Good evening, everybody, and welcome to another Thursday night members webinar. My name is Bruce Stevenson, and I have the honour and privilege of chairing tonight's webinar. I don't think we've got any new members in tonight, but just remember if you've got any questions for us, Mika, pop them into the Q&A box and we will deal with them all at the end of the fabulous presentation.

So our speaker tonight is Doctor Doug Tam. He is the Barbara Cox Anthony Professor of Oncology and director of clinical research at the Colorado State University, Flint Animal Cancer centre. Doug has authored over 150 peer-reviewed publications and 20 book chapters in veterinary and basic cancer research.

He is co-editor of the most recent edition of the textbook, Withrow and McEwen's Small Animal Clinical Oncology. And he is co-editor in chief of the journal, Veterinary and Comparative Oncology. Doug's clinical and research interests include novel targeted therapies for animal and human cancer and ways to integrate these therapies with existing treatment.

Doug, welcome back to the webinar vet and it's over to you. Wonderful. Thank you so much.

It's great to be back, talking to you guys. It's been, it's been a while. And again, it's always a, a great opportunity to get to speak to the, the webinar vet crowd.

So thanks again very much. We are going to be talking about perianal tumours in the dog for this hour. And, you can see my email on the bottom here.

So if, there are questions that come up either that we don't have time to address. At the end of this session or even after the fact, if you think of some things that you'd like to, to ask, please don't hesitate to reach out by email. I'm always very, very happy to talk to my colleagues, and answer any queries that they might have about individual cases or general questions as well.

So with that, Let's just do a brief overview of sort of the topics that we're gonna cover today. So, we'll cover perianal gland tumours. We'll cover anal sac tumours, and again, sort of these two categories really cover most of the, of the tumours in the perianal region that we're likely to see.

And then we will spend just a minute or two at the very end of the hour, talking about some sort of horizon therapy, some things that might be new or different. That, that we should be keeping an eye out for, either that we could employ now or things that we hopefully will hear hear more about in the near future. So, we'll start, just by talking about a little case here.

So this is a doggie that we saw named Boots, who's a 12 year old female spayed mixed breed dog. And, you know, really, she has a pretty unremarkable medical history who has been doing well through her whole life, but has a two-week history of of straining to defecate. And for the past week, the owners have reported a sort of a change in the shape of her stool, so sort of flattened or ribbon like stools, and, and that's really what brought them into the vet.

So the primary care veterinarian or the first opinion veterinarian actually reports really a, a fairly unremarkable physical examination with the exception of the rectal examination. So we always do. We talked to our, our students about the importance of doing a rectal exam on every dog, and this is just a great example of that.

And actually, what this veterinarian was able to palpate was an approximately 4 centimetre, very firm mass in the region of the right anal sac. And again, to the extent that that it could be appreciated, there wasn't any obvious evidence of, of swellings in the sublumbar region on rectal exam that, that could be consistent with sublumbar lymphadenopathy and, and we'll talk a little bit more about that in just a moment. So, still at the primary care veterinarian, some additional basic work was done.

So some basic lab work was performed, so complete blood count was unremarkable. On chemistry panel, there was a very mild increase in alkaline phosphatase, but importantly, there was a normal calcium. And again, we'll talk a little bit more about that in the upcoming slides.

Urine specific gravity was a bit low, but otherwise, the urinalysis was unremarkable. And then chest and abdomen radiographs were obtained as well, and those were unremarkable. And just like we do with any other mass, the next thing that the vet decided to do is obtain a fine needle aspirate and submit that for cytology.

And here's the, the cytlogic appearance of, of this particular mass. So, you know, what we seem to have is a, a, a pretty cellular aspirate that consists of these sort of clusters or clumps of very sort of tightly packed. Cells, based on sort of the, the way that they appear, we would guess that they're probably epithelial in origin, but actually one of the things that you'll notice is, is really, they're very uniform in size and shape.

They're not particularly worrisome looking in appearance. They have a fairly benign cytlogic kind of appearance. However, this is really sort of a classic cytologic appearance for a carcinoma of the, of the anal sac.

So that's one of the sort of the take home messages that I think can be very important is these can have a very boring. And very benign cytologic appearance. And this is one of those situations where if the submission form that accompanies the cytology is sort of incomplete and maybe there isn't information provided about exactly where this aspirate was obtained.

A cytologist might come back and say, oh, this, this looks like it's some kind of benign epithelial tumour, maybe consistent with an adenoma. But again, a clinical pathologist who's worth their salt, if, if they know that this is coming from the anal sac, might be very much more likely to say, oh, you know, despite its benign cytologic appearance, this certainly is consistent with the appearance of an anal gland carcinoma. So again, having a, a complete set of information about history and the origin of the mass can really help your clinical pathologist out for, for this kind of tumour.

So certainly we do know that an anal sac carcinoma is not the only differential diagnosis for a mass in the perineal region. So one of the things that we see with some frequency obviously is impactions or abscesses of the anal gland. Then we can see tumours that arise not from the anal gland, but from the sebaceous glands in the perineal region, which are called perianal gland, rather than anal sac tumours.

And we can see both benign adenomas and malignant carcinomas that actually occur in these perianal glands, and we'll talk about those separately. Then, of course, we can see our apocrine gland carcinoma of the anal sac. And then there's a variety of other kinds of tumours that we can occasionally see that just happened to appear in this perianal region.

So, melanomas actually have been reported of the anal sac, proper, which is actually quite interesting. I have occasionally seen squamous cell carcinomas develop in the anal sac proper as well. We can certainly see mast cell tumours and various kinds of soft tissue sarcomas that can obviously develop anywhere in the body.

That happens to occur in in the perineal region as well. So, again, hence the, the logic behind some amount of at least a cytologic diagnosis to see if we can at least narrow down the list to say, well, it doesn't appear that it's something infectious, and it doesn't appear to be one of these sort of oddball tumours that, that are less common but occasionally seen as well. So with that, let's, let's take a step back and sort of talk specifically about the perianal gland tumours.

So that's not what our patient Boots has, but it is again, certainly another differential and something that we will encounter in in practise. So the perianal gland. Again, is a, is a, a secretory gland that occurs in sort of the, the vague perineal region.

But as you can see, these glands actually occupy quite a bit of real estate, sort of in that perineal region. So they can be true perianal. We can sometimes see them on the tail base, we can see them in the inguinal region.

We can even see them on the prep you. So even if you have a tumour that's not, not really purely in that, true perianal region. This perianal gland tumour really should be on the differential list because of the distribution of these glands in the dog.

These are sometimes also referred to as hepatoid gland tumours, and that's actually because cytologically, these, these tumours have an appearance that's actually very similar to liver cells, to hepatocytes. So that's where that term comes comes from. And again, these are quite distinct from the tumours that occur in the anal sac proper, in terms of their derivation.

In some, to some degree in terms of their behaviour as well. So probably the most common of these tumours that we'll encounter are the perianal gland adenomas, and I think we're probably all familiar with this particular disease being a disease that's actually fairly common in older intact male dogs. And the reason for that is that this is actually an androgen-dependent neoplasm.

So, it's that androgen that comes from the presence of the testes actually that drives the proliferation of this tumour in many cases. So we can see them occasionally in castrated males and females, and actually when we see them in these in these other groups, we do tend to to worry a little bit more about the possibility of some kind of endocrinopathy. That could be contributing to their development.

So, again, specifically just jumping down to the bottom here. Hyperadrenal corticism is one of our rule outs when we see perianal gland adenomas in castrated male or female dogs. And the reason is that cortisol actually has some very weak androgenic activity.

So it's possible that a dog with Cushing's disease could actually develop perianal adenomas because of that. So we'll usually test them for that. It does seem like a concomitant testicular tumour like a lated or interstitial cell tumour which secretes excess androgen might also increase the risk.

So again, in that intact meal, good for a palpation of the testicles is probably reasonable as well. So these can have a variety of clinical appearances, so some of them can be actually quite large, some of them can be very, very small and focal. Some of them can occur actually almost right on the the anal orifice.

And again, some of them can be way up here on the tail base, for example. So a very, very wide range of appearances, behaviours, locations, sizes. Some of them can be ulcerated, some of them can sort of have normal haired skin overlying them.

These are just two examples of perianal gland carcinomas. So, really based on the clinical appearance, it's not possible to make a distinction between an adenoma and a carcinoma. Obviously, one thing in a particular case like this, that could increase our suspicion for a, a more malignant tumour is the fact that it's actually, progressing relatively rapidly.

So you can see in the course of a Month, it's actually more than doubled in size, and that would be atypical for for a dog with a perineal adenoma. I guess the other thing that I would mention is that we can see these be multifocals, specifically the adenomas in dogs. So some dogs will have more than one of these at the same time, or have the potential to develop more than one of them over time.

So, speaking specifically about perianal gland carcinoma, so there's really only one large case series that describes these, and this case series is now about 30 years old, and, actually one of my mentors, David Vaile, was was the first author here. So this is an older dog disease. It appears that the German shepherds and Arctic Circle breeds may be at increased risk.

And again, this is generally a disease where the clinical signs are referable to the local disease. So the presence of a mass, perianal pain and irritation and tenesmus, licking, scooting, those kinds of things tend to be most common. The, the majority of them are solitary at presentation, but some of them can be multifocal as well.

And again, it's a very, very variable, sort of how long these masses may be present for and, and how quickly they may be progressing. One of the things that's actually another very important take home here is that much like the anal sac carcinomas, these can have really, really boring cytologic appearances. So it's really virtually impossible to make a cytologic distinction between a perianal gland adenoma and a perianal gland carcinoma because they look so similar cytologically.

It really requires the pathologist to be able to actually look at the way the cells are interacting with the normal tissue in the area and actually look at the degree of invasion that's present in order to adequately make a call between, again, the benign version. And the malignant version of this tumour. How do we recommend treating this disease?

So, for the benign, perianal adenomas, actually the, the simplest treatment to, to pursue is usually castration. So if this is an intact male dog. Castration can actually usually result in very substantial regression of these masses.

In some cases, especially with the smaller masses, they may go away completely. If if they are not able to go away completely, they'll usually shrink up substantially so that it actually makes for a much simpler surgery. If castration is performed first.

If we have a castrated male animal or a female, generally we'll recommend again marginal excision is usually sufficient for these. As I mentioned, sometimes we will test these animals for Cushing's disease, if it's in, if, if it's in a non-intact male, just to make sure that that's not a contributing factor and something that might require treatment irrespective of the presence or absence of the tumour. And there are certainly reports, sort of anecdotal reports of androgen blockers occasionally being applied in situations where we have an owner who refuses to castrate.

So it's, it's complicated. It's it's really the stuff of case reports. I don't think there are any good case series that are published in the literature to describe exactly how a case this this approach is or doses to use or anything else like that, but could be a consideration again for that that that owner who just refuses to castrate.

In the perineal gland carcinomas, surgery remains the treatment of choice. But again, if possible, we might shoot for a more aggressive surgery. So rather than sort of a marginal excision, we might shoot for, for a bit more of substantial normal tissue margins to the extent that that's possible given the anatomic constraints of the location.

Really, the, the outcome data that we have is with surgery alone. And the largest concern seems to be with local recurrence for these tumours. And that's, I think, why, again, tumour size tends to be a major prognostic factor.

So I think it's easier to get some modicum of normal tissue margins with smaller primary tumours. So the likelihood of local recurrence is reduced, but with larger primary tumours, I think the tumours tend to come back more, more commonly and more rapidly as well, which is probably responsible for this difference in survival time that you see. So if we have one of these that's unequivocally malignant, And and we know that it's been incompletely resected.

I certainly might consider radiation therapy to try to prevent local recurrence. It's likely to be very effective, as we'll talk about more when we talk about anal sac tumours. It's likely to be very, very effective, but it's complicated, it's expensive, and in this particular location, it is a location that where, that's associated with some adverse effects.

I think if I, I saw a tumour that really appeared extremely aggressive on histopathology. So really bizarre morphology, high mitotic index, unequivocal evidence of vascular or lymphatic invasion, or if, God forbid there was already evidence of lymph node metastasis based on, on our staging, I certainly might offer some, some postoperative chemotherapy. Similar to what we'll talk about with anal sac tumours, but again, really no good information about about how effective that might be unfortunately, due to the infrequency with which we see this disease.

So moving on, let's let's talk about anal sac carcinomas, which if you compare perianal gland carcinomas and anal sac carcinomas, we certainly see more of the anal sac variety, but I think both of them are dwarfed by the incidence of the perianal adenomas, which thankfully are quite easy to to address in the majority of patients. So this is a fairly uncommon cancer, which appears to be equally distributed between males and females, and castration neuter status does not seem to play a role in the incidence of this tumour. And again, contrary to what we see with the perianal gland tumours, this seems to be a a tumour type that's more common in the smaller breeds.

So I think of it as a cocker spaniel disease and then some of the other terrier type dogs as well. Again, an older presentation, and this is generally a a unilateral disease. There are, are some reports of bilateral manifestation of anal sac carcinoma, but it's actually fairly uncommon.

So the majority of these are unilateral. So there's a variety of ways that dogs with this disease can present. So much like what we talked about with the perianal gland tumours, we may see just sort of non-specific signs of of perineal irritation manifesting as licking or scooting.

We could see dogs, like the little dog we're talking about here who's presenting with straining to defecate or flattened, ribbon-like stools. Sometimes a mass in the perineal region could be observed by the owner or by the groomer. Sometimes these are detected incidentally at the time of a yearly physical exam.

And between 25 and 40% of dogs with this disease. Actually maybe hypercalcemic at presentation. So if we have a dog who presents for polyurea polydipsia, and during our workup we find hypercalcemia, one of the major differentials that we need to keep in mind is a is a anal sac tumour.

So one of the first things I'll usually recommend if it hasn't been done already, is a is a a good rectal exam to make sure that we don't have a perianal or sorry, an anal sac tumour. So as part of our physical exam, obviously, the rectal exam is, is gonna be absolutely critical in determining, well, A, is there an abnormality back there, and B, how large is it? Does it appear to be unilateral or bilateral?

Does it appear to be freely movable or fixed or other things like that as it pertains to resectability? And to the extent it's feasible, we certainly do like to sort of try to palpate that that sublumbar region. To just see if there's any obvious evidence of sublumbar swelling.

However, I do think it's important to, to realise that this is a, a really insensitive measure for assessing that and really does not take the place of imaging, as far as making sure there isn't evidence of metastasis. And then I do think that, again, findingle aspirate is a great thing to, to do, because again, one of our other big differentials here is infection or impaction and that's actually a distinction that can be made pretty readily cytologically. Versus, again, an appearance that would be more consistent with neoplasia.

A pre-surgical workup, as we discussed in, in the case is gonna be generally very straightforward. So conventional, clinical pathology, a complete blood count, chemistry profile. So again, assessing primarily for suitability for surgery.

And anaesthesia, and again, obviously taking a close look at hypercalcemia as well. So there are some studies which do suggest that hypercalcemia is a negative prognostic factor. And so that may be information that's important for an owner to have if it influences the way they choose to treat.

And then we're usually gonna recommend some kind of imaging, primarily to look for metastasis. So, we do like to evaluate radiographs, specifically of the thorax. And then some kind of imaging of the abdomen as well.

Ultrasound or advanced imaging like CT tend to be more sensitive and preferred over flat radiographs for this purpose. So the likelihood of finding measurable pulmonary metastasis is that presentation is pretty low in dogs with these either anal sac or actually perianal gland carcinomas. It's probably on the order of about 5%, but 5% is not zero, and certainly, if God forbid, we saw a dog that had Evidence of pulmonary metastasis, it would in most situations be pointless to contemplate surgery unless it was needed for palliative reasons.

So this would definitely change the way an owner chooses to pursue additional treatment in most situations. So a very worthwhile test. I, I mentioned that flat films are not particularly sensitive, but in some cases where we see really profound.

Sublumbar lymphadenopathy. Certainly that is something that can be appreciated on on flat radiographs. One of the things that's actually quite interesting about this particular disease is, it's not uncommon to see really substantial regional lymphadenopathy in patients with relatively small primary tumours.

Sometimes I have occasionally seen situations where we have a a lymph node that looks like this. And really a primary tumour that can't be palpated, which is quite remarkable, but just an interesting fact. That being said, we really do feel like abdominal ultrasound is a much more sensitive test for being able to assess that sublumbar region, and, and really have a better understanding about whether there's disease there or not.

And again, this is a critical piece of information to have because it does really significantly alter our surgical approach and some of our post-operative recommendations as well as having an impact on outcome. Again, which may change how the owner chooses to treat. So, again, having this information preoperatively, I think is really very, very beneficial versus sort of taking out the primary tumour, confirming your diagnosis, and then going back and doing your staging.

CT and, and ultrasound are actually both very sensitive for for looking for changes in the sub lumbar region. There are some folks who prefer CT scan for this purpose because it also gives them some information that might be very useful for surgical planning, if they're planning to actually go in and remove these lymph nodes, which we'll talk about in a minute. So back to our friend, Boots.

So Boots, after the diagnosis was obtained, was actually referred for diagnostic imaging and an oncology consultation. And during that consultation, actually an abdominal ultrasound was performed, which revealed no evidence of metastatic disease to those regional lymph nodes, and then the plan was to pursue surgical excision of the primary tumour. So, as I just sort of gave away, surgery is really the mainstay of treatment for this disease.

Assuming that the disease is local regional only. So there's no evidence of disease beyond those regional lymph nodes. So, I'm not going to spend a lot of time talking about the surgical technique associated with removal of anal sacs, primarily because I'm not a surgeon.

I can't even spay a cat anymore, so I'm the last person you want actually talking to you about the details about the surgical approach to, to this disease, or really any other disease, . So, however, I am able to sort of talk a little bit about potential complications and postoperative management. So, obviously, analgesia is a, a key component of this, just like any other surgery.

I think you'll hear different things from different surgeons about the utility of post-operative antibiotics in these cases. Obviously, the perianal region is a comparatively dirty region and we do worry a little bit more about infection in this area than in some other areas, but it's also an incredibly well vascularized area. So, I think the risk of infection most of the time is not particularly high.

However, I also think there's little downside to postoperative antibiotics. And Echoar is obviously a real critical component of this, because self trauma is just gonna multiply the, the potential complications here. In general, it's recommended to avoid external sutures in this situation and either do subcuticulars, or again, oppose your margins with something like tissue glue instead.

And again, the two big complications that we worry about the most are dehiscences and secondary infection. I think again, keeping the good hygiene and keeping the dogs away from the area are probably the most important components of that. So what if we do have disease that we've identified in the lymph node but not beyond.

I think this is actually really important because the presence of disease in the lymph node is not a showstopper for surgery in the vast majority of cases. So it's actually very, very common for us to, to go into the abdomen after these lymph nodes and the outcomes can actually be quite good in these dogs if that's, if that's actually performed. So I don't think there are any really good statistics about this, but if you had to ask me to guess, and I've actually talked to our surgeons here, they'd say probably 85% of the time.

These lymph nodes will actually come out fairly readily at the time of surgery. So maybe 10 or 15% of the time, they're truly stuck on to things in there, especially like the great vessels, etc. That would make for a much more complicated surgery.

But the majority of time, they, the, the surgery to remove these lymph nodes is fairly straightforward in the hands of someone who can, can do this kind of surgery, which is not me. Again, some of our surgeons here will, will request advanced imaging like a CT scan first to make sure that a dog doesn't fall into that unfortunate 10%. But a lot of surgeons will say that the results of pre-surgical imaging really are not particularly predictive of how easy it's gonna be to remove these lymph nodes and, and nothing is a, is a substitute for the surgeon's fingers when it comes to that.

But again, here's a very recent, I think a 2021. Article that actually reports on a, on a series of dogs with just that. So primary tumours with regional lymph node metastasis that were treated surgically to both sites.

And actually, the the outcomes are reasonably good and the risk of perio-operative complications were actually quite low. So this is a very well tolerated procedure. So definitely a consideration.

We don't want to write off those dogs that have lymph node metastasis only because as I mentioned, they can actually do quite well, and we'll talk about that in just a moment. So in Boots' situation here, so Boots went to surgery and histologically, this was a well-differentiated anal gland carcinoma, with no evidence of lymphatic or vascular invasion and actually complete surgical margins. So in this particular situation, the oncologic recommendation was just for quarterly rechecks.

And the reason for that is that this would be a dog who has, a stage 2 tumour, so that's bigger than 2.5 centimetres, but without evidence of metastasis, normal calcium and complete excision. So what do we do with these quarterly rechecks?

Generally, obviously, good physical examination, including a rectal exam, and abdominal ultrasound with special attention paid to the sub lumbar region is generally the recommendation. I will generally recommend repeating chest X-rays every other visit, which would make that twice a year. And the reason for that is that in the vast majority of these cases, the pattern of, of metastasis is very predictable.

So, almost always, we will see disease manifest in the regional lymph nodes before we see disease occur in the lungs. So, again, nothing is 100%, but I think if, if the regional lymph nodes look good, the likelihood of finding something in the lung, it's actually pretty low. Hence, we only look there every other visit.

So here's a real seminal paper that's now almost 15 years old, from Jerry Poulton and Malcolm Brearley, who you guys probably know. Looking at the post-surgical outcome in dogs with anal sac carcinomas based on their clinical stage. So you can actually see the clinical staging system that was utilised here.

So stage one tumour is a small primary tumour without metastasis, stage 2 tumour, a larger primary tumour without metastasis. Then a stage 3 tumour is a dog who has lymph node metastasis but no disease beyond the lymph node. And a stage 4 tumour is a dog that has metastasis beyond the regional lymph nodes.

And as you can see, there's, so this is actually two separate cohorts of dogs. This was a retrospective cohort that was actually used to kind of develop the staging system and then this was a prospective cohort. That was that was followed.

And as you can see, the outcomes are actually quite excellent in those dogs with locally advanced disease, without evidence of metastasis. So in this group of dogs, median survival time was in the neighbourhood of about 3 to 4 years with surgery alone. In this separate group of dogs, actually, the median wasn't reached, so most of those dogs were doing great when they got to 2 years.

And then even the dogs with node positive disease here. Actually did reasonably well. So with surgery alone, you're looking at median survival times in sort of the 300 to 400 day range.

And those dogs that had gross evidence of metastatic disease, you know, you're looking at about 6 months or so on average. So overall, this is a disease that does tend to progress relatively slowly and as a result, even dogs with fairly substantial disease burdens can do well for a while. So here's just another way to present the same data.

If you look at stage versus median survival time or percent alive at a year. So again, you've got your stage 3 dogs here, doing well for 300 to 450 days, and your stage 4 dogs, again, this says 2082 days, with 22% alive at a year. So, I think that in in my practise, I think a lot of these dogs if they're asymptomatic at presentation, may do well then for longer than this.

But still, again, the post-surgical outcome can be actually be quite good. However, there certainly is a role for other kinds of therapy that we have in our, in our toolbox as an oncologists, things like radiation therapy and surgery. I'm sorry, radiation therapy and chemotherapy.

So we can think about radiation therapy, either occasionally postoperatively, we'll talk a little bit more about that, but we can either use sort of palliative type radiation therapy or curative intent radiation therapy as a salvage kind of treatment for unresectable locoregional recurrence or lymph node involvement that can't be resected. And then we certainly will talk about chemotherapy as well in certain circumstances and we'll go over those indications in a moment. So radiation therapy, the kind of radiation therapy that we're generally talking about in this situation would be conventional external beam radiation therapy delivered from a a linear accelerator.

And in general, this is something that's used most commonly, again, for the, for the palliation of unresectable disease, either a local recurrence or metastatic disease. And again, the goal here is to reduce clinical signs that might be present like straining, obstipation, etc. So is there a role for, for the postoperative use of radiation therapy in cases like this?

I think that's really hard to say for certain. So there are a few studies that have suggested that the likelihood of seeing local recurrence, even with incomplete resection is actually quite low. It's only in the neighbourhood of maybe 1 in 5 dogs.

So, so I think it's hard to justify this kind of very, very aggressive local radiation therapy for a disease that only has a 20% likelihood of local recurrence, given some of the morbidities that are associated with it. And normally with most parts of the body, I'm actually a huge proponent of radiation therapy. It's actually incredibly well tolerated and it works really, really well.

But the perineal region is kind of an exception to that. So it's actually very sensitive to the effects of radiation, and it's actually pretty common to see some fairly unpleasant, acute radiation burns from, from radiation for this particular location. So yes, it's self-limiting, it goes away in a couple weeks, but really it's, it's pretty unpleasant for the majority of dogs for a brief period of time.

And then as late complications, we can see obviously some changes to the skin like hyperpigmentation and alopecia, but we can also see, not that common, but occasionally we can see things like rectal or colonic strictures. And again, that can result in clinical signs like obstipation and straining to defecate that are not that different from the signs that the dog might have presented for with its tumour initially. So, you know, in our practise, we really have a hard time strongly advocating for post-operative radiation therapy for these, even if our our resection is histologically incomplete.

Again, because of a really high likelihood of adverse effects. And a relatively low risk of local recurrence, even in the face of incomplete resection. So again, palliative radiation therapy types of approaches can be used for the treatment of bulky disease.

And the idea behind these sorts of approaches is a relatively small number of treatments that may be given in a less focused way, but using doses that are low enough that they're unlikely to be associated with a lot of adverse events. And again, studies have suggested that you can get 6 to 12 months of control using these forms of hypofractionated palliative radiation therapy by itself. So, again, this is not something that we would generally use postoperatively, but in the situation where we've got again, local recurrence or lymph node metastasis that's unresectable, it definitely plays a role and again, is well tolerated and can definitely result in clinical benefit.

So moving on to chemotherapy, you know, obviously, as a medical oncologist, this is near and dear to my heart. This is what I do every day. Under what circumstances would we consider using chemotherapy for this disease?

So certainly, we'll consider trying it for the palliation of recurrent or metastatic or unresectable disease if radiation therapy is not feasible or if that's sort of been declined by an owner or if it's already been tried, that's certainly a situation in which we'll consider using it. And there are circumstances where we'll consider using it as adjuvant therapy as well. So certainly in those dogs that already have evidence of lymph node metastasis, if those lymph nodes and the primary tumour are removed, certainly the literature suggests that the outcome Those dogs are not nearly as good as those dogs who don't have lymph node metastasis.

So you're looking at median survival times of the year versus 3 years with surgery alone. So we certainly hope that we might be able to improve that with the addition of some medical therapy. And then there's certain histological factors that have been reported to be associated with a higher risk of, of failure.

And these include things like a high mitotic index, sort of invasiveness, which is something that can't be really quantified, but you may have reported a presence of lots of, of in tumour necrosis, vascular lymphatic invasion, and a high degree of cellular pleomorphism. Have been again associated with a higher risk of, of early failure. And so these things, even in the absence of lymph node metastasis, might make me want to at least offer chemotherapy to follow.

However, one of the things that's important to know is, we really don't have great information about exactly how effective chemotherapy is when it's used postoperatively. So there's no study that I can pick up that says, while I'm talking to an owner, if you would like to do chemotherapy after surgery, you know, your dog will do well for an average of 10 times longer than if you don't. So, there are rumours that such information is pending from an extremely large, retrospective study that's been performed, but that has yet to be published in the peer reviewed literature.

So, some of the drugs that have been reported to be used for this disease include oral mephan, and then intravenous carboplatin, doxorubicin, and midazantrone. I tend to be a carboplatin fan here. And at least in the states here, it's very inexpensive.

It's only once every 3 weeks. We generally do a total of 5 of these postoperative treatments. It's very, very well tolerated, and this is the one drug where there are at least reports of reduction in size of, of measurable tumours.

So, in other words, if you do have a dog with with unresectable disease and you give carboplatin, there are reports of actually seeing meaningful tumour shrinkage. And intuitively, we certainly feel like if we can kill enough tumour cells to shrink a big tumour with carboplatin, we can certainly kill some tumour cells that might be left over after surgery. So, these others are not wrong choices by any stretch of the imagination, but I feel like there's a marginally higher level of evidence for the use of carboplatin than there might be for some of these other choices.

Some of the other things that we think about when we're treating this disease. So one of them is the treatment of hypercalcemia if it's present. So, again, between 25 and 40% of dogs may be hypercalcemic.

By far and away, the best treatment for that is to take the primary or take the source of the, of the hormone, the parathyroid-related protein out, and that means surgery. So surgery will usually result in very brisk reduction. Of hypercalcemia.

But if surgery is not possible or there are other things that need to happen, pending surgery, we certainly can do those as well. So these can include sodium chloride, diuresis, corticosteroids, and bisphosphonate drugs like permironate or zoledronate, which can be very potent at reducing calcium. So these are all things that can be considered, but as I mentioned, really they are no substitute for removing the primary tumour.

And then, as palliative measures, sometimes we might need to do things to address obstipation. So things like high fibre diets, the use of fibre supplements like Metamucil, stool softeners like lactulose, and periodic enemas can all be useful in some of these patients. So again, postoperative or post-therapy monitoring, as we discussed, local site, including a good rectal exam, regional lymph node assessment with abdominal ultrasound, and occasional thoracic radiographs are really how we tend to monitor these diseases.

So many, many of these dogs will go on to develop either local recurrence, although that's not as frequent or metastatic disease in the future. So what do we do with those patients? So one of the reasons that again, we really do advocate for periodic re-staging is if we do see lymph node involvement at one of these rechecks, there's actually good evidence that going in and removing those lymph nodes surgically, sometimes even multiple times, can be associated with really a significant improvement in outcome.

And in those dogs who are presented initially without, Lymph node metastasis. If they then develop lymph node metastasis, I'll generally follow up with, with chemotherapy if I didn't the first time, or an alternate chemotherapy if chemotherapy was used the first time. Radiation therapy is still a consideration in those, in those situations where we have locally recurrent disease.

And certainly, we will talk about medical therapy. As a palliative measure, if surgery is not possible, if radiation is not possible. And one thing I think it's important to keep in mind here is when we're dealing with with gross, unresectable, locally advanced or metastatic disease, I would certainly consider lack of progression to be actually a very acceptable outcome when we're.

Medically. So, of course, we love to see tumour shrinkage, but absence of tumour shrinkage wouldn't make me say, oh, this isn't working, we should try something different. So, if we can keep the disease at least stable, I'm usually very happy with that as an outcome and we'll continue with whatever medical therapy we've been using as long as the disease remains stable or better.

So, this is actually a very recent paper that again looked at at lymphadenectomy as a treatment for dogs with with anal sac tumours. And again, one of the interesting take homes from this was that dogs whose owners elected for additional therapy at the time of disease progression, actually had a substantially better outcome, about a fivefold better outcome than those owners who elected to treat palliatively at the time of disease progression. So, again, because this is a disease that can sort of progress so slowly and so predictably, I think an important thing to make sure that owners understand is you can buy a lot of extra time by continuing to treat even after the detection of, of recurrent or metastatic disease.

So great thing I think for owners to to be able to know about. And then finally, just, just one or two new pieces of information out there that do give us some new tools in our toolbox that might be worth considering in certain situations. And so one of these, which isn't actually all that new, it's coming up on 10 years old, is actually a study, again, from the group at Cambridge that actually looked at expression of cyclooxygenase 2.

In anal sac tumours. And cyclooxygenase too, I think most, most everybody knows is actually the enzyme that catalyses the the production of prostag glandin E2, which is responsible for pain and inflammation, but may actually be associated with tumour progression for some kinds of tumours as well. And so, although the majority of these tumours sort of had low to moderate expression of, of cyclooxygenase too, they all had at least some expression.

And in most cases it was substantially higher than what was observed in normal anal glands, that were assessed during the same study. And actually what this suggests, although there's no data, is that perhaps there's a role for non-steroidal anti-inflammatories for the treatment of this disease. And again, when I'm treating palliatively, so when I'm doing medical treatment or other kinds of things to address bulky disease, I generally will start a dog on an NSAID.

And again, I don't have a particular favourite NSAID for, for use in, in this particular situation. I think if you happen to like paroxicam, because it's been studied a lot for other kinds of cancer in dogs, that's a great choice. If you'd prefer to use one of the, the more Cox 2 selective non-steroidals like meloxicam or Derek Coxi or, you know, take your pick, I think those are all fine too.

So that's definitely a consideration, I think, if we're sort of looking at palliative things that we can do that are inexpensive and and generally well well tolerated. But the other thing that's that's now been looked at a bit is Treatment with palladia. And I think, you know, most of us probably are aware that that palladia is actually a drug that's approved by the US FDA and the EMA for the treatment of mast cell tumours in dogs.

But there's actually been quite a bit of accumulating evidence over the last few years of some amount of anti-tumor activity and actually a variety of other non-mass cell tumor-related cancers. And I've been told by Zoettas that actually more than half of Palladius sales. Go to the treatment of non-mast cell tumour cancers these days.

So the way that we think palladia is actually working for most of these non-mast cell tumour cancers is actually not by directly killing cancer cells, but probably by doing two other things that are very important. One of them is potentially modulating the immune system in a way that can be beneficial and a second is actually through interfering with the growth of blood vessels that are required to provide nutrients and oxygen to the tumour. And two of the growth factors that are really key in supporting and promoting blood vessel growth are vascular endothelial growth factor, which is also referred to as veF, and platelet derived growth factor, which is also referred to as PDGF.

As it turns out, despite the fact that palladia is marketed. For mast cell tumours, because of its ability to inhibit a different growth factor receptor called CIT, which is present on mast cell tumours. It also inhibits the receptors for vascular endothelial growth factor and platelet derived growth factor, which does mean that it may have some important activity as a as a, a therapy that can be directed against tumour blood vessels.

So quite a ways ago, there was a sort of a survey-based study that was performed, trying to ask an early question about what kind of other tumours might there be a role for palladia with. And this particular study actually looked at 4 different tumour types anal sac tumours, osteosarcoma, thyroid, and squamous cell carcinoma. And actually the largest number of of study cases was in anal sac.

And in this particular, again, retrospective survey-based study, they saw that upwards of about 80% of dogs experienced what we would be considered clinical benefit. So either had disease stabilisation or experienced partial tumour shrinkage, and that lasted for an average of about 6 months or so. So, here's just one quick example.

This is one particular dog that had actually again massive sub lumbar lymphadenopathy that, you know, reduced fairly substantially after just 4 weeks of palladia. So, obviously, this is not a complete response. This wasn't complete disappearance of everything, but you can certainly understand how even a partial shrinkage in this location could be enough to really substantially reduce some of the clinical signs that this dog may have been experiencing, like such as obstipation.

And this is actually a separate case of a dog that did have pulmonary metastatic disease, where you can see actually quite robust resolution of of pulmonary metastasis in in this particular dog, which was a quite exciting finding. So, again, this is an older study that was done based on a survey, the quality of the data, you know, might not have been as great as with some other studies. So there is a very, very recent study that actually looked at a single institution retrospective study looking at again the outcome with Palladia.

In, a small number of dogs again with stage 4 or metastatic anal sac tumours. So in this particular study, there were no dogs that had, that met the criteria for a true partial response, but 13 out of 15 dogs actually had disease stabilisation, that persisted for a, you know, a quote unquote clinically meaningful period of time, you know, at least many months. And in this group of dogs, the median progression free interval was about a year.

So with with palladia by itself, and again, I think in this particular study, some of these dogs may have been co-treated with a with an NSAID, . We got an average of about a year and these dogs with, with metastatic anal sac tumours. So I do think that this is a, a tool that certainly is worth considering in that situation where we have locally advanced or metastatic disease, either in conjunction maybe with some other things or as a palliative measure if radiation therapy, surgery, etc.

Have been declined. I do think just in one minute, I, I do need to mention the fact that despite the fact that you know pyadia is widely available and it's approved and it's oral, this is not a benign medication. So we actually do see a fairly substantial incidence of adverse effects from this drug in dogs.

At least half of the dogs that I Put on palladia will generally require some kind of dose modification, drug holidays, things like that to deal with, side effects. The most common of which is GI side effects, so loss of appetite, diarrhoea. But occasionally we can see other things that can be problematic too.

So neutropenia, protein losing, nephropathy, etc. So yes, these, these are pills. However, again, they, they do require actually quite rigorous monitoring.

An owner who's very willing to pursue recheck exams for blood work and urine monitoring and blood pressure monitoring. A dog who's watching their dog, an owner who's watching their dog very carefully, who's gonna report side effects to you promptly, etc. So, definitely something that's worth considering, but, you know, because of the side effect risk and the cost, I'm not sure I would, I would classify it as a palliative treatment.

So, just food for thought there, doesn't mean it can't be useful, but, you know, certainly, it certainly needs to be used in the right hands. And with that, I thank you very much for your attention. I'd like to thank the, the doctors that you see listed here who actually provided me with, some of the materials, some of the slide material that I used in this presentation.

And as I mentioned at the very, very beginning, you can see my, email address at the bottom of this slide. Please don't hesitate to reach out anytime if you have any queries about canine anal sac tumours or really anything else having to do with medical oncology. I'm always very, very happy to communicate with my colleagues to discuss oncology-related matters.

And again, thanks very much for your attention. Doug, thank you so much. That was absolutely fascinating and really nice to see sort of quantifying results and everything else, which is, is really great.

We do have one question in from Greg, and he asks about the role of electro chemotherapy in these patients. Oh, that's a great question. So thanks for that, Greg.

So, I have to, in, in the issue or in the, in, for full disclosure purposes, I must say that elective chemotherapy is not a modality that we offer here at Colorado State University. So, my experience with it is, is, is not firsthand. But I think what I would say in general is that It, I think it's a, it's a potentially a problematic tumour type to use for for the treatment of large, unresectable anal sac tumours again, because of the size of them.

So, you know, electro chemotherapy seems to be very, very useful for small tumours, that might be in bad spots, so distal limb or on the ears or on the muzzle or things like that. But if we have a tumour that's so large that it can't be surgically resected, I think it's gonna be a challenging tumour to, to treat with electro chemotherapy because of those symmetry issues. So how much drug you have to put in and the number of electrodes you have to use and things like that.

Electro chemotherapy is a Local treatment modality. So it's not something that we would generally think of for the treatment of, you know, metastatic disease, for example. I'd, I'd be worried about trying to figure out a way to do that, for example, for a, for metastatic lymph nodes in the abdomen.

That being said, I do think that there is some information suggesting that it can be actually a very useful palliative measure for perianal gland adenomas. So if we do have again one of these owners where it's an intact male dog and the owner simply will not castrate. And we do worry that even a marginal resection could be challenging.

I do think that there's some information suggesting the electro chemotherapy might be a very useful treatment for some of those tumours that may be smaller and again, potentially in an area that's challenging like especially the tail base, prep use, etc. So I do think it'd be more of a consideration for the perineal gland adenomass. Yeah, yeah.

Interesting. Steve just made a comment to say that he's had success, with resolution of two anal adenomas, with the use of slain. And he said one of them, has no growth whatsoever after 10 months.

So it's, it's another sort of quiver in the. Or, you know, in the, the arsenal of what we can try for these cases. Yeah, definitely a consideration again, especially for those owners who refuse to castrate.

But you know, I mean in my hands, I'll usually do everything in my power to just try and talk the owner into castration. You know, versus all the other sort of crazy things that we can do that that are gonna be more complicated and probably not work quite as well. Yeah, yeah, and it, it seems so simple, but I, I think all of us who have been in private practise for any length of time have come across those absolutely doggedly adamant.

There's no chance you're cutting those off owners. So, absolutely. Yeah, it's normally the men.

I don't know why, but anyway. Doug, thank you once again for your time tonight and thank you for sharing your experiences and all your extensive knowledge with us. It really has been worthwhile.

So thank you for your time. Thanks so much I'll look forward to the next time. And to everybody who attended tonight, thank you very much for your time.

I hope you enjoyed it as much as I did. And, look forward to seeing you on the next webinar. To Dawn, my controller in the background, as always, thank you for making everything run smoothly.

From myself, Bruce Stevenson, it's good night.