Good day everyone. Thank you again for participating in our conference and I hope that you are enjoying all of the talks. Today's topic for me is going to be treating soft tissue sarcomas in dogs and injection site sarcomas in cats.

So we're gonna start with the soft tissue sarcomas in dogs. Soft tissue sarcomas in dogs are for the most part going to be either a cutaneous or subcutaneous tumour. We also see some in the oral cavity, and they will have very many different clinical presentations.

So this is one tumour on the lateral thigh of a dog. This is an ulcerated tumour that is on the, Caudal aspect of the hind limb. This is the CT of a soft tissue sarcoma that is in the pelvic canal of a dog.

And then, soft tissue sarcoma that is involving the caudal maxilla and penetrating into the orbit of a dog. And then a subcutaneous soft tissue sarcoma being dissected out that is on the lateral aspect of the hind limb over the distal aspect of the tibia. And one more, soft tissue sarcoma that is also ulcerated, where the skin is ulcerated, and this was again on the, as on the hind limb of the dog as well.

So you can see that there are many different clinical presentations and there are there are a number of ways that these could be approached therapeutically. And we will go through the decision makings and the different possibilities as far as treatment goes, to determine what might be the best treatment approach in different situations. So this is the flow chart, and we are going to go through the flow chart systematically.

So hopefully by the end this will make more sense and particularly also what what are the reasons behind the decision making that is very important. So in order to better appreciate the decision making, I think it's very important to understand the biologic behaviour of a soft tissue sarcoma. They are locally invasive, they possess a pseudo capsule, and we're gonna talk more about that pseudo capsule, .

And the, although they may seem to be very well encapsulated on palpation and at surgery, when you do the surgery, you may think this is very well encapsulated at the microscopic level, it might not be, and therefore, they have the ability to go beyond what appears to be the capsule and to penetrate into what looks to be normal tissue. And they have a relatively low rate of metastasis. The rate of metastasis is grade dependent, and when they do metastasize, it is most often to the lungs.

So because they are locally invasive and they do not metastasize very often, then the therapy for most dogs is going to be concentrating on the local disease. So here is a histo slide of the pseudo capsule, and the pseudo capsule is made of the The compression of the surrounding tissue as the tumour grows, the surrounding tissue is being compressed, squished at the edge of the leading edge of the tumour, and that creates this impression of of being well encapsulated, and it can also be comprised also, from tumour cells that are also being compressed from the growth of the tumour from the inside. So, this is at a higher magnification, what the pseudo capsule, looks like.

But, there, as I was saying a little bit earlier, it can be deceiving that the capsule seems to be containing the tumour, but it is not. So you can have some tumour cells that are going beyond. The capsule and infiltrating into the normal tissue.

So because this is microscopic, we do not appreciate that at surgery, so we don't know where that is happening. We don't know how deep this is going. We just know that it might be happening.

So we briefly mentioned the grade and the grade can be prognostic for metastasis. The grade is assigned with histopathology. And it is determined by looking at the degree of differentiation, percent necrosis, and mitotic index.

And just recently, a paper came out looking at the ability to grade a soft tissue sarcoma with his or cytology, and the results were, were that cytology was actually pretty decent in correlating with the histological grade. So the pathologist is gonna take these three criteria into consideration and then assign a grade, and the grade can be 12 or 3. The grade has been shown to be prognostic for the likelihood of local recurrence after marginal excision.

So with grade one, it was 7%, with grade 2, it was 34%, and with grade 3 it was 75%. And, and again, this was after marginal excision. Unfortunately, sometimes this this data and paper are being misquoted.

People say that this is the rate of local recurrence after an incomplete excision. And when you go into the definition of how they define their margins in the paper, this is not an incomplete excision. It was a marginal excision, and yes, some of these were probably very likely to be incomplete.

But some of them were also likely to be complete excisions and therefore, we cannot assume that these are the the rate of local recurrence for incompletely excised soft tissue sarcomas, but the grade, nonetheless, the grade is prognostic for local recurrence again for marginal excision of soft tissue sarcomas. The metastatic rate is also dependent on the grade. For grade one, it's about 10%, for grade 2, it's about 20%, and for grade 3, it is 40 to 50% is the metastatic rate.

Now, this is the metastatic rate throughout the course of the disease, and literally this past week, I got my Jama, and so this is very, very recent, This is the rate of detectable metastasis at initial presentation. So different scenario, because over the course of the disease there are dogs that will manifest their metastatic disease later on. So this is that initial presentation.

Most dogs, got a CT, so it was very, sensitive from that perspective. It was 6% for grade 1, 6% for grade 2, and 38% for grade 3. So you can see that the grade here again was prognostic with grade 3 being a higher risk of metastasis.

And then also the odds were lower if the tumour was present for 3 months or less compared to a tumour that was there over 3 months. So, Initial presentation, client comes in and then you ask, how long do you know that this mass has been there? If the person says, oh, I just started to feel it on my dog last week, then the chances of metastasis are lower compared to the person that comes in and says, yeah, it's been there for 6 months and Didn't get a I have a chance to get around to bringing my dog to see you, in that instance, the odds are gonna be greater.

So, if you remember, mitotic index was one of the three criteria for grading. But it turns out that mitotic index is also by itself a prognostic factor for survival, and so, the cutoffs are less than 1010 to 19, and over 19 or 20 or more. And so if you look at it, the The dogs that had a low mitotic index definitely had a better survival than the ones that were intermediate, and those were better than the ones with a high mitotic index.

So, again, mitotic index is prognostic by itself. But it's also part of the grading scheme and the grading scheme is also prognostic for the likelihood of metastasis, which then translates into also survival. So what are the classic soft tissue sarcomas and why do we Why do we talk about them as a group?

So it turns out that There are different members of a soft tissue sarcoma, and some of them are classics, some of them are so, so, and some of them are not, and we're gonna go through the list. Those that are classic soft tissue sarcomas, what we mean by this is that they have the typical behaviour that we've just talked about, locally invasive. Does not metastasize very often.

The grade is prognostic for metastasis, and when they do metastasize, it's almost always to the lungs. So the classic ones are fibrosarcoma, myxosarcoma, malignant peripheral nerve she tumour, which in the older lurture has also been called neurofibrosarcoma or schwannoma, hemangiorecytoma, and then another old term that we don't see much anymore, malignant fibrocystocytoma. So our pathologists, when they see a soft tissue sarcoma, they actually pretty much have stopped telling us what is the, the exact soft tissue sarcoma.

They're gonna basically tell us it's a soft tissue sarcoma and leave it at that. And part of it is also because some Soft tissue sarcomas are very difficult to impossible to tell apart on H&E alone and so for all these reasons, clinically it does not matter which one it is, as long as you are part of this classic list. So less and less, we will see the, particular, and the, the, the specific soft tissue sarcoma and rather more and more pathologists are just gonna call those soft tissue sarcomas.

Sarcoma that are sometimes considered soft tissue sarcoma. So what I, what I mean by this is that there are studies that when they do a study on soft tissue sarcoma, they will either, they will say these were included or these were excluded. So liposarcoma.

Sorry. It used to be that we would say, you know, we don't know a whole lot about liposarcomas, and so we're not sure what to make of them now. I, most people, including myself, think of the liposarcoma as a classic soft tissue sarcoma.

Rhabdomyosarcoma, very rare tumour, we, so we don't know much about it, and so we don't really know if it behaves in a classic way. And there are some very specific anatomic locations where rhabdomyosarcomas are more likely to arise. So orbital area, larynx, heart, and then the bladder, the bladder being the buttreoid rhabdomyosarcoma.

So again, not sure what to make of it, so that's why, maybe, maybe not. Liomyosarcoma usually develops from the genitourinary tract or the gastrointestinal tract. So not your classic, you know, cutaneous, subcutaneous and and so, again, some, sometimes people say yes, some people say no.

Synovial cell sarcoma, you know, for the most part, we're not really sure anymore what to make of it, in my opinion, because the most of the studies that were done were done before we knew about the histiocytic sarcomas. And now we know that peri-articular tumours will often be histocytic sarcomas. So my suspicion is that the older studies that said that looked at synovial cell sarcomas, many of those were histocytic sarcomas.

And synovial cell sarcomas were described as being able to metastasize to lymph nodes, which is rare for a soft tissue sarcoma. And we also know that histocytic sarcomas like to go to lymph nodes and so it just gives an argument that probably many synovial cell sarcomas in the older literature were truly histocytic and so we don't really know what to make of them anymore. Pleomorphic sarcoma and undifferentiated sarcoma again, because historically, people were not really sure what their origin was.

They sometimes considered them soft tissue sarcoma, sometimes not. More and more though, I think, again, you know, because the pathologists are staying away from the, this terminology, they're basically Helping us determine whether or not this should be a soft tissue sarcoma or not. Sarcomas that are definitely not considered soft tissue sarcomas are are histiocytic.

We just had a little discussion. They like to go to lymph nodes. They're highly metastatic, so do not behave like a classic.

Hemangiosarcoma, typically from the spleen can be from the heart, highly metastatic in that instance, whereas the cutaneous and subcutaneous and the muscular hemangiosarcomas. The literature is very not in agreement as to how they behave and so most people don't think of a hemangiosarcoma as a classic one. Chondrosarcoma and osteosarcoma rarely rarely develop out of the skin.

And and so we don't really think of them as being soft tissue and then particularly osteosarcoma, very high metastatic rate. Melanoma, melanoma, so you have the oral one, which is very malignant most of the time, the cutaneous one, which tends to be more benign. You have the digital one, more malignant, and so for these reasons, we don't have melanoma in the classic soft tissue sarcoma, and they like to go to lymph nodes, which is not the classic behaviour.

Lymphoma, it's its own disease, it's own beast. We know that lymphoma, we know a lot about it, so now the soft tissue sarcoma and then lymphangiosarcoma, we don't know very much about, but it seems to be quite an aggressive disease and so we do not consider it classic. So, When we have or suspect a soft tissue sarcoma, the workup and the staging will include the blood work and urine analysis, thoracic imaging, so either CT or radiographs, even though we just showed data that it's rare, particularly at the initial presentation.

Initially, you may not know the The grade and so if it's a high grade, it still is close to 40%. Plus or minus abdominal ultrasound, they do not metastasize very often to the abdomen. But you know, what if you're in the presence of an unusual sarcoma such as histocytic, you definitely would want to see the abdominal lymph nodes if it's the tumour is on the rear end.

And then just, you know, these typically are older dogs and so it's never wrong to take a good look, make sure we're not overlooking anything. Find the aspirate of the mass and regional lymph nodes. So find the aspirate of the mass to find out what the diagnosis is.

Because it's a sarcoma, sometimes the needle aspirate will be non-diagnostic, so you might have to go to the biopsy and then it's never wrong to aspirate lymph nodes. And then imaging of the tumour is so that you can do a planned excision that can be either with computer tomography or magnetic resonance imaging. But these are, you know, more expensive, requires anaesthesia typically.

Ultrasound is a great alternative, so it's not as good in my opinion. More difficult to really assess the tumour very well, but it still is a good, very good alternative. So, if you have a little tumour that is over the trunk, freely movable under the skin, and not attached to body wall, you don't need to do an imaging of the tumour.

Imaging of the tumour are for tumours that are larger in anatomic locations that are difficult, so let's say the mouth, the head, the orbit, the pelvis. If they are attached to the body wall or to underlying structures, then yes, and or if they're very large, in size, then I think that doing imaging, is very helpful, very important to do the best surgery, but little one that's freely movable in an anatomic location that's easy, no need to image that tumour. The biopsy.

So the goals are to provide a diagnosis, but also to provide a grade. However, we know from a past study that grading a soft tissue sarcoma on an incisional biopsy is not the most accurate. So, one study was 59% accurate, where 29% of them were underestimated and 12% of them were overestimated in terms of the grade.

So when you do a biopsy, yeah, it's a great thing to plan, to know what it is, but as far as the grade goes, just be careful. Just don't think that this is the end all be all answer. And then as I said earlier, you're imaging the tumour, sometimes what you see or what you can palpate is the tip of the iceberg.

So tumour in the cervical area fixed. And so we ended up doing the CT and you can see that it's going into the muscle, which is not a very common behaviour for a soft tissue sarcoma to invade the muscles. But if you didn't know that, you wouldn't know how deep to go to go around the tumour.

Otherwise, you might have gone around too soon and then, touched the tumour, penetrate the tumour, and then you have the risk of disseminating tumour cells in the surgical bed. So, treatment for soft tissue sarcoma, the best treatment is a wide surgical excision if possible. So, when you see a case, you're gonna ask yourself, is a wide surgical excision possible, then obviously, the two possible answers are yes or no.

We're gonna start with yes and then later on, we're gonna come back to no. What do we do when a wide surgical excision is not possible. So if it is yes, then our goal is to get the complete margin.

So that's our goal. And the way that we're going to do this is, as we just said, with a wide excision, the reason being that as we've talked about, they are locally invasive, so that if you don't go wide enough, then you leave tumour cells behind, so you do want to go wide enough and therefore capture all of these extensions with your excision. Again, just showing that there can be local invasion and you wanna be wide enough to get all the tumour cells.

So, what do we mean by wide enough? This is likely to change. You know, I just showed you some data that suggests that the grade is helpful to know how deep the tumour goes.

And so much like mast cell tumours where we have learned that the grade is prognostic for how deep and how wide you need to go. I think that in the near future, we're gonna also have that data for soft tissue sarcomas. But for the time being, the recommendation is around the tumour.

The side margins, 2 to 3 centimetres all the way around. But then the deep margin, we're gonna go what we call the fascial plane, and the reason being that the fascial plane is a vascular poor collagen rich tissue, and that's been shown to be natural barriers against cancer. That's why I was saying it's rare for a soft tissue sarcoma to penetrate into a muscle.

So that shows that there are exceptions. However, for the most part, soft tissue sarcomas have a really hard time going through a fascial plane. So we're gonna use that to our advantage, and we're gonna use that as a deep margin.

So, for the side margins, we're gonna go for quantity. There are no fascial planes that are perpendicular to the skin. And so for the side margins, we're gonna go quantity 2 to 3 centimetres, but then for a deep margin, we don't necessarily need to go 2 to 3 centimetres, we're gonna go for a fascial plane, that's gonna be a quality margin.

And the way that we do this is that we go 2 to 3. Centimetre out of the tumour, we go down to the fascial layer and then we don't skim over the fascial layer. We go underneath, remove it, on block with the tumour so that we have the best chance for taking out all of the tumour cells.

So wide surgical excision for a cure at least locally, And we, we like to measure so that we don't cheat and stay away from the edge of the tumour. And then obviously that will create some large defects. So when we are over the trunk, abdomen, chest, even the proximal area of the limbs, more often than not, we're able to just close what I call primarily meaning that we just bring the edges together.

And then there might be a lot of tension, but you can use some techniques like I really I'm a big fan of the bolster bandage to take care of the tension. But there are some areas of the body where closing primarily is not possible. And so there are different strategies.

You can do skin grafts and things like that. You just wanna make sure that the donor site will not be contaminated with tumour cells, so the donor site has to be, where you use new instrument, new gloves, and you don't go back and forth between. The donor site and the recipient site.

So you need to treat that as a completely different surgical field. But another option is to just to leave the wound open and let it heal by second intention. And so there was a study done that looked at that.

And so wide excision, the forelimb is convenient because there's the antebrachial fascia, which is a really nice fascia that peels away very nicely, so that's a nice deep margin. In that study, just to give you an idea of how big the defects were, the median tumour size, in its largest diameter was 4 centimetres, but the range was up to 10 centimetres. The median surface of the wounds was 40, almost 44 centimetres square.

The range was 18. To 113. And then the wounds encompassed a median of 44% of the circumference, but that was only measured in three patients.

But it gives you an idea, you know, almost half of the circumference, the skin was removed. 93.5% of the wounds healed completely by second intention.

However, the median time was 53 days, almost two months, that's the median time. So yeah, 50% was less, but 50% was more. So not for everybody, not for every owner, not every owner is gonna be in.

With all of the bandage changes and having this long with managing an open wound. 6.5% of dogs required a free skin graft procedure to facilitate healing, complications during open wound management developed in 22.6% of dogs.

The long-term complications were detected in a quarter of the dogs. It was intermittent epidermal disruption. So oftentimes when very large wounds healed by second in attention, this is not normal skin.

You're not gonna have all of the layers of the dermis, and it can be thin and very susceptible to trauma. And then wound contracture in less than 10%. Local tumour recurrence was detected in only one case.

So, from that perspective, you can see that they were very successful in getting all of the tumour cells out. And so second attention healing in a nutshell, definitely doable. It, it, you know, for the majority of dogs, it, it was successful, but it took a long time and definitely not for everybody.

All right, so now, what do we do if we had incomplete margins? And I'm just going to point out that if you were to say no, I will not be able to get a a wide excision, then you do a marginal excision. And then that will lead to planned incomplete excision.

So we knew that we were gonna get it, whereas over here we were hoping to get complete margins, but we just didn't get it. So in that instance, Our treatment options are re-excision, amputation of the location is a limb. However, if the owner went marginal excision here for a tumour that was on the limb, and they were probably not in favour of an amputation, so amputation may have been discussed right from the beginning.

Radiation therapy, metronomic chemotherapy, electro chemotherapy, and then active surveillance where you say to the client. You know, we just let it be, like there's no guarantee that it will grow back. And and so it's probably best for grade one where the rate of metastasis is low and based on some evidence, there's a low chance that it's gonna come back.

And so, you basically say we're just gonna watch the the site and see if it's ever gonna come back and if it does, then we'll address it then, but hopefully, it will not come back. So we're gonna go through these different options here. So, surgical excision, so we know that if we have an incomplete margin, the chances of local recurrence are much greater.

They're 10.5% more likely to recur. In that one study, 28% of dogs with incomplete margins had local recurrence, so you can see, not everybody is gonna have local recurrence, and then only one of 39 dogs had with complete margins had local recurrence.

So if you look at it in a Kaplan Mayer, you can see that only one dog had local recurrence. Although only 28% of dogs had local recurrence, because this is a Kaplan Meyer analysis, dogs are being censored, and so because of that, you could argue that at 1500 days or even close to 2000 days, 75% of dogs, approximately maybe 70% of dogs had local recurrence. But you know, for some dogs it took a long time.

It took over 1000 days. So, active surveillance for the low grade is not a bad idea. It may take a long time or it may never happen, and this is independent of the grade, when that paper came out, we were not aware of the grade.

So soft tissue sarcoma, again, just to mention that the grade is prognostic. So again, for low grade tumour, it might be appropriate to do local or active surveillance, but for the higher grades, probably best to recommend a treatment. So we talked about re-excision, might be an amputation, irradiation, metronomic chemotherapy, also elect electro chemotherapy, active surveillance.

We're gonna go through them. Here is a dog that has had an incomplete excision and we go for the 3 centimetre margins, and we're gonna go for the fascial plane. There's a study that has looked at the re-excision for incompletely excised soft tissue sarcoma, so it's often, oftentimes we're gonna call this the second surgery.

Local recurrence was seen in 15% of the dogs. That would suggest that the second surgery was effective for reasons that we don't know, liposarcomas and fibrosarcomas had more local recurrence. I think this is probably a statistical aberration.

We really don't know of any reasons why that would be, but that were the results of this study. And then, presence of residual tumour cells in the excised scar was not predictive of local recurrence, so they saw. Tumour cells in only 22% of the excised scars, and if they were able to see them or not, that was not prognostic for local recurrence.

So the fact that there were very few cases where they saw tumour cells is really not that surprising because we know that they, these were microscopic disease that was left behind. And then you take a big chunk of tissue and there's no way for the pathologist to know where they would be, and so they literally have to find a needle in a haystack. So not surprising that they did not find them.

But it's very important to remember that if they don't find tumour cells, don't think I didn't have to do the surgery. You have to go back to the original pathology report that said this was incompletely excised and that was, was, that was the justification to go back the second time around. And again, if you don't find tumour cells, there, there still is as good of a chance of local recurrence the second time around.

Then if you did not find, then then if you did find the tumour cells in the scar. So radiation therapy, radiation therapy alone, meaning without surgery is not considered an appropriate treatment for soft tissue sarcoma in the curative intense setting. When used as an adjuvant following incomplete excision, local recurrence rates vary between 17 to 43%.

So, so good but not great, depending on the city that you read, but we will tell clients if you have the money. And if you are logistically able to do so, we believe that this is the best way to To control the tumour if a second excision is not possible, so a second excision is our primary choice. If it's not possible, Or they decline amputation, then radiation therapy is our treatment of choice.

See Metronomic chemotherapy is where traditional chemotherapy drugs are used but at a different dose and intervals. So the best example is cyclophosphamide, or you're using drugs that are typically not thought of having anti-neoplastic effects, and that would be proxicam and thalidomide. Thalidomide in the United States is not being used, and so we don't, we don't use thalidomide in the metronomic setting.

There is one study that was done, and that study had some really great results that unfortunately, our experience is that it does not work so well, but the study was actually had a control group, so there were 30 dogs that were treated and 55 that were not treated with the metronomic. You have here the cyclophosphamide and peroxicam, those, sorry. 40% of side effects is something to keep in mind.

The majority had low grade side effects, but one dog had cystitis grade 4, and then in the presence of side effects, drugs were given every 48 hours instead of every 24 hours. And when you look at it, this is the Kapln Meyer curve, then dogs that were treated did not have very many local recurrence, about 20% in the long run, whereas dogs that were not treated with metronomic, . All of them based on the metronomic had local recurrence.

However, you can see that there are many, many dogs that were censored, which is the appropriate way of doing the Kapln Meyer analysis, but with that many dogs being censored, you wonder if they had not been censored, what would have happened, and same thing here, a lot of dogs are censored as well. So, The study suggests that metronomic chemotherapy is very effective, however, that's not been our collective experience, and so we still will favour radiation therapy over metronomic chemotherapy. Electro chemotherapy might be a good alternative.

To my knowledge, there's not a lot of information out there. There's this one study, they were all high grade, which is important because these are the ones that are more likely to recur. It it was all after incomplete excision.

They applied the electrical field with leomycin and recurrence was seen in 6 dogs, so 6 dogs out of 22. And the meantime to recurrence was 730 days. So, I think we need more information, but electro chemotherapy may have a place, for adjuvant setting with, soft tissue sarcomas.

So then, we also need to talk about maximal dose, . Yeah, maximal tolerated dose chemotherapy, which is typically doxorubicin. So if you have a grade 3, then we are going to recommend the chemotherapy maximal tolerated dose doxorubicin.

And then if you have complete margins, but not a grade 3, then we're gonna go to recheck every 3 months for 18 months, and if there's no evidence of disease, either local recurrence or metastatic, then we go every 6 months for the rechecks. But again, the grade 3, we're gonna recommend maximal tolerated dose chemotherapy. So what is the role of maximal tolerated dose chemotherapy?

Well, they could be used in a palliative setting, for a non-resectable soft tissue sarcoma where owners declined surgery. With or and or adjuvant radiation, but For treating a soft tissue sarcoma, if you, if you have that as your creative intent, you're gonna be very disappointed. So it's really more palliative and even in a palliative setting, you know, it's not great, but it, it's an option.

It can be used as an adjuvant in patients with high grades, so grade 3 tumours. The current proof of efficacy is lacking. So we recommend it, but as I was saying, There's actually no evidence to support that it's gonna make a difference.

And then you can use it in patients presenting with detectable metastatic disease, but again, there again, we are likely to be disappointed with the response. So the drugs that have been used are doxoricin, mitoantrone, and the the VA protocol, which has been cristine doxo and cyclophosphamide. There's one study that looked at it for treating grade 3 soft tissue sarcomas.

There were 39 dogs, 21 dogs that received doxerbain as an adjuvant to surgery, 18 that had surgery alone. The median disease interval was 724 days. Medn survival time 156 days.

However, Doxoricin did not provide an advantage, and so doxericin in that study did not help. . And so we, we are aware of that study, but yet we're still gonna recommend it to dogs that have a grade 3 because grade 3 have a decent chance of metastasis and we feel like we should try something.

So, we're now gonna go on to know why surgical excision was not possible, and we're gonna go in the palliative setting. While I'm here, I'm just gonna say curative intent. So curative intent with stereotactic radiation therapy, I would say the jury is still out.

There's a paper that came out recently that suggests that it's actually has a decent response. The paper from Colorado State University should be coming out soon and Our results are not as good. So, the role of stereotactic radiation therapy, I would say, still being debated.

Palliative radiation therapy, so again, we're not going for a cure, we're going for palliation. There are different protocols out there that one study reported on 8 grade fractions once weekly for 4 weeks, or 6 grade fractions administered once or twice weekly for 6 weeks, and 3.5 grade fractions administered twice daily for 2 consecutive days.

So there are different protocols out there and different studies as well. So if we look at the results of that particular study with respect to palliative radiation therapy, and we're gonna look at the sarcomas. We can see that 3 tumours had a complete response and the 3 tumours had a response that lasted from 106 days to 173 days.

And the dogs lived for 206 days. Some dogs had, or some tumours had stable disease. The majority of them had stable disease, which makes sense because we're in a palliative setting, and the duration was from 31 days to 443 days with a median of 251.

And then 4 tumours had progressive disease. And obviously the survival time for these dogs was much shorter because they did not respond. But I think we can say that palliative radiation therapy is effective in achieving that particular goal being palliative.

If we compared with other studies, the overall response rate in that one study that I am referring to, was 87%. And then in other studies, it was 50 to 93%. So I, I would say, you know, very comparable, same ballpark, and then the median survival time ranged from, well, 180 to 322 days if we look at other studies.

So it gives you an idea that yes, palliative radiation therapy is effective against soft tissue sarcomas. But there again, you know, to emphasise we're not in a curative setting, we are definitely in the palliative setting. So, we have gone through the chart, of how the treatment for soft tissue sarcoma goes.

Again, just to re-emphasize, if you can do a wide surgical excision, that is the treatment that is the most likely to achieve local control. And for the majority of dogs to cure because they're not very metastatic, so wide surgical excision will cure the majority of dogs. And the goal is to achieve complete margins.

If we don't have complete margins, then there are some adjuvant therapies that can be done. Or if you're not able to do a, a wide surgical excision, then you can go ahead with marginal excision. It was planned, so you're likely to get incomplete margins and then do your adjuvant therapies.

Grade 3, we're going to recommend maximal tolerated dose doxorubicin, even though I told you that the evidence is lacking. And then we're gonna monitor the dog every 3 months for a year and a half and then go to every 6 months. If there's no evidence of disease.

If you're not able to do a wide excision, you can go into the palliative setting and then like I mentioned, SRT, we're still trying to decide how effective it is, but just keep in mind that, that we are gonna get more and more data as time goes on. So we're gonna switch now. We're gonna go to the feline injection site sarcomas, historically, that's been associated with the vaccines, so it's been called vaccine associated sarcomas, but over time, we have learned that it's not just vaccine, but really any injection that can cause irritation will be able to be a risk for developing a sarcoma.

They are very aggressive biological behaviour locally. They are very invasive locally. There is a very high risk of local recurrence.

The metastatic potential varies from some studies. Did not document any metastatic disease in their kitties, and some other studies have gone up to, I believe, 25%, but it, it is the local disease that will be the cause of death for the majority of these cats. We have the rule of 123, that refers as to when do we recommend a biopsy if a mass is detected at the site of vaccination, but it should really be injection.

So we're gonna recommend to do a biopsy if the mass is still growing one month after the vaccination. The mass is at any point bigger than 2 centimetre in diameter, or if the mass is still present 3 months after the injection. So if you meet any one of those criteria, 123, then we're going to recommend a biopsy.

So obviously, the message to the client is that if you find the mass, you come and see me right away. And then you will apply these three criteria to decide do we biopsy it now or not. And if you say no, then obviously you wanna keep monitoring the site to decide if you're going to biopsy it at some point later on.

So the idea is that when you give an injection, some injection sites will develop a granuloma and then the granuloma has the potential to become, to undergo a malignant transformation. Granulomas, they're rare, so the incidence in that particular study was about 12 per 10,000 doses of vaccine given. And the majority of them regress.

So 96% of them regressed within 3 months and 100% of them within 4 months. But obviously, even though in that study, all of them regressed within 4 months, that is not the case for all of them. Some of them will become a sarcoma.

The benefit of removing a granuloma is unknown, meaning that, yes, we do know that some of them are going to become sarcomas, and therefore you would think that if I remove it, then I take away that possibility, but there are anecdotal reports of a granuloma having been removed, and still the sarcoma developed at that location. So we don't know what is the benefit of removing a granuloma. When we treat a feline injection site sarcoma, we want to stage the patient even though the metastatic rate is low.

If it is there, it greatly changes the prognosis, so we wanna do chest radiographs. They don't go to lymph nodes very often, but still, it's a good idea to evaluate the lymph nodes. Minimum database, CBC, CA panel, urine analysis, and then always a good idea to know what the FELV and FIV status is.

This is one where we absolutely want advanced imaging, even for the small lesions. And so unlike the dog where I said, if it's small and freely movable, you don't always need advanced imaging. Well, this one, even the small one, we want advanced imaging because they can be very Deceiving and sometimes the CT will show the gross extension and then realise that there's also the microscopic extension.

And so imperative so that we can properly plan the therapy. So here's a CT that shows how intimate those tumours can be here and with the spinous process and the scapula. Marginal excision should not be performed.

It should be wide excision provides the best prognosis, complete versus incomplete excision, if you had tumor-free, interval was 6 months with complete versus 4 months with incomplete excision, and the survival was 16 months with complete versus 9 months with incomplete. And then radical versus marginal excision, radical at 325 days versus 79 days for the marginal excision in that particular city, but I'm gonna show you more data, but this is just to start the conversation that we don't want to just do a little surgery, we want a wide excision and even we're gonna talk about the radical surgery. But this shows the cats without evidence of .

Recurrence, and you can see that the vast majority of cats will have recurrence. However, there is that 10% of cats that will keep on going without local recurrence, and these in that particular study, these are the cats that were having an amputation. So, And then you can just see the overall survival.

So there are some cats that have a long survival, but we want to achieve no local recurrence. So if we look at cats that have tumours located on the hind limbs, the triangles versus other locations, you can see that on the hind limb, cats can have a long survival, and that is because the radical first excision was an amputation. So cats that have their tumour that is high or proximal in the limb, it may be hard, but if you have it more distal and you do an amputation, these cats can have a a cure.

And so, that's where the recommendation came to vaccinate on the limbs and distal as much as possible on the limbs, and I realised it's easier said than done, but with an amputation, you can see these cats can be cured. So then that prompted the idea that, well, why don't we be radical everywhere on the body if we can. And so a study was done where we they did 5 centimetre side margins and two muscle planes deep as their deep margins, so 5 centimetres and 2 muscle planes.

In that study, they had 14% local recurrence and 20% metastasis. So you can see that the local recurrence was relatively low. This is the best The lowest local recurrence, to my knowledge in a study for injection site sarcomas in cats, the median overall survival 900 days, however, without local recurrence, Almost 1500 days and with local recurrence, 500 days.

So you can see that if you don't have local recurrence, then you can do very well. . And so this is a case series, there's another case series that support radical surgery as well that I don't present the, the data here, but overall, you can see that radical 5 centimetres, two muscle planes, and if it's on the limb, well, that means amputation.

So wide excision, you can see that we're gonna go big and deep. So definitely you can make some big holes in the cats. Versus the radical, obviously, if it's a small tumour, that's gonna be a lot easier to achieve radical excisions, but you do end up with some very wide, very big holes, and, you know, some, oftentimes it's the, because it's two fascial planes, you end up removing part of the body wall.

But the positive thing about cats is that their skin is highly stretchable. And that you are able to close big defects without doing some crazy skin grafts. So I'm just gonna go back one side.

This is the whole, this is the closure in the same cat. So radiation therapy, traditional radiation therapy alone has only a palliative role, but if you, and then there is stereotactic radiation therapy. 8 of 11 cats had a response.

The median progression free interval was 242 days, and the median overall survival 301 days. So stereotactic that is without surgery. If you do surgery stereotactic, once the surgery is done, you cannot do stereotactic after.

Radiation therapy is indicated for wide surgical excision. So, at CSU Colorado State University, our preference will be to do a radical excision. If we can do radical excision and we have a complete margins, then we just monitor the cat.

If we're not able to do a wide or a radical excision, then we're gonna do preoperative radiation therapy followed by a wide excision. But stereotactic is a possibility and we're starting to have data with stereotactic radiation therapy. So radiation therapy and surgery, it's not awesome.

The data that's out there is not awesome, and I'm gonna point out why. It's good, but it's not awesome. So in this particular study, 16 daily fractions of 3 greys, so a total of 48 grades, median disease-free interval, 398 days, and median survival 600 days.

It's good. But there were still 19 treatment failures, 11 local recurrence, 44 metastases, and 4 with local recurrence and metastases. So we showed the proportion with without failure or death.

You can see that at 1000 days, you still have over 50% of dogs or cats, I'm sorry, cats that have failed or have died due to the disease. And you can see that the margins was important, so. If you did not have complete, if you had tumour cells at the margin, definitely a faster failure.

If you had clean margins with radiation therapy, you did better, but I will still point out that still 60% of cats failed even with clean margins and radiation therapy, so very disappointing. This is a study, this was post-op radiation in 76 cats, median disease free interval 400 in 5 days, median survival 730 days. 41% of cats had local recurrence.

And then interestingly, in this particular study, wide versus marginal and complete versus incomplete margins were not prognostic for local recurrence, and that study may be the exception. This is a study where they did preoperative radiation in 92 cats. Medium time to first event, that being local recurrence, metastasis or death, was 584 days, and you can see that complete and incomplete margin was prognostic for that.

So you definitely want to achieve a complete margins if you can, in spite of the other study which had different results. And then you can see the difference between complete margins and dirty margins. But when you look at cats that have clean margins, so clean margins, radiation therapy, you still have 42% of cats that have local recurrence.

So very, you know, disappointing from that perspective in that, well you can make the argument that a lot of cats did well, and yes, but there still is a fair number of cats that you put through surgery, radiation therapy, you get a complete excision. And nonetheless, there can still be 40% of cats that have local recurrence. Chemotherapy alone is for owners that declined surgery and radiation therapy, so not, we don't have good we don't have, we don't have high expectations for chemotherapy alone, so we reserved that for more palliative setting.

Maybe be able to decrease the tumour size for a tumour surgical excision, . In one study, 50% of tumours had a 50% or more size reduction, so may be helpful, but we don't really know how well it helps. And the drugs are doxepicin, carboplatin, miocentrone, cyclophosphamide, vincristine have all been described.

When we do radiation and Doxorin for incompletely excised tumours in cats, it was done in 71 cats, 29 with doxo, 42 without doxo. And they we did achieve a prolonged disease free interval with the dox in 15 months versus 5 months, but there was, statistically no difference in survival in this particular study. So unfortunately, in this particular study, doxericin did not prolong survival.

In another study, doxericin did not improve the risk of local recurrence or metastasis. However, in another study where they had neoadjuvant. And adjuvant epirubicin, local recurrence was 14%, median survival was not reached, with a mean follow up of over 1000 days.

However, there were only 21 or 21 cats in that study. So a lot of mixed results that is being published regarding the role of chemotherapy. Another study where they did doxericin, and it did prolong the disease-free interval after surgery.

The median disease-free interval was 388 days versus 93 days for a historical control. So, I would say that the evidence is very, Conflicting regarding the role of chemotherapy for this disease. So bottom line, what we do, as I mentioned, we like to do radical excision if possible, and that includes an amputation that provides 5 centimetre margins.

So we're gonna go for 5 centimetre margins, two fascial planes. If we are dealing with a, a situation where we're not able to do so, we will do fractionated radiation therapy preoperatively, and then we're gonna follow with a wide excision. If radiation therapy is declined, we're gonna recommend chemotherapy.

Alternative is stereotactic radiation therapy. Not much existing data, but likely durable palliation. Also used for unresectable tumours.

And then, I'm sorry, we're gonna offer chemotherapy with unknown benefit with doxorubicin. So we This is how we go about, and we're not saying that this is the end all be all, this is just based on the data that currently is available. This is our approach.

On the horizon, immunotherapy with gene therapy, or viral therapy, expressing IL2. That may be where this is going. So just recently there was a study that was just published about the use of electro chemotherapy, and this was in cats that had an incompletely excised tumour.

Retrospective study, 27 cats. The side effects were local inflammation in 3 of 27 cats, it was very well tolerated. 5 cats had local recurrence, but remember, these are cats that had an incomplete excision.

The median time for the cats that did have local recurrence was 180 days, but the median for the overall population was not reached because only 5 cats out of 30 or 27 had local recurrence, and the median survival was 1000 days. So small study, but there might be a place for electro chemotherapy, as an adjuvant, as opposed to radiation therapy if that's not available. So, something to, keep an eye on as well.

So, Injection site sarcomas in cats are challenging. They're very locally invasive. If we can do a radical excision, this is what we do.

The good news, if there's any good news is that at least for us, and I'm talking to my colleagues around the country, here in North America, it seems that we're seeing less and less of this disease, and I think it's because the vaccines are different nowadays. So, this is all I have for today. I hope to see you guys in the near future and thank you very much and have a great conference.