very different times. We also don't want to look at survival time because that's affected by much more than one treatment, that's often affected by lots of other different types of treatments. So the key thing that we should really consider is the objective thing we can measure, and that's tumour response.
So let's consider the types of tumour response here. And actually, these ones have got a higher rate of tumour shrinkage, the partial response. And so for a dog like Jess who's very clinical, I would go for one of these first.
To maximise the chances of shrinking the tumour, getting control of the disease. Clorambil is a drug I'd love to use because it's oral and the others are injectable. And chlorambicil you can dispense in a pot and the owner gives it at home and that's low stress and it's low cost, and then what's not to like.
Well sadly, although the overall response rate with chlorambil is similar. Only 3% of tumours will shrink and 67% will maintain stable disease. So stable disease in a dog like Jess who is intensely uncomfortable, is not gonna do anything.
So we need to use something that will bust the disease down. If we did happen to discover a TCC incidentally and clinical signs were mild or absent, then I think loamicil would be a great first line choice. But the title of this talk was what more can we do for these guys, so let's explore some more advanced things now.
First, people often use palladia to serine phosphate because it's readily available and it's easy to give. And actually, the results with palladia are similar to Cloranduil, they're kind of mediocre. In 37 dogs, you've got about 7% had tumour shrinkage, 80% had stable disease.
It isn't dreadful for this tumour. But the average duration for which that lasted was about 4 months. And can you combine to serinib with other drugs like Vilastine?
Well, you can, you can do that safely. But there's no clear benefit of giving just the the serenib on its own or the lasine on its own. One particularly exciting study I'd like to draw your attention to was published in Nature.
A human journal from this team in Japan, and they use a small molecule inhibitor that's licenced for human use called lepitinib. Now this inhibits the epidermal growth factor receptors 1 and 2. The latter is more commonly known as HER2.
And in a non-randomized clinical trial, they had 44 dogs with lepitinib and peroxicam, and 42 dogs, with just paroxicam only. OK, they were all age, sex, and tumour stage matched. So it's a very, very well designed study.
And you can see some of the cases of the tumour at baseline here, these two photos, that kind of shrank drastically compared to the post, you know, when they looked at it post treatment. And if you look at this waterfall plot here, OK, the green ones are the ones that had peroxicam and lapitinib, and the vast majority of these had tumour shrinkage and in some cases that's up to 100%. When we looked at the type of response you get, you know, a large proportion of these responses are complete and partial.
And then when you look at the survival curves, there's a clear difference both in progression free interval and overall survival between the group, the dogs who are treated with lepitinib and those who weren't. So the average remission time is in the order of about 6-7 months with lapitinib and paroxicam, and overall, considering other treatments they got, they live for about 14 months, vastly better than paroxicam alone. You can also do interventional treatments, which is really cool.
It's where you feed a catheter up an artery, you cannulate a peripheral artery, feed a catheter up. And you're able to visualise what's going on under fluoroscopy. So you can cannulate the arterial supply to the tumour itself, and you can give intraarterial chemo.
But to cut a long story short, the published results show modest benefits. They've said that there's significant change in tumour length and the longest unique dimensional length. But no change in the tumour width or importantly, the tumour volume.
Let's step back a bit though, because I've told you about medical treatments, and is that really the best treatment for this disease? When you're choosing the right treatment for cancer, you have to consider the problems it may pose. First is local invasion, and secondly is metastasis.
If the most of the problem is caused by local invasion, then you really want a local therapy like surgery or radiation. And that's what I've said is the case for a TCC. If the principal problem is systemic spread, then sure, you'd use drugs.
So what information is there for a local treatment for TCC? Well, in this paper here, you had dogs where the TCC had occurred in an unusual place. It was not on the tri-drone of the bladder, partial cystectomy was performed.
And for those dogs who had daily paroxicam after the partial cystectomy, they had a survival of over 2 years. Sadly, this isn't often possible because they think very important things like ureters, bladder sphincters, nerves will limit their ability to resect those areas. You also need to consider the field effect.
That is that if you, the lining of the bladder has the same genes and has been exposed to the same environmental carcinogens. And so it, you can get neoplastic transformation occurring at several different folk like within the bladder, the dog with a TCC and this is something that we do see clinically. So when therapeutic intense surgery has been performed, .
The tumor-free margins are only achieved in about 3% of cases. And this illustrates the field effect here. You can see the tumour at the tri going to the bladder and another one at the cranial pole.
This is a more recent paper looking at total cystectomy and urinary diversion for dogs with a TCC. And they reported a lot of complications. Remember, these are trigonal TCCC cases.
They had a total cystectomy. The ureters were implanted in different parts of the body. And he had the essence of the ureterostomy, pyelonephritis, azotemia, urethral obstruction, and this is not to mention the fact that all the dogs would be permanently incontinent afterwards.
So this is not a treatment I would want to explore with a TCC case in myself personally. But radiation therapy, well, just possibly I might do. This is an illustration of how much radiation has gone on, has come on in the last 20 years.
This 2004 paper here gave radiation, mitoxantrone and peroxicam to dogs with TCCs, and they concluded that radiation was no, no more benefit over chemo alone. Now, we've got more advanced ways of planning the radiation and the results are quite different. 12 dogs they had whole pelvic radiation with a VAt boost.
In 6 doses, they found it was well tolerated, and for the cases that were non-metastatic diagnosis, average survival was 3.5 years. So now we're getting somewhere.
And if you're interested in what's changed in radiation therapy, it's all in the planning and the ability to fine tune the dose you get. This is the the starting point, 3D conformal radiation therapy. And you have a multi-leaf pollinator here which will allow you to shape the dose of radiation to the shape of the tumour.
As I've tried to illustrate in the schematic here. And then the, the beam is turned on and it will radiate the full dose into the tumour here. But there will be healthy tissue in the way where the tumour is thinner or smaller, that you can't avoid having this collateral damage.
And that limits the amount we can give. This is an illustration here, a cats with an unusual type of lymphoma affecting mandibular lymph nodes and nowhere else. Receive radiation.
To the lymph nodes, but got conjunctivitis as an adverse effect. And this resolved and it was fine, but we, we limited in the amount of radiation we were able to give to the cat's lymph nodes. Because, because of the planning.
Now we've got things like intensity modulated radiation or VATs as used in the paper I just showed you. And basically that's where these leaves of the collimator will move throughout treatment. Because the energy transferred to the tumour is dependent on the time for which the tumour is exposed to the radiation beam.
So in terms of planning, this will effectively divide the beam into lots of different beamlets where you can specify different energy deliveries. So you can have less radiation delivered to thinner areas of the tumour that need less radiation, and it helps to preserve the healthy tissues in the way. Currently in the UK there's 2 machines offering IMRT as far as I'm aware, that is in Southfields in Basildon and Edinburgh University.
And I'm very pleased to say that my home institution, Bristol Vet Specialists will also be offering this from autumn this year. Finally, a quick note on monitoring TCCs because this is the key. We start one treatment, we want to be able to pick up when the chip treatment starts to fail as soon as possible and to change.
To cut a long story short, CT is much more accurate at doing this than ultrasound. You can, you have reasonably good inter-observe the variability with the CT but very poor with ultrasound. And also, CT isn't enough.
You need to make sure you standardise the way you measure things on CT. Are you gonna measure volume or are you going to measure linear measurements? If you look at say tumour 5 week 16 here.
Two of the CT techniques said the disease had progressed, but one of them said the disease was stable, and that could mean the difference between abandoning a treatment and using something new or continuing a treatment. So what I'd say is that at the outset, you need to think very, very carefully about how you're going to monitor this and make sure you standardise. There is also a quantitative version of the BA test I showed you earlier.
It is commercially available and it should allow you to quantify the number of cancer cells by serial urine samples and what's not to like about that. Well, I don't have much experience with it. I've used it a few times, and in my limited experience of 2 or 3 times, it didn't correlate well with the imaging.
So I'd still be a bit nervous about using this myself. Ultimately, if you're on a shoestring budget and you're managing a TCC, you've got to go by comfort of the dog. If that bothers the dog, that bothers the owner, that's got to be the gold standard.
If you've got a comfortable dog with a good quality of life, then you're doing something right. And let's look at some complications. When you're treating a TCC, there will be occasions when you need to see the dog quite urgently, and that will happen in pretty much every case.
Suddenly the dog's more uncomfortable, slightly reverted back to the clinical signs when they were first diagnosed. If that happens, I'd consider urinary tract infection, progressive disease, urethral obstruction, or possibly ureteral obstruction or pyelonephritis causing azotemia. Now for some of these, culturing urine, giving analgesia, giving antibiotics would be an effective treatment.
But for obstruction. Radiation therapy would be my treatment of choice. This paper here using teletherapy just with a linear accelerator, showed that I mean 3 dogs that had the urethral obstruction, spontaneous matuition was restored, often within a few days.
It also worked for the Ers too. And another very clever technique is brachytherapy, which, for want of a better description, involves catheterizing the dog's urethra with an iridium wire. And that's brilliant because it imparts a huge dose of radiation where it's needed in the cells blocking the urethra and the radiation dose dies off as you go further and further away.
I'm not currently aware of this being offered in the UK, but these pictures were given to me by Jerome Benoit, on Covets in Lille. And he's had some really good results, offering, often causing the obstruction of the dog within about 24 hours. And he typically combines this with teletherapy using a linear accelerator to get maximal treatment benefit.
The other thing that might be a bit more accessible to us in general practise, the urethral obstruction is stenting. And to stent a dog, you need to take some very well positioned radiographs and the contrast series of the bladder to demonstrate the obstruction, the stenosis. And you take some measurements, one of the width and the length.
And then you can order in a stent and pass the stent there. As you can see here, the stent is currently unfurled, currently furled just around a balloon. And then when it's in position, You pump up the balloon.
And then you can deflate it and withdraw the catheter and the stent should stay in place. Yes, you need to order this stent in, that may take a few days, but the act of just placing a urinary catheter will shave enough tumour off the inside of the urethra that the dog will be temporarily out of trouble for a few days at least. So some things are really interesting and satisfying thing to do to deobstruct these guys, but I don't like doing it.
Because you lose patency of the urethra and the dog's incontinent, it's 75% of the cases afterwards. And you know, 26% are severely incontinent where they just have no continence at all. What we said at the start of the lecture was that often where you have a physical obstruction or physical irritation to the bladder, it's very difficult to control the pain.
And that's what you're doing here, you're putting a physical irritant in and the dogs can find it really uncomfortable and they can be straining even more. You can get re-blockage as the tumour grows through the holes in the stent. You can get recurrent and resistant UTIs or persistent UTI's.
And through what whatever reason. For which the dogs were stented, a study showed an average survival of only 2 to 3 months in dogs have been stented, probably for many of these reasons. And finally, you could consider laser therapy for an obstruction as well.
There's not an awful lot published on it specifically for obstruction of the urethra, but I know people who have used it and report reasonably good effects. But again, this is a temporary type of treatment. And just to say as a quick note, if you have obstruction of the ureter, you can do similar things, OK?
The stenting, the radiation therapy. I wouldn't consider a subcutaneous ureteral bypass though, just because you're seeding of the cancer tissue. So to complete the treatment plan for TCC.
I would say let's treat those UTIs. Let's analges and give supportive care is appropriate. Ask the question, could surgery or radiation be employed?
Because your best responses will involve these. Use a COX-2 inhibitor if safe to do so. Choose a medical treatment based on response rate.
I would opt to monitor every 8 weeks or so, re-imaging if possible, but the deciding factor has to be control of clinical signs. When you get disease progression. Defined as 20% increase in lesion size, I would change therapy.
And if you get an obstruction, I'd consider radiation therapy or a stent. Most dogs that are as clinical as Jess at least will live 5 to 10 months, occasionally 1 year before the pain is intractable again, and they have to be put to sleep. Prognosis is related to things like younger age, involvement of the urethra, those who have the urethral involvement do worse.
They have prosthetic involvement do worse and the bigger size of the tumour. It's also related to control of pain and related to potential complications like obstruction, as I said. So just then She received lastine injections every 2 weeks, concurrent meloxicam.
And she got a really good partial response, I'm pleased to say. We control those clinical signs very well. And the rectal exam, at least, the urethral component of the disease was reduced very significantly.
Costs were a big issue. We were able to repeat the ultrasound twice and I was pleased to say that the pilectasia was no worse, stable in size. And we continued the blast until disease progression of about 8 months.
We switched to Mitoxantro and had a modest progression free survival for about another 3 months. Then he had some flare-ups of bacteria, treated with antibiotics, and overall she was put to sleep at about 10.5 months, I believe.
Now I left urethral cancers to the end really because. They're kind of the same. Usually it's either a TCC of the bladder or a TCC of the urethra.
In most cases. And you can see one here. There's the bladder tumour is gone and it's rearing its head again in the urethra, OK.
Just let this clip play again. So you've got a bladder tumour up here. Swelling there in the trigone.
And another swelling in the urethra. So often they're part of the same process as the TCC and it's hard to say is it a urethral tumour with bladder extension or vice versa. These are more likely to cause problems though just due to their location and urinary diversion procedures may be needed.
Treatment in response to chemotherapy is very similar to TCC of the bladder. And for feline bladder tumours, well, these are rare. Again, TCCs are common.
Probably in cats you're more likely to have other histologies like lymphoma be an important one in the bladder. But for the TCCs, at least in cats, the clinical signs and the current co-occurrence of lower urinary tract infection is broadly similar to that of dogs. They're well reported as occurring at the cranial pole of the bladder.
And a recent study has shed some doubts on that, actually the commonest single location was the trigone in cats just as well as dogs. However, in cats, the majority of cases don't occur at the trigone, so not that they occur at the cranial pole of the bladder, that's quite rare, but they don't tend to occur at the trigone. The best treatment is not really well established in cats, but we know that if you've got a non-trigonal case that you can have a partial cystectomy and then medical treatment, they'll be better.
Just like dogs, we don't know the optimal chemotherapy treatment for these guys. We do know that the partial cystectomy and the NSAIDs are associated with the best outcomes. And finally, we'll talk about prostates as well, and there's many, many similar features here.
Prostate tumours overall are uncommon. But they are very painful and very aggressive. You certainly like the urethral cancers, there's gonna be a component of their location, exacerbating the pain because they're more likely to cause obstruction of the urinary bladder, and they're more likely to cause constipation due to being in a, in the bony box that is the pelvis.
And that's true. They're also more biologically aggressive though, and you see that in a much, much higher metastatic rate. So In many ways they're similar to the nastiest and most aggressive TCCs of the urinary bladder.
They affect dogs of a similar age. Histology is often slightly different, adenocarcinoma is more common. PCC is also very common though, transitional cell.
And an important point is that they tend to arise from the urothelium or the ducts, rather than the asiny of the prostate. Most of these tumours are androgen independent, and that's a big difference from humans, of course. And the TCCs are obviously developed from the prostatic urethra, rather than the prostate tissue itself.
And if you have a TCC of the prostate, it raises the question, did it start in the prostate or did it start in the bladder? Often it will involve the bladder and the prostate and the urethra. On rare occasions you can get other tumours involving the prostate as well.
I've noticed this study here, published in a human journal. It's looking at the effect of neutering on prostate cancer, and they amassed over 2000 male dogs. You can see that the most common ones for the transitional cell carcinoma and the adeno carcinoma.
And they showed that neutering dogs will increase the risk of a bladder TCC 4 times by prostate TCC 8 times, and a prostate adenocarcinoma by 2 times. You also see certain breeds are predisposed to prostate tumours and the Scottish terrier is predisposed again, it's a very unlucky breed. And that's even after exclusion of the TCCs, they still remain predisposed, and the same goes for the Shetland Sheepdog.
Things like Dobermans, miniature poodles are also overrepresented. The clinical signs of prostate tumours will overlap with TCCs of the urinary bladder. As I said, they're more likely to cause urinary obstruction.
They can also cause things like flattened faeces or constipation. And being more metastatic. Prostatic tumours are more likely to present due to issues related to metastatic disease.
On clinical exam, on rectal, you should find a large painful or asymmetrical irregular, fixed prostate. You may also find enlarged sublumbar lymph nodes. Don't write off the subtle findings though.
If you have a normal sized prostate in a dog who was castrated at a young age. That's a very sinister finding as far as I'm concerned. Even if there's no pain or asymmetry.
This Also, if you've got a dog who is castrated at a young age, and you have a mineralized prostate on radiography, that as well is a similar is a very sinister finding. If you've got an intact dog and you've got a mineralized prostate, then there could be lots more innocent explanations for that like benign prostatic hyperplasia, prostatic cysts, but the prostate should not mineralize in a castrated dog. To diagnose these, I do a very similar technique to the catheter suction biopsy, do a prosthetic wash.
He's a male dog urinary catheter. Now for these, I routinely will empty the bladder of urine and flush several times. I will then withdraw the catheter to the level of the bladder and neck or prostate, and the best way to gauge this is palpating per rectum.
If you've got an assistant who's able to have the ultrasound probe on the bladder as well, that also helps. I would instil just 1 to 2 mLs of sterile saline. Massage for about a minute.
An aspirate with a 5 mil syringe and put in EDTA. And then I'll repeat that. Some people would also consider cutting the end of the catheter for this as well.
I would rather not do that. And here's some prosthetic carcinoma cells. So just the degree of horrible preamorphism there.
You can also use the BA mutation for confirming a diagnosis, so you have a prostatic mass and dyseria. And I, if we've got appropriate clinical signs and imaging findings, I would be OK with breath positivity, even if the cytology is equivocal. And I just remind you, please don't aspirate these guys transabdominally.
You will get seeding of the tumour. Now, castrated dogs do have a different disease to the non-castrated dogs, or so it seems. And sadly, I think it's the castrated dogs who get the more aggressive disease and some of the entire dogs will have a much slower course of disease.
Again, the younger dogs I think have a more aggressive disease with this particular tumour. But overall, metastatic rate is 80% and 22 to 40% involves skeletal metastasis. So when you're staging these guys, bone imaging I think is really, really important.
Here's some pictures of bone metastasis from a prostatic tumour. Quite commonly we find that prostatic nets are very osteoblastic, that is they're productive rather than lytic of bone, as you see by these kind of like white densities here. They can of course be lit it like in this mass over here.
In the one on the right here you see the typical location of a bone net, that's in the mid diaphysis. Note if you saw an aggressive bone lesion at the epiphysis of a bone, you might think of, sorry, the metaphysis of the bone, you might think of an osteosarcoma, for example. But the bloodborne metastases tend to go into the bone where the blood goes into the bone at the nutrient foramen and end up mid diaphycele.
He's a picture of a dog called Bertie, and you see this horrible lesion eating through the scapula. This dog presented to me as a query osteosarcoma, acutely lame with this horrible osteolytic lesion there. And we actually found a number of osteolytic lesions elsewhere in Bertie.
We found one here, for example. And this is Bertie's pelvis. You can see lesions here and here.
For example, And you can also see when it comes around again, there's probably lesions within this vertebra here judging by the level of periosteal reaction. When you talk about treatment for these guys, I'm afraid it's miserable. Most published survival times for prostate tumours are in the order of several weeks.
The same principles apply as per a TCC of the bladder. Make sure your analges multimodally treat those UTIs. Please consider things like a non-steroidal drug and things like bed in vetmab, which you can use quite nicely alongside non-steroidals, particularly those who have skeletal nets.
The nerve growth factor has been shown to be an important algesic ligand in some bone tumours, and so it makes a lot of sense to try to combine labrella in the treatment for these guys. And again, we're still in the same difficult situation as we are for TCCs that. Historically we found surgery is not possible for a lot of cases and radiation wasn't possible.
So we were treating these with the second best treatment, so these medical treatment. In this study here, the guys used total prostatectomy for treatment of prostatic carcinoma, OK? And it was a difficult surgery, they had to ansomize the urethra.
There's associated morbidity with that. Permanent incontinence developed in about 13. However, the average survival was extended to about 8 months, and the thing that limited life was local recurrence or metastasis that occurred in at least 1/3 of the cases.
They did emphasise in this study that case selection is important. If you've got an intracapsular case. That is relatively early, and surgery is possible without significant issues, and astomos in urethra and things.
These dogs may do a lot better than in the more advanced cases, which certainly for me are the ones I tend to see the most. But something I want to alert you guys to as well is the use of the more sophisticated radiation treatments. Here we have this term intensity modulated radiation therapy again.
And in some cases, we've had some brilliant results using IMRT for prostate tumours. OK? In this group of dogs, the, they were treated with IMRT and the first signs of disease progression occurred 7 months later.
Which is much better than several weeks, and the average survival was in the order of about 18 months. And I like this because this is less dependent on picking up the tumour early and less likely to have the adverse effects that some of the total prostatectomies can do that. In this study we found dogs who had the tumour discovered incidentally have the best survival.
As well as those who didn't have metastasis. And those who did had chemo also did significantly better. And the final exciting thing I'll show you this evening is this drug, a monoclonal antibody called mogaullizumab.
It wasn't me who chose that name. But it's probably a much cleverer person who developed this potentially very, very useful agent. It's an immunotherapy, OK.
Now, the hijacking of the body's benign deregulatory cells, such that they will create an immunosuppressive bubble to protect the cancer, is a key means by which the cancer is able to survive. The cancer will be very of considerable interest to the body's immune system because it will have lots of weird antigens and the body's immune system will in principle, want to destroy it. But the tumour will hijack Tregulatory cells to nullify any incoming lymphocytes that want to make a response to the tumour, OK?
So these Tregulatory cells that have a normal function of protecting you and me from dreadful immune mediated disease are also used and abused by many solid tumours to protect themselves. Anyway, This is a monoclonal antibody directed against a particular receptor that's involved in the mechanism by which the cancer recruits these deregulatory cells. And the same team in Japan did a very good non-randomized clinical trial.
Between dogs who had megaullizumab and paroxicam, and those who had peroxicam only. And very similar to the data for the Pittinib. Dogs who had the drug of interest almost always had reduction in the tumour size.
And you know, the average survival of the dogs who have this agent is coming up about 10 months. And progression free survival, about 7 months. You can also see a greater level of partial responses here, and very, very different survival curves between the two groups.
Finally, I'll just mention if the prostate tumours cause obstruction or isotemia, then the same treatments can be used as per TCCs of the urinary bladder. So in summary then, most bladder, the urethral, and prostate tumours have many features in common, and it's often much easier to just use the term urothelial carcinomas to refer to all of them. As we said, a tumour may start off in the urethra and involve the prostate and the bladder, and it's a bit arbitrary to just choose one of those organs and call it one of those.
The prostate and urethral tumours cause more problems just by virtue of their location, but additionally, the prostatic tumours are biologically more aggressive. Please familiarise yourself and get comfortable doing a catheter suction biopsy or prosthetic wash to diagnose these. The BA mutation can also play a very useful supportive role.
Staging is useful for identifying distant, potentially painful metastasis that may change the plan. Consider non-steroidal therapy and monitoring and treatment of UTIs as the first step in managing all of these tumours. Remember that local therapy, that is surgery or radiation, is important in obtaining the best outcome, and it should be at least a consideration, even if it's just for a few seconds in all cases.
When you're choosing a systemic therapy and choose it based on response rate. Monitor response closely and decide how you're gonna monitor before you start the drug. And change the treatment each time you notice disease progression.
But ultimately though, and especially where you're on a shoestring budget, remember that control of clinical signs in animal welfare day to day has to be the most important goal. To show you some exciting new pictures of our new hospital in Avonmouth in Bristol, and we've got a linear accelerator there, brand new, be able to offer IMRT and lots of other treatments. I like to acknowledge my team.
We've got our residents Kate and Beth, Andrea, and other specialists, and you've got Shannon, Lottie, and Inga, our specialised nurses, and Jerome, our radiation consultant. And these are some of the guys in surgery, imaging, anaesthesia, who we work with very closely every day, and without whom our job would be impossible. There are actually more of these guys, but many of them ran away when someone got out the camera.
Thank you ever so much for listening. I'm very sorry I've gone on a bit, a bit long tonight. If you've got any questions, I'll do my very best to take them now.
Thank you, Owen for presenting tonight's webinar and thank you, to the Bristol Vet specialist team as well. I must say I did not know that the K9 TCC was very metastatic as well. I know we have run a little bit over, therefore, so if anyone has any questions for Owen, either please feel free to email questions to Dawn, who's popped your email in the chat box.
And I also see that Owen has popped that, email, of his on, the screen now also. But, just like to say thank you once again, Owen, for an informative session. And we hope that everyone enjoyed tonight's webinar and thank you all again for joining us.
Good night. Right, thank you.