OK, well, welcome everybody. We're pretty excited to to have this series of oncology lectures that are being filmed, in this case for on-demand viewing instead of, for live viewing. And the one big thing that that changes, for me and for us is, obviously, there's not the opportunity for you to ask questions, and have them answered in a real-time fashion, but you'll notice that on this title slide and you can come back to it, obviously, at any time, you will see my email address.
And I am more than happy, and I mean this sincerely to answer anybody's questions, whether they're about the content of these lectures or other things that are oncology related, really at any time if you'd like to reach out by, by email, so please don't hesitate to do that if you have any questions. So this first lecture that we're going to do is about soft tissue sarcomas in dogs and cats. And one of the things actually that we start with about this has, has actually to do with the nomenclature of these tumours, and that often can be extremely, extremely confusing.
And I'll often get consultation calls from the same veterinarian about the sort of multiple tumours with these names. And, often we really have the ability to sort of lump them together because of a very similar type of biologic behaviour. So just going through the list here again, we can see, these are all tumours that are derived from some kind of mesenchymal tissue, but as you can see, we can see fibrosarcomas which are derived from obviously fibrous connective tissue, hemangioparicytomas, which are derived from the linings of blood vessels, nerve sheath tumour slash swannomas are obviously from the linings around nerves.
We have a mix sarcomas, which is just a term for one of these tumours that's making a lot of a mus in this kind of matrix. We have soft tissue sarcomas from fat, soft tissue sarcomas from skeletal muscles, soft tissue sarcoma from smooth muscle. And really all of these, we do tend to sort of lump together as, generally having relatively similar biologic behaviours.
So they can be treated kind of as one entity almost. And In general, we think of these types of tumours as having very high likelihood of sort of infiltrating local tissue in an aggressive way, and as a result, a high likelihood of local recurrence if they're not completely removed, but a relatively low risk of spread. The risk of spread is zero, but again, it's considered low in general.
So you will see these three tumour types listed at the bottom of the list here. So your anaplastic sarcoma, sometimes you'll also hear the term undifferentiated sarcoma. And then one specific tumour type, histcytic sarcoma that you see over here on the right, which, again, has the moniker sarcoma attached to it, but it's actually a tumour that's derived.
Not from the encomal tissue, but actually from hematopoietic tissue. So this is generally a tumour of, of monocytes or macrophages. So the reason that these three really sort of are the, are the exceptions to the rule is that these, these three kinds of quote unquote sarcomas actually have a considerably higher likelihood of spreading.
So if you do see these terms anaplastic or undifferentiated, these are the ones where you might think, maybe this isn't going to be my typical soft tissue sarcoma. This does have the potential to be potentially more aggressive. So here, we're looking at a At a metastatic potential, probably in the 40 to 50% range.
With our histocytic sarcomas, it's probably more in the 80 to 90% range. So very different. So, all of these, you can kind of lump together these guys down here.
We need to potentially treat, in a little bit of a different way, as we, as we'll discuss. So, how is a dog with a soft tissue sarcoma likely to show up at your clinic? So this is most likely going to be your typical sort of quote unquote check lump appointment that you'll see on your appointment books quite often.
So they're usually gonna come in because the owner feels the lump. Most of the time, the lump is not gonna be particularly painful. It's not usually going to be open oozing, bleeding, ulcerated, etc.
It's just something that the owner notices. Most of the time, these can be relatively slowly progressive, but again, there certainly can be exceptions to this rule. The classic soft tissue sarcoma may be relatively firm, but again, we can see some that can be sort of soft and squishy as well and actually have a consistency that's not that different from a lipoma.
So, again, another one of those examples where we can Just assume something is a lipoma because of how it feels. Again, often the haired skin, overlying the tumour is normal, not necessarily alopeciic like this one is. Again, not erythematous or ulcerated or anything else.
But again, generally a solitary cutaneous or subcutaneous mass is going to be the presenting complaint we have from most of these peripheral soft tissue sarcomas. Here's an exception to that, to that rule. So this little dog, actually presented to our neurology service and, the presenting complaint was falling over.
And, I wish, I was, I wish I was making a joke about this, but it was actually true. So the weight of this tumour was actually pulling the dog over and they thought it had neurologic disease. This was able to be resected, although again, it was quite a, quite a heroic surgery.
So as I mentioned on the previous slide, in general, we really worry about the majority of these tumours because of their ability to infiltrate tissue in a in a in a in a aggressive way. And as a result, conservative excisions, so these little small marginal excisions has the potential to be associated with a relatively high risk of local recurrence. Most of them have a relatively low metastatic rate.
When we get into visceral sarcoma, so not these ones that are occurring in the cutaneous tissue in the subcutaneous space, but let's suppose we have a prime. Splenic sarcoma or primary liver sarcoma, for example. In general, many of these do have the potential to be considerably more aggressive, with a much higher metastatic rate.
The one exception to that seems to be smooth muscle tumours that arise from the gastrointestinal tract and actually, these tumours can often have quite good outcomes with surgical resection alone. One of the other sort of oddball tumour types that I always like to mention when we discuss soft tissue sarcomas, is this one that you can see on the top here, this histologically benign but biologically malignant sarcoma. Often you'll also hear this referred to as a halo sarcoma as a sort of a shorthand for that.
And this is something that classically we see on the maxilla of retriever breeds, Labrador and golden retrievers. Again, we can sometimes see it in other parts of the body. We can sometimes see it in non-retriever breeds, but it's really fairly specifically.
A retriever breed thing in the oral tissues and especially of the maxilla. And the reason that these can be actually very, very frustrating is that histologically, these tumours can look incredibly boring and benign. They can come back with these diagnosis of things like, oh, it just looks like some benign fibrous connective tissue proliferation or a fibroma, which would be a Benign connective tissue, tumour.
So it'll have this very bland and boring cytology, but these tumours will actually sort of eat these poor dogs alive. So you can see that one that I showed you on the previous slide actually has an intraoral component and you can see that it's actually eaten through the, the hard palate onto the roof of the mouth here. So this is one of those examples where Making certain that adequate information is provided on the histopathology request form can actually be extremely useful for the pathologist and for you as the submitter as well.
So if you've got a pathologist who's worth their salt, and they see this kind of really boring looking kind of tissue under the microscope, hopefully again on the On the request form, they'll see, oh, well, this is from a maxillary mass and oh, it's actually from a, from a Labrador retriever, and they'll go, ding, ding, ding. Oh yeah, I remember that this is a, a a syndrome that these retrievers can have and you should be very concerned about the possibility that it's this histologically benign biologically malignant sarcoma of the maxilla. So, again, one of those garbage in garbage out things, when you fill out your form completely with all the relevant information, it's gonna be easier for the pathologist to help you out with this particular disease.
So, with most kinds of cancer, one of the things that we really try and hammer home to, the students is the the utility of fine needle aspirates. So anytime you have a lump or bump, you should do a fine needle aspirate of it to see if you can figure out what it is. That is unquestionably true also for soft tissue sarcomas.
But if you look at sort of the average soft tissue sarcoma and you compare it to the average carcinoma or the average melanoma or the average hematopoietic tumour. We're less likely to be able to obtain a firm diagnosis from a sarcoma. Than we are from some of these other kinds of tumours.
And these tumours are just generally considered to be poorly exfoliated. So the tumour cells don't like to let go and actually go up into your needles, so you can expel them onto the slide. So these are the situations where you're more likely to run into either what we call our dry needle situation where we aspirate and aspirate and aspirate and just don't get anything at all, or we do end up with some stuff, but it's mostly blood.
So this is the situation where depending on which of those two problems you have, there's some simple things that you could do that may increase the diagnos the diagnostic yield. So if you do have a dry needle, you could certainly try a larger gait needle or trying again some syringe aspiration instead of just doing the, the pecking thing with the bare needle. On the flip side, again, if you end up with a lot of blood, and it's really obscuring your ability to see anything else, consider a smaller needle.
If you started with the aspiration technique, try the bare needle technique. And finally, again, for these excessively bloody samples, you can also make sure that your, your index finger is completely occluding the hub of the needle, and that'll actually minimise the wicking of, of blood into the hub of the needle through capillary action. So those are all things that you can try.
Again, if you either have a dry needle or you have an excessively bloody sample. But one of the sort of take homes that I do have in those kinds of situations is if you have a fair Fairly worrisome mass on a dog, and you end up with, again, a dry needle situation or an excessively bloody sample that's non-diagnostic, we really try hard not to say, oh well, you know, it's probably nothing. Don't worry about it, you know, let us know if it changes kind of thing.
Really, that should sort of throw up a red flag and say, yeah, maybe this is one of those sarcomas that we should be a bit more concerned about. And these are the ones where we would actually want to use some other methods to try and achieve a diagnosis. So, for example, an incisional biopsy.
So here's an example cytologically of a, of a soft tissue sarcoma that was actually very nicely exfoliated. So we had lots and lots of cells that came out here. And you can see Sort of the classic soft tissue sarcoma, rather than being truly round, is actually gonna often have sort of an elongated sort of nucleus, so not the round, perfectly round nucleus, but the sort of elongated nuclei.
You can see these spindly kinds of trailing, cytoplasms, very much not round but more of these sort of irregular spindly shaped. Cytoplasms. Again, as far as the criteria of malignancy go, you certainly can see that there's quite a bit of variation in the size and shape of the nuclei.
You can see there's quite a bit of variation in the size and shapes of the cells overall. You can see a very, very basophilic cytoplasm, but overall, a fairly high nuclear cytoplasmic ratio. All these things that would really be indicative of a, of a malignant rather than a benign condition.
So again, quite often, just because of the difficulties we can sometimes encounter establishing a firm diagnosis with cytology, we will be thinking about some kind of biopsy in order to get a diagnosis here. And certainly one of the things that we'll consider, especially if we have a tumour that's kind of in a tricky spot, would be some sort of incisional biopsy. So not going for cure, but actually just trying to get a diagnosis.
So we can do this with the keys type of skin punch biopsies if we go through the skin and down into the subcutaneous abnormal tissue. We do this all the time with needle core biopsies, also known as True cuts, which is actually a brand name, and you can do things like wedge biopsies as well. I'm a big fan of the true cut biopsy for these kinds of tumours if they're sizable enough.
And the main reason for that is that this can often be done just with either manual restraint, and a little bit of, of local anaesthetic, or again, some, some very, very mild. sedation and a local anaesthetic. So it's really not all that different in terms of what you need to do to the dog than a plain old fine needle aspirate.
So that's usually my choice, just because it's easy on the dog and easy on the owner and, and you're saved the, the complications associated with more heavy sedation or anaesthesia. You certainly can also offer an excisional biopsy. That is an appropriate thing to offer.
But when we use an excisional biopsy in a situation like this, if we're suspicious of a soft tissue sarcoma, I do think it's worthwhile informing the owner about the possibility that more treatment of some kind might be necessary after that excisional biopsy is performed. So if you're going in there and you're just kind of doing a very, very minor surgery around the mass itself, it's, and this is a sarcoma. There's a very high likelihood there are gonna be tumour cells left behind.
And you may be sort of coming back to the owner talking about the possibility of recut or saying, well, now that we know this is a soft tissue sarcoma, it would be a really good idea to take some chest X-rays, etc. So really, making sure ahead of time that they understand this is really just a diagnostic test and may not be the be all and end all as far as therapy goes, is a really nice conversation to have before that, excisional biopsy is performed, rather than trying to explain the results after the excisional biopsy is performed and have to say, well, we didn't really get it all and the owner says, what do you mean you didn't get it all? Why should I have to pay for more surgery if you didn't do it right the first time, you know, those kinds of, of issues can really be avoided, if you, just have a 45 2nd conversation about the purpose of the excisional biopsy with the owner before it actually takes place.
So, how accurate are these, these pre-treatment biopsies? So there was actually a study that we did a few years ago. One of my, former residents was the, the lead author on the study.
He's actually double boarded in, in medical oncology and surgery. And so this was of great interest to him. And actually in this study, about 60% of the time, the pre-treatment biopsy results were accurate.
And again, most of the time, it's very simple for to to be able to tell that it's a soft tissue sarcoma. So the, the difficulty doesn't come from saying, yup, it's a soft tissue sarcoma or not. However, there's a grading scheme for soft tissue sarcomas that we'll talk about in just a second.
And again, there is some difference in grade between this incisional biopsy sample that you provide and when the entire tumour is looked at under the microscope. So that's where, again, that 40% of the time there could be a difference comes in. It's not a diagnosis of soft tissue sarcoma, but it's the grade of that sarcoma primarily.
So again, as I mentioned, the majority of these tumours do not spread, but, the likelihood of spread is by no means zero, so it's probably in the 10 to 15% range for the average soft tissue sarcoma. And as a result, it really is worthwhile to shoot chest X-rays in these dogs because God forbid, a dog should fall into that unfortunate 15%. That's obviously information that the owner should should be aware of and, and may sort of change how they choose to move forward, what else they choose to do, etc.
What about lymph nodes? So again, in, in a lot of these tumours that we talk about, we talk about interrogating the regional lymph node very carefully to make sure there isn't evidence of metastasis there. Again, as a, as a general group, we tend to see less metastasis to regional lymph nodes with soft tissue sarcomas.
Than we do with other kinds of tumours like carcinomas, melanomas, and hematopoietic tumours. However, the risk of metastasis is certainly not zero. And especially if we have a regional lymph node that feels unusual, it's plump, it's enlarged, it's asymmetrical, etc.
Unquestionably, it should be aspirated. So here, for example, is a cytology slide of a dog, who had a mildly enlarged, regional lymph node from a soft tissue sarcoma. And you can see, those little black arrows, actually are pointing to metastatic sarcoma cells within that lymph node.
So it can happen. If it is, if it has happened, we unquestionably want to know about it. But, but again, it's not as common as, as what we see with the carcinomas in the round cell tumours.
So, given the fact that the majority of these tumours do seem to be primarily local problems, We do think that local treatment is generally the best treatment that we can move forward with. And again, whenever possible, that constitutes aggressive surgery. And what do we mean by aggressive?
So again, the party line from, from our surgical oncology colleagues is that we want to shoot for 3 centimetre margins, 360. Degrees around the tumour and at least one uninvolved fascial plane deep. Again, whenever possible, we want to make sure that those margins are well identified for histopathology and again, obviously that, that resected tissue is submitted in total rather than just representative sections, so that margins can be adequately assessed.
And again, this is a tumour type where we won't hesitate to be, to be ruthless with our surgical approach because again, for your garden variety, low or intermediate grade soft tissue sarcoma, radical surgery is curative, in the majority of cases. So again, we won't hesitate to talk to owners about things like mandibulectomy, maxillectomy, amputations, full thickness, body wall resections, those kinds of things, if that's what it takes to actually affect the cure for these patients. This is a little, a little thing that I really like to do more for the owner's sake, so that they can understand a little bit more about why we need to do as big a surgery as we do.
You know, a lot of times the owners will say, well, you know, my dog has this 4 centimetre tumour and you're telling me that it's gonna come home with a 12 centimetre scar. Like, I don't understand why, why that needs to happen. But again, if we spend just a little bit of time sort of educating them, hey, the part of the tumour that we can see and feel, you know, is obviously or often just the tip of the iceberg, and these kinds of tumours are known for being able to extend little microscopic fingers into the surrounding tissue such that if we do a small surgery like this, we leave those fingers behind.
That's a problem and that's where we have the potential to see those tumours grow back. However, again, if we take a generous margin of normal looking tissue all around the tumour, we have a higher likelihood of being able to get out all those little microscopic fingers and that As a result, the risk of local recurrence is gonna be much less. Again, it's, I feel like I'm preaching to the choir telling you guys this, but again, as a discussion that you can have with your owner, ahead of surgery to help them understand why we're doing such a big surgery, I do think that that can actually be very useful.
So here's an example. So this is actually a, a series of slides that I got from my colleague, Rod Straw, who is a, a cancer surgeon in Brisbane, Australia. So this is a dog that had a very, very large, soft tissue sarcoma that was actually adhered to the thoracic wall.
And as a result, in order to treat this effectively, actually a full thickness thoracic wall resection was necessary. So here's the hole that was made after the surgery was performed. You can see proline mesh was put in there and the defect was sutured up.
Just in case anybody is concerned, this other little guy over here is not part of the soft tissue sarcoma. This is actually an unrelated like Poma and this was cytologically confirmed. So again, you had a tumour that was, you know, probably about maybe 7 centimetres in diameter or so, and you've got a surgery site that actually runs the entire length of the thorax.
Again, so explaining to an owner why we have to do a surgery like this if we want to cure the patient, is really a very helpful exercise to have. So, let's suppose for the sake of argument, we do our surgery, we get our histopathology report back. There's pieces of information that we're gonna wanna make sure are on that report that's really going to help us assess whether any additional therapy is necessary and what the potential outcome might be.
So histotype is often one of the things that we want to know. So, I mean, generic soft tissue sarcoma is a piece of information that you can usually get from cytology. But again, because we do have these oddball forms of sarcoma that can be associated with worse behaviour like histiocytic, for example, we can see things like hemangiosarcoma and occasionally even extra skeletal osteosarcoma in the subcutaneous tissue.
Really having them put a histotype onto the tumour whenever possible is great. And again, there is a grading scheme for soft tissue sarcomas. It's a 12 3 scheme, not that different from the older mast cell tumour grading scheme.
And this is something that we think is actually very, very important. And the reason for that is, as I mentioned previously, and as you see on this slide, high grade tumours or tumours that are called grade 3, or tumours that have these monikers like anaplastic or undifferentiated tend to have a metastatic rate more in the 40, 45% range rather than that sort of 10 to 15% that we see with most of the others. And one other little thing that's actually quite interesting that I think we'll get to in a second is that low grade tumours, so low grade or grade 1 tumours tend to be actually very slowly progressive and as a result, there's quite a few of those that may never grow back, even if they appear to be incompletely resected.
So those are ones where we may make a different treatment decision even if it appears that our surgical margins are incomplete, again, depending on the grade, especially if it's a grade one tumour. And then we certainly do want an assessment about margins. And again, not only do we want a simple thing, margins are clean, margins are dirty, margins are closed, but a more qualitative and quantitative assessment of those margins can often be very variable.
Rather than just saying, yup, completely excised, if we actually say, well, how close was the nearest tumour cell to the nearest margin, you know, is it, is it a centimetre? Is it 100 microns? Is it one cell body, you know, so that kind of information can help us kind of ramp up or ramp down our concern for local recurrence, as can the kind of tissue that actually can, comprises that boundary.
So, I'm gonna feel a lot better with, you know, 0.5 centimetre of, of dense fibrous connective tissue than I might with 0.5 centimetre of fat, just because it's a lot easier for the tumour cells to crawl through that fatty tissue than it would be for them to crawl through that dense fibrous connective tissue.
So what do we do in that situation where we have an incomplete excision. And again, these are the situations where we're quite concerned about the potential for local recurrence. So, ideally, again, the majority of these tumours are local problems, so we like to use local treatment whenever possible.
And the two local treatments that tend to be the, the most useful in this situation are more surgery, so what we call a recut surgery. Or radiation therapy, both of which can be extremely useful. We tend to think of chemotherapy as kind of a second tier choice in a situation like this.
Again, we like to use local treatments for local diseases, but if it's a choice between nothing or considering chemotherapy, we certainly will consider offering chemotherapy with an attempt to try to delay or, you know, maybe if we're really lucky, prevent local recurrence. We'll talk more about that in a second. One of the things that we really try to make sure the owners are very, very aware of though is that we tend to have, a lot of diminishing returns with sequential marginal excisions.
So if we go in and we do, you know, a little carve out kind of surgery, we know we're leaving disease behind. We know the likelihood, it's gonna grow back is quite high. If we go back and do that again, let's say the tumour grows back 8 months later and we do a second surgery, it's probably gonna come back in half the time.
And again, the time after that, it's probably gonna come back yet again in half the time. So we're getting less and less utility out of multiple marginal excisions. So again, I mean, it's not necessarily the wrong, the wrong approach for every single owner, but we definitely think that the very first chance to treat this tumour is the highest likelihood that we're gonna permanently cure it.
Not, well, let's see what happens and if it grows back, we'll get aggressive then kind of approach. These tumours are more likely. When they grow back, to be multifocal and spread out across a longer area and potentially ulcerated.
And again, there's some evidence to suggest that they may be more likely to become a high grade tumour, which again is associated with a higher risk of metastasis. So it's not really clear from this picture, but this little Pomeranian not only has disease kind of in its elbow region, but this disease is actually tracking onto the thoracic wall as well. So in this poor guy, even an amputation really wouldn't have been sufficient.
To adequately control his local disease because of the way it's recurred after multiple marginal excisions. Similarly, here's a kitty cat with an injection site sarcoma where again, we've seen multifocal, multi nodular recurrence all along the surgery scar after this tumour has been removed several times, which really makes additional surgical resection extremely challenging. And again, it's even better assessed or better kind of proven in, in cats than it is in dogs that multiple recurrences are associated with a significantly worse long-term outcome.
So just like we're all sort of trained at the very beginning, the first chance to cut is the best chance to cure, and we really feel that that's especially the case with soft tissue sarcomas. So what about radiation therapy? So radiation therapy, again, is an incredibly useful treatment.
If it's being used as a postoperative management technique for soft tissue sarcomas. So again, not being used instead of surgery, but being used to kill hopefully whatever microscopic tumour cells are left over after surgery can actually be incredibly useful. So it's complicated.
It usually requires a lot of treatments that take place over quite a few weeks. There can be some local Side effects that we'll talk about. But again, we're looking at about an 85% likelihood of 3 years or longer control when these tumours are treated with radiation therapy after surgery.
So let's flip that around and say, well, what's the likelihood of recurrence if we don't do radiation therapy? Depending on the study that you pick up, it's probably in the 40 to 80% range are going to recur. And the average amount of time it takes for that to happen is about 8 months.
So contrasting that with this, where the likelihood of seeing recurrence is about 15%, it really makes a very, very big difference. So can radiation therapy be used to try and control a big unresectable tumour? The answer is yes, it certainly can, but it's not nearly as effective.
So generally, again, if we're using radiation therapy to try and treat a big bulky soft tissue sarcoma, I'll generally give the owner about a 50/50 likelihood that we'll be able to control the disease for a year. So we're not gonna have an 85% cure rate. Again, if we're lucky, we'll be able to keep things under control for an average of about a year.
So what are the downsides to radiation therapy? So, one of them is, again, we can see varying degrees of sort of a local sunburn-like effect that occurs at the site where the radiation therapy is put. So this is a local reaction.
So we don't tend to see any systemic adverse effects from radiation therapy. We don't see nausea, we don't see bone marrow suppression. We don't see other things like that.
Again, there can be some, some side effects associated with the daily anaesthesia or heavy sedation that's necessary, but we do this every day in multiple patients and if they're otherwise healthy, it's usually fairly trivial for them. So those daily serial anesthesias are usually not a big deal. But again, we can see there's varying degrees of kind of a local acute reaction that can occur at the site where the radiation therapy is put.
So this is an older, like a 13 year old beagle who actually had an incompletely resected liposarcoma on the medial thigh. And this dog had 4 weeks of radiation therapy. And you can see at the end of treatment, we're seeing some hyperpigmentation and alopecia of the skin in the region.
And again, right along here, which happens to be right along the scar, we can actually see some ulceration. So this can be itchy, it can be uncomfortable, it can be painful. It's the kind of thing that the dogs are gonna wanna lick and chew at, etc.
Etc. But it is generally self-limiting. So here's the same dog a month later where you can see actually the skin is quite healthy.
It's very common actually for us to have some degree of permanent alopecia. Sometimes, again, we can also have some permanent, permanent hyperpigmentation. And sometimes we can actually see leuko trachea, so sometimes the hair will grow back a different colour, often white in the area where the radiation therapy has been put.
These are generally purely cosmetic changes, but there are things that the owner may want to know about. So again, general husbandry kind of things, so pain medications, anti-itch medications again, potentially. Prophylactic antibiotics to prevent, secondary infection on top of the ulceration can all be useful.
But the number one thing that tends to actually sort of stop this from becoming a problem is keeping the patient away from it. So, Elizabeth and cholera, etc. For that period of time because self-trauma can vastly worsen the signs that we see from this kind of acute reaction.
So here's the second example. So this is actually a golden retriever. I had a soft tissue sarcoma right in the region, of its carpal pad, which is a really unfortunate location for this.
So obviously without amputation, it's very, very hard to achieve a wide margin excision from a tumour in this location. And on top of that, pads and, and, and, digits and things like that. So, fingernails, toenails are actually extremely sensitive to radiation and it's quite common, when the pad is actually in the radiation field for us to see it slough completely off.
So you can see that's what's happened in this case. This is obviously something that can be associated with quite a bit of discomfort. And as a result, again, good pain control, good, systemic antibiotics to try and minimise the likelihood of secondary infection.
And above all else, and Elizabethan collar can be very, very useful. And here's the same dog a week later, and again, to the uneducated eye, one might say, oh my gosh, this looks really worrisome. I don't like how this is looking.
But again, to a, to a veterinarian, you can look at this and say, oh my gosh, this is a beautifully healthy granulation bed. Things look like they're healing up just great. And again, on the right here, we can see that same dog two months later, where again, we do have some probable permanent alopecia.
We do have a a carpal pad that probably won't grow back to look the way it did before. And again, very, very healthy skin within the radiation field. So again, the side effects that we can see are usually relegated to the local side only, and they generally are manageable and self-limiting.
Oh, multiple general anesthesias, as I mentioned, is something that we do see although the average anaesthesia duration is like 15 or 20 minutes a day. It's actually quite short. But for practical reasons, obviously, there may be some hospitalisation time.
So there's no medical reason why hospitalisation is necessary in order to do this treatment. There's no reason it can't be done purely on an outpatient basis, but unless, You know, the owner happens to live right around the corner from a veterinary radiation facility. For practical reasons, there may be some time away from home, just so they don't have to bring the dog in every day.
They don't have to take time off of work and things like that. So something that again, that's worth discussing with an owner. And then again, cost is certainly another factor for for curative intent radiation therapy here at Colorado State University.
Again, we're generally in the neighbourhood soup to nuts for the entire treatment course of between $500 and $8000 US. This includes time in the hospital, it includes anaesthesia. If imaging is necessary to figure out where to put the radiation and includes that as well.
But again, if, so we're a state institution here at Colorado, we're certainly on the low end of the cost, spectrum. So for the same kind of treatment in a private practise situation, it certainly could be considerably more than that. And again, I'm not well versed enough to know what the situation is in the UK to be able to tell you whether this price is, is equivalent to what you'd see there or elsewhere in the EU for example.
Oh, there are some situations where we certainly would think about chemotherapy for a disease like this. I am a medical oncologist, so you'd have to know that chemotherapy would be thrown in there somewhere. Generally, we do think about offering chemotherapy if we have a tumour that after surgery is read out as being high grade or anaplastic or undifferentiated.
So I know this is the 3rd time that I mentioned this, but again, these are tumours where we do think about a metastatic rate more in the 40 to 50% range. So in this particular type of cancer, if you didn't get chest X-rays before surgery, certainly it would behove us to go in and get those chest X-rays to make sure that this dog doesn't already fall into that bad 40 to 50%. And then again, we will generally talk to the owner about following up with chemotherapy.
Unfortunately, we really have a lack of good meaningful statistics about exactly how well postoperative chemotherapy works for this disease. And I'm usually very forthright with the owners about this fact that we don't know for a fact. If, if I give my dog these drugs after surgery, it'll live 10 times longer than if I don't.
We simply don't have those numbers. But again, based on what we know about treating other kinds of sarcomas and what we know about treating soft tissue sarcomas in certain circumstances, I do think it's something that's fairly reasonable to offer in this circumstance. Then again, some of the other bullets you see here, there are certain histotypes where we would consider it.
And again, histocytic sarcoma would be the big one. We'll talk about that in a separate lecture. There's some evidence to suggest that sarcoma in young dogs, so if we see a sarcoma, for example, in a dog that's younger than 2 years, that may be associated with a considerably more aggressive behaviour, almost irrespective of histotype.
And then the other situation in which we might consider it. Is as a, again, sort of a second tier choice if aggressive local therapy is not possible. So if we have a gross unresectable mast cell tumour that is so large that even marginal excision isn't possible, we might consider chemotherapy as a palliative measure.
We have an an incompletely resected tumour after surgery, and there is no no option to do another surgery and radiation therapy is not possible. Again, we certainly will talk to the owner about medical therapy as a less than optimal alternative, in that situation as well. So what do these chemotherapy protocols look at, look like?
So for the post-operative management of high grade. Soft tissue sarcomas in dogs. Generally, we, we tend to go for doxorubicin-based chemotherapy protocols.
So these can be doxorubicin by itself, standard dose that you'd find in the veterinary formularies. Some people will use what's called AC which is doxorubicin plus cyclophosphamide. Some people even use VAC, which is oxorubicin cyclophosphamide and cristine.
And again, when we're using it in the postoperative setting, generally, I'll consider 4 or 5 postoperative treatments, and then if everything's continuing to go well, we'll quit. Here at my institution, we tend to be fans of just plain old doxorubicin. It's simple.
We don't have any good, really meaningful statistics to say that these more complicated multi-agent protocols are superior. And as a result, again, sort of the simpler we can keep it, I think, the easier it is on the dog and the owner. So, this is a very, very old paper that is actually looks at how well doxorubicin.
Works, and if you look in the first column there, Adriamycin is a brand name for doxorubicin. So if you look at that first column there, you can see that almost half of dogs with various kinds of sarcomas had some amount of objective tumour shrinkage through doxorubicin-based protocols. And again, so Adriamycin here, VAC, and AC are the three kinds of doxorubicin containing protocols.
So again, we think, well, if you have an unresectable tumour, medical therapy could provide some short-term benefit that could be useful. And again, this is really the thing that sort of gives us the ammunition to consider using this kind of treatment postoperatively. So our thought is, well, if, if we can kill enough tumour cells to actually shrink a big tumour, Then those same drugs have a reasonable likelihood of being able to kill microscopic tumour cells that might be floating around somewhere after surgery in the lungs, for example, in these high grade sarcomas.
So again, I wish the level of evidence was higher about the activity of these drugs in the post-operative setting, but this is really what we have to go for or go on in in dogs at least. . So another kind of treatment that you may have heard of, and I think I've actually done an entire lecture on before for this group, is what's called low dose continuous or metronomic chemotherapy.
And this is the idea of giving little tiny doses of chemotherapy in a continuous fashion instead of giving great big slugs of chemotherapy, on an intermittent basis with prolonged breaks in between. And the, the logic or the justification for this kind of approach with chemotherapy is not necessarily that it's better at killing the tumour cells directly, but depending on the drugs that are used, it may actually be able to interfere with the growth of blood vessels that are necessary to provide nutrients and oxygen to the tissues. And again, depending on the drug, there may be some beneficial effects on the immune system as well.
And this is actually something that has been looked at in a couple of studies. One of the first studies was about 10 years ago now, actually here in Colorado. That was a retrospective, non-controlled, kind of study that looked at dogs with incompletely resected grade 2 soft tissue sarcomas.
So 55 dogs got nothing after surgery. 30 dogs got a combination of cyclophosphamide, and in this case, paroxicam, and there's some debate about whether paroxicam is magical or whether other non-steroidals may be equivalent. I think the jury is still out on that.
So about 40% of dogs had some kinds of adverse events. Most likely, they were primarily attributed to the paroxicam and not the cyclophosphamide. But about 10% of dogs did develop sterile hemorrhagic cystitis, and that is something that can be very severe, especially if the clinical signs are ignored.
And in this particular study, here's our little Kaplan-Myer curve comparing the dogs that received, low dose continuous chemotherapy, where about, again, 80% of those dogs did not relapse to the dogs that received no additional therapy where their median disease-free interval was in the neighbourhood of a little less than a year, about 8 to 10 months or so. So, I think there are a couple of issues with this, this, this data that, that bear, noting and, and again, one is that this was not in any way, shape or form controlled, and as a result, there's a huge potential for bias in one way or another. I don't think any of us think that.
This combination works as well as what was reported here. And really it is the kind of thing that we talked to owners about really with the intent of trying to delay potentially rather than permanently preventing local recurrence the way we can with surgery or radiation therapy. So, again, if it's a choice between no further therapy or metronomic therapy with cyclophosphamide and an NSAID, I certainly do think that this is worth considering, but I do not think that it is an appropriate substitute for the aggressive local therapy that we already discussed.
The other thing that I will mention is that this dose of, of, of, cyclophosphamide especially was really determined empirically. As far as I can tell, they just sort of pulled it out of a hat and decided, oh well, let's just try this dose. But subsequent to the publication of this paper, we actually did some work, trying to be more scientific about finding a dose of cyclophosphamide that might actually have beneficial effects.
In this case, it was specifically in dogs with soft tissue sarcoma. In this study, we actually started at a dose that was a little higher than the dose that was used in the previous study. So we started at 12.5 milligrammes per metre square per day, and then increases, increased in cohorts of 3 by 2.5 milligrammes per kilogramme increments.
I'm sorry, milligramme per metre squared increments. And then we wanted to actually look not only at, well, is it tolerated and things like that, but can we actually measure things in the tumour or in the blood. As an indicator that our drug is actually doing something beneficial.
This was funded by the Morris Animal Foundation. And what we can see, this is actually looking at at a certain kind of, of cell in the blood called a regulatory T cells, or also called a T-reg. And these are actually immunosuppressive T cells that float around in the blood and, and again, depletion of these T cells is one of the ways that metronomic cyclophosphamide is thought to work.
And actually, what you can see. Is that both in terms of a percentage and an absolute number, there's a significant reduction in the percentage and absolute number of these regulatory T cells in dogs that receive the higher dose of cyclophosphamide, so the 15 milligramme per metre square dose of cyclophosphamide. And in this particular study, at least in a subset of patients, we were able to obtain serial biopsies on the tumour tissues.
So these are all dogs that had measurable soft tissue sarcoma. So we got a biopsy before treatment, after 2 weeks of treatment, and again, 2 weeks after that, and actually we're able to count the number of blood vessels within the tumour tissue. And again, only at that dose of 15 milligrammes per metre squared per day were we able to document.
A significant reduction in tumour blood vessels. So as a result, we really think that if one is going to use this, this low dose continuous or metronomic chemotherapy approach, for the postoperative treatment of a soft tissue sarcoma, that really a dose in the neighbourhood of about 15 milligrammes per metre squad per day is the dose that one should shoot for. Again, based on some nice science here that my colleague, Barbara Miller was able to generate.
I mentioned this very briefly in passing before, but I do think it's worth hammering home again. So here's a study, that's actually out of Italy that, suggests that in dogs with low grade, and I do again want to emphasise that this only applies to low grade soft tissue sarcomas, it actually appears that the likelihood of local recurrence may be relatively low. In these dogs, even with incomplete resection.
And the average amount of time that it takes for that local recurrence to occur is actually quite a long time. So, for example, so here's our dogs that have, that have truly incompletely resected tumours. So, the first recurrence out of any of these dogs occurred at around the 600 day mark.
And even in those dogs that were followed out for longer than 3 years, only about 30% of these dogs ever had their tumours grow back. So again, this is not the case with higher grade tumours, but again, if we have a dog with a low grade, Incompletely resected, soft tissue sarcoma, I do think one reasonable option for the owners to consider could be careful monitoring, what we call active surveillance. And again, especially in an middle aged to older dog, it's certainly quite conceivable that this dog could have other old age-related problems.
Before the tumour grows back. And again, I think if all of our dog patients lived an extra 20 years after surgery, the majority of these tumours would probably grow back. But I think the, these tumours in general are so slowly growing that again, something else will often catch up with these dogs before it's the tumour.
So, something to keep in mind, but again, purely for those low grade sarcomas. So, cats also get soft tissue sarcoma. And one of the, the sarcoma types that I think we're all probably familiar with, is a tumour type that used to be called vaccine associated sarcoma.
Now the, the sort of more common. The used term is what's called the injection site sarcoma. And the reason for that change in nomenclature primarily has to do with the fact that sarcomas have been very well documented following injections of things into cats that are not vaccines.
So that includes things like antibiotics, microchips, I think there are a couple of reports of subcu fluids, and believe it or not, even, anti-inflammatory drugs, so things like NSAIDs. And and steroids. So, it's thought, based on the, the epidemiologic literature that's been collected that a sarcoma has the potential to develop in between 1 in 3000 and 1 in 10,000 vaccines that are given in cats.
It appears that the likelihood of, of a sarcoma development from other kinds of injections is considerably lower than this, but not zero. And it appears that, that the development of sort of setting up of chronic inflammation in the skin and subcutaneous tissue appears to be a predisposing factor to the development of these sarcomas. And there's a little bit of work that's been done suggesting that there could be some genetic determinant to this, so there may be certain gene polymorphisms, etc.
That could be associated with a higher than average risk. Of sarcoma development. Although again, to my knowledge, there are no groups that are offering any sorts of genetic testing to really assess that risk.
One of the other things that's been important to, to note is that there can be actually a quite variable onset between the time of injection and the time of sarcoma development. And this can range from less than 3 months to longer than 3 years and actually I think my my all-time record is something like 7 years post-injection for a sarcoma to develop. So just because a cat hasn't been recently vaccinated, for example, doesn't mean that a vaccine associated sarcoma is not a possibility.
These tumours tend to be both histologically and biologically aggressive. And again, a variety of different kinds of vaccinations have been implicated. So this isn't something that's unique to you know, the, the feline combo vaccine or to rabies vaccine, or to feline leukaemia vaccine.
So a variety of different types of vaccine, a variety of different brands of vaccine have all been implicated in this phenomenon. And again, much like the dog soft tissue sarcomas, the majority of these are local problems. But again, the, the metastatic rate that's been reported has been a bit variable.
It's been as low as 5% and as high as about 25% depending on the study that you look at. So just like with our canine soft tissue sarcomas, it really does appear that surgery is the mainstay of treatment for this disease as well. And in this particular situation, there's, there's fairly compelling evidence that aggressive or radical surgery is associated with a considerably better outcome than conservative surgery.
And really in this situation, the cats who have a tumour on the limb. Who go on and have that limb amputated are oftentimes virtually the only cured animals. And this, really is one of the major justifications for the recommendations that have been made for vaccinating cats, as far down on their distal limb as possible.
So, in the rare event that a sarcoma does does develop, there's an opportunity for amputation which has the potential to be curative for that cat. What about radiation therapy in this situation? So radiation therapy has been looked at for the treatment of vaccine associated sarcoma in cats.
And it's fairly convincing that postoperative or preoperative radiation therapy actually significantly improves the outcome. So if we go back here and, and again, look at this data, so if we look at cats who purely have conservative excision. Their median disease-free interval is something in the neighbourhood of 2 to 3 months.
So these tumours tend to grow back very rapidly after conservative surgery. So with a combination of conservative surgery, I, and, and radiation therapy, again, we're looking at disease-free intervals more in the 400 to 600 day range. So, an important thing to think about here is unlike in dogs, it seems like there are fewer cats who are truly cured.
With radiation therapy, combined with surgery with these vaccine associated sarcomas. But again, if we're, if our goal is to sort of keep this tumour at bay for as long as humanly possible, the outcome is far superior with radiation therapy than without, even though, again, the likelihood of cure may not be as high as it is in dogs. So here's another relatively recent thing that's been looked at, and this is what's called stereotactic body radiation therapy.
So this is a form of radiation therapy that requires some extremely sophisticated equipment that allows very, very high doses of radiation. To be delivered in actually a very, very specific way, so that a very high dose can be delivered to the tumour tissue specifically, but actually very little radiation is delivered to the surrounding tissue. So this is a cap with a soft tissue sarcoma again on its sort of dorsum, and this is what's called a colour wash view.
So red, there's a lot of radiation. And blue is a very low dose of radiation. And you can see using this very fancy technology, you're able to deliver a super high dose of radiation to the tumour itself, but actually avoid a lot of radiation dose to the very sensitive structures in the abdomen, and in this case, also avoid a dangerous sort of radiation to the spinal cord.
The other thing that's really encouraging or, or nice to know about this particular form of radiation. It's generally delivered in a very small number of treatments. So a very, very high dose per treatment, but a very small number of treatments.
So something like 3 to 5 total treatments. An important thing to know about though, however, is that this is the kind of treatment that can really only be done for gross unresectable disease. You need to have a tumour target to shoot at with your radiation in order to use this form of stereotactic radiation therapy.
So we really consider it to be a palliative treatment or, or a salvage type treatment. But again, here's the 1st 11 cats that were written up. So 8 out of 11 cats actually had meaningful tumour shrinkage, which is pretty impressive, and the median progression for interval was about 8 months.
So again, so these were cats generally that had had multiple, multiple rounds of prior surgery. A lot of them had prior chemotherapy, prior radiation therapy. So this was really sort of a salvage procedure.
So the fact that we were able to control their tumours for an average of 8 months after every single The other thing that we had at our disposal had failed was actually somewhat encouraging. So again, we do think of it as really a way to deliver what we call durable palliation rather than cure, but it is a very interesting technology. It's extremely well tolerated.
And I do think that as things are moving along, we will see more facilities, not only here in the United States, but, in Europe as well, who do have this capability. There are some sites in the EU that do as we speak. So what about chemotherapy for this disease?
So there are quite a few different drugs or protocols that have been looked at for the treatment of big unresectable tumours. So again, just like what we talked about with stereotactic radiation therapy, and some of the drugs that seem to be associated with some amount of activity include carboplatin, again, doxorubicin, Doxil, which is liposomal doxorubicin. There are case reports of vincristine being useful, and Lomustine as well.
So, again, there are many things that can be tried. If we have a gross unresectable tumour that we're trying to control for as long as we can. Again, these are, we're so we're looking at response rates and roughly the 25 to 50% range.
Most of the responses that we do see are partial responses. So not complete disappearance of all evidence of disease, but some amount of quote unquote meaningful tumour shrinkage. Generally, we think of that as meaning seeing things shrink up by at least 5.
The average duration of the responses that we see are kind of in the 2 to 5 month range in average. So they're not incredibly durable, but again, those are only averages. And again, half the cats may do better than that, half the cats may not do that well.
The only drug that's really been looked at in a post-operative setting. Is doxorubicin. Either regular old doxorubicin or again Doxil, which is called liposomal, which is also called liposomal doxorubicin, and the EU I believe it's sold under the brand name Calixx, not Doxil.
So again, there was no statistical difference between the cats who got doxorubicin and the cats that got Doxil. So we don't think that there's a lot of advantage to getting Doxil in this setting and there may be some cumulative adverse events that would make it less than optimal. So I think the doxorubicin is probably appropriate.
And when the outcome in these cats is compared to historical controls, there does seem to be a significant improvement in outcome. So again, here's our cats that get surgery alone. This is a historical group of cats, not randomised.
Again, a median a median disease-free interval of about 3 months or so. Cats who get surgery followed by chemotherapy, however, they have a median disease-free interval of about 400 days. So very much like the, like the dog situation that we talked about previously.
We love aggressive local therapy for this disease if it's possible. So amputation for those tumours that are on the limb, excision as wide as you can go followed by radiation therapy for those tumours that are not on the limb, or where, amputation even, even that might not be sufficient. However, if, it does appear that, that doxorubicin postoperatively certainly also has the potential to significantly delay local recurrence.
Again, it's not likely to prevent it, the way super radical surgery can, but it does have the potential to delay it. And again, this is a drug that's cheap, it's generally very well tolerated. It's only once every 3 weeks.
So it's at little cost to the owner or the, or the cat. So, what kinds of things can we talk about to owners to try and, and minimise the likelihood of these tumours occurring in the future or occurring in the first place? So one of the things that's been talked about quite a bit is limitation of vaccine frequency.
So trying to move to instead of maybe yearly vaccines to every 3-year vaccines. And is there an opportunity for more laboratories to start offering vaccine titers to actually know when we need to revaccinate our cats. Vaccine location, we talked about already, so distal limb as low down as you can get.
Avoid multiple vaccines in the same site. That's definitely true. So multiple vaccines delivered in exactly the same location significantly compounds.
The risk of sarcoma development. people are still continuing to look at alternate routes of vaccination. So for example, could we use an intranasal route for vaccination or an oral route for vaccination instead of subcutaneous, that might be better tolerated.
Certainly, you're probably aware that Mariel, or what used to be Mariel, it's now called Bring or Engelheim, does have a series of non-adjuvanted vaccine products. And there certainly is good published evidence to suggest that the use of these non-adjuvanted products does result in significantly less inflammation at the site where the vaccine is injected. However, really, there's not as compelling statistical evidence yet about whether that translates into a reduced incidence of sarcoma formation.
Although there is some evidence which suggests that that may very well be the case. So the use of non-adjuvanted products could be another strategy for minimising the risk of sarcoma development. Vaccine location.
Again, so especially here in the States, the, the American Veterinary Medical Association has come out with some guidelines about which vaccine should be delivered in which parts of the body, primarily so that we can then go back and track what vaccine was responsible for a sarcoma if it occurs. And then owner education about how to monitor vaccine sites for problems is also very, very important. And again, the vaccine associates sarcoma task force here in the US has come up with what's called the, the 321 rule, which states that again, the owner should be educated to notify the vet if there's a lump at the vaccine site that lasts for more than 3 months after the vaccine has occurred, irrespective of the size of that lump.
If it ever becomes larger than 2 centimetres in diameter, or if it's continuing to increase in size more than a month after the vaccine is given. So if any of those three things occurs, this is a a cat who should be brought back to the vet so that that mass can be interrogated and it could be at a bare minimum evaluated by cytology and potentially even resected so that it can be submitted for histopathology. So, that is, sort of the, the lowdown on soft tissue sarcomas, in cats and dogs.
And as I said at the very beginning, I am more than happy to answer any questions that anybody has about the content of this lecture by email, and you can, rewind this presentation at the beginning and you can actually get my email from that very first slide. And again, I thank you very kindly for your attention.