Good evening everybody and welcome to our Thursday night members webinar. My name is Bruce Stevenson and I have the honour and privilege of chairing tonight's session. And I've had a peek at the slides before we started, so we're in for a goodie.
I don't think we've got any new members in tonight, so the usual. If you've got any questions, just hover your mouse over the screen, click on the Q&A box and we will keep those over to the end and then we will have those discussions with Doug. So Doug Tam is the Barbara Cox Anthony Professor of oncology and director of clinical research at the Colorado State University, Flint Animals Cancer centre.
He has authored over 150 peer-reviewed publications and 20 book chapters in veterinary and basic cancer research. He is the co-editor for the most recent edition of the textbook, Withrow and McEwen's Small Animal Clinical Oncology, and he's the co-editor in chief of the Journal of Veterinary and Comparative Oncology. His clinical and research interests include novel targeted therapies for animals and human cancer, and ways to integrate these therapies with existing treatment.
Doug, welcome to the webinar vet and it's over to you. Thanks so much, Bruce, for that kind introduction, and I'm very glad to be back. Just, for those of you who are feeling the cold where you are, we're expected to hit about -30, -40 coming over this weekend over the nighttime and, it's not gonna be very pleasant, but right now it's pretty OK.
We were just talking about that before we started. So, we're gonna talk about osteosarcoma today. And one of the reasons that, that I really like to talk about this particular topic is that, Colorado State University, where I work has kind of been known as somewhat of an osteosarcoma centre of Excellence.
Going back, I don't know, 30, 30, 35 years thanks to some real pioneering work that was, done by the founder of the, the Animal Cancer centre and my colleague, Doctor Steve. And I'd like to think that it's really sort of continued since then. So, I'm gonna try and do a, a fair and biassed overview of kind of what's new with, with osteosarcoma, but, definitely sort of highlight some of the things that, that have, sort of come out of this institution and, and sort of put them in the context of, of what we know about osteosarcoma and what's relevant.
So, before we get started, I will just show you my, Conflict of interest, so you will see that there's a company in bold here called NBC Pharma. Who I consult with and, sponsor some of my research. I will be mentioning very briefly, a drug that they have developed that could be very interesting for osteosarcoma at the very end.
It is not yet available or approved, in animals or humans. So just a very, very quick background about osteosarcoma that's probably going to be reviewed for most of us in dogs. So this is a disease that can affect any bone, of course, but about 85% of the time it actually affects the bones in the appendicular skeleton.
And classically, there are certain parts of the bone that are most commonly affected and, and this is sort of the meta metapocele region. Of these long bones. And I think many of us remember from vet school learning this, this moniker that you see at the bottom here, away from the elbow and toward the knee, in terms of the, the regions of the bones that are most commonly affected.
So in the thoracic limb, we tend to see the proximal humerus and distal radius. In the pelvic limb, we see the distal femur and proximal tibia. Now, this little moniker actually holds up quite well for the thoracic limb.
We really do not see it around the elbow joint very much. The pelvic limb, really not so much. And of course, one of the important things to keep in mind is there are always exceptions to these rules.
So one of the other things that most of us probably know is that this is a disease that tends to affect large and giant breeds primarily. In fact, the this predisposition is so great that if I see a a lytic bony lesion in a small dog, a small toy breed or small breed dog, actually, statistically, that's more likely to be something other than osteosarcoma. Than it is to be osteosarcoma.
And we'll go through that list of differentials in just a second here. The other thing that's interesting and important thing to remember is the fact that there are two very distinct age groups of dogs that are affected. So this is what we call a bimodal distribution.
So we can actually see that sort of typical cancer-bearing age in that sort of 7 to 9 year old range affected commonly. But then we can see a little spike represented right here, of quite young dogs who can actually get this disease, so young adults. So one of the things that we need To keep in the back of our mind is, oh, we, we see a, you know, large breed dog that comes up lame.
We can't 100% completely discount the possibility of osteosarcoma if it's, let's say a 1.5 or 2 year old dog. That may not be as common, but it really does still need to be somewhere on our differential list.
So as with most cancers in, in veterinary medicine, we really don't have a good understanding of exactly why or how these things occur, but there are a few kind of oddball cases where there does seem to be some amount of predisposing factors that have been identified. So one of them are, are implants and hardware, so, screws and, and pins and areas of prior fracture are actually predisposed to osteosarcoma development. Radiation can actually cause osteosarcoma.
So rarely, many, many, many years, 5 years or more after we've seen a patient undergo radiation therapy for some tumour that they've been cured of, we can see an osteosarcoma develop at the site where that radiation was put. And then, although it's rare, and this is primarily a dog osteosarcoma talk, we can occasionally see osteosarcomas as a phenotype that occurs with what used to be called vaccine associated sarcoma, what we would now call injection site sarcoma in cats. But that leaves 99% of the cases where really we don't understand what the pathogenesis of the disease is.
So how is a dog with osteosarcoma likely to show up at our practise? So lameness is usually the presenting complaint, and occasionally we can see dogs who come up. Profoundly lame, very, very acutely, with really very little in the way of pre prodrome or, or a history of more mild lameness or anything else like that, at least that the owner reports.
And when we see this very, very acute and very severe lameness, we do worry about the possibility of a pathologic fracture. So that's why again, if we do have an animal with a fracture, it really does pay to, to really take a very, very careful look at those X-rays prior to thinking about surgical repair and of course, taking a very careful look at the tissues intraoperatively if if repair is undertaken to make sure that we don't have anything that looks like neoplasia. One of the things that, that has been a question and is actually a subject of some debate in human oncology is whether the presence of a pathologic fracture actually affects the outcome in dogs.
So in other words, if I'm a dog and I have a pathologic fracture, is my outcome likely to be worse than, than if I don't? And that does not seem to be the case in dogs. So Nick Bacon, who's actually at the University of Surrey.
Actually took a look at this from our database here at CSU about 10 years ago, and there was no difference in outcome between those dogs that had a fracture at presentation and those dogs that did not. Occasionally, there can be ways to potentially do a repair of a pathologic fracture, but the complication rate is extremely high, and really it's something that we would only do as a last ditch effort if amputation is completely out of the question or completely refused by the owner. So not recommended, but occasionally possible.
A more common scenario is certainly one of sort of chronic or progressive lameness that sort of gets worse over the weeks. And actually, it's very, very common for us as practitioners to maybe make an initial recommendation of take it easy on the leg. Here's some symptomatic therapy, some NSAIDs, or some other analgesics.
And actually, it's quite common for dogs with osteosarcoma to initially respond. To those kinds of symptomatic measures. So the fact that they tend to get better doesn't necessarily rule out osteosarcoma.
But again, the typical things that we would talk to an owner about as triggers for us to want them to come back in certainly apply. Hey, if it, if it seems like it's getting worse despite the NSAIDs and rest, please come back in. If the signs come back after we discontinue the NSAIDs and rest, please come back in.
The other thing that we, we hear quite commonly is, is that owners sort of ascribe some kind of traumatic event to the onset of the lameness. So they'll say, oh, he slipped on the ice outside, he was playing with the other dog and took a spill. Those kinds of things.
And, and to some degree, I think that's human nature, really for all of us to want to sort of ascribe a cause and effect to things like that. So while, of course, those things can be very, very important, I really caution. The students, who I'm instructing not to put too much stock into that and say, oh, it can't possibly be osteosarcoma because the owner says the dog slipped and fell on the ice.
So I think we're all pretty attuned to sort of, not discounting what owners say, but making sure that we take it with a grain of salt and really do an unbiased assessment. So, again, very important for this disease as well. So what are some of the initial steps that we're gonna wanna do if we do have this dog where somewhere on our differential list is going to be osteosarcoma?
Obviously, a good physical examination is gonna be really the first key to this, and really what we want to do is try and localise the lameness, just like we would with any other lame dog, so that we can then go ahead and radiograph the affected part. So the other thing that we do sort of talk about that's important to keep in mind is that This is a disease, and again, most sarcomas in general with rare rare exceptions, are diseases that don't often spread to the regional lymph node. So sarcomas in general are much more likely to spread hematogenously, which would make the lung usually the first site of metastasis.
But occasionally we can see lymph. No involvement. So certainly, if we do palpate lymphadenopathy in a dog, and that lymphadenopathy is on the same leg as where the lameness is, it's definitely worthwhile to sample that lymph node cytologically.
And again, what you can see here is actually an example of a lymph node that has actually multiple sarcoma cells colonising it. And the reason that that's important, A, you may be able to get a diagnosis quite quickly and cheaply, and B, the outcome is actually extremely poor in these dogs. So you can see the numbers there, so a little less than 2 months versus 8 months for dogs who have disease in their nodes versus those that don't, although again, only 5% of these dogs are positive.
So here that is in in Kaplan Meyer survival curve terms. So again, we don't try and aspirate every single lymph node that we can find in these dogs only really if they're enlarged. But actually, if we have an owner that's going forward with a surgical treatment for this disease, we do, we do try very hard to dissect out that lymph node and submit it for histopathology separately so it can be evaluated.
Again, because of this profound effect that it can have on outcome. And then really the number one thing that we're gonna wanna do is take radiographs of the limb to really try to achieve a diagnosis. And that would be for any lame dog.
Again, we can rule out arthritic disease versus ligamentous disease versus again, potentially neoplastic disease. And again, the classic appearance of an osteosarcoma is this mixed politic and proliferative pattern that's generally arising from the metaycele region of the long bone. In this case, obviously, this is the distal radius.
And again, Historically, this is a disease that does not cross a joint space. So it would be very unusual to see involvement down on the carpus for in this particular example, or to see it across the scapulohumeral joint if you had a proximal humeral osteosarcoma. So that being said, there are a lot of variations on this that we can see in individual animals.
So we can see lesions that are almost purely lytic, we can see lesions that are almost purely proliferative. We can see mid diaphyseal lesions, etc. Etc.
So plenty of animals don't read the book, this is just sort of the textbook, clinical presentation. So, is this the only thing that we could see that could cause cause lytic bone disease in a dog? Well, of course not.
So there's a variety of other kinds of neoplastic diseases that can be associated with bony lysis. So there's lots of other kinds of cells that we can find in bones that could potentially neoplastically transform. So osteosarcoma really does account for the lion's share of them, but some of the others that we can occasionally see would include chondrosarcoma, fibrosarcoma.
These are important distinctions because actually they generally carry much better prognosis due to a lower metastatic rate. We can see hemangiosarcoma of bone occasionally, and that's actually an example up here, which is actually quite, quite an aggressive disease. And then we certainly can see primary joint tumours as well, synovial cell sarcoma or periarticular histiocytic sarcoma.
And again, this is kind of an example of of one of those that's occurring on the elbow joint. So then of course, we can also see metastasis to the bone. And classically, this is something that occurs with carcinomas, so carcinomas of the lung and urogenital tract are most commonly observed.
And again, this is something that that's actually common in small dogs with lytic bone disease. And then occasionally we can also see bony involvement from systemic disease, so we can see plasma cell neoplasms like we're seeing in this particular case, and occasionally we can see a solitary bony lymphoma as well. And then one of the things that we talk about all the time is, could this be some kind of strange osteomyelitis?
And certainly that can be, depending on where in the world one is practising, one can see fungal diseases that can manifest in bone. So here in the United States, in in other parts of the United States than where we are, we can see blastomycosis and coccidioidomycosis that can cause lytic bone disease. In Australia, they see Aspergillus that can do it, etc.
Etc. And then often a bacterial osteomyelitis is talked about. Hey, should I put this dog with, with bony lysis on antibiotics for a few weeks or something like that.
And actually, it's in a, in a skeletally mature dog. It's actually quite rare, and you'll almost always have two things if you have a bacterial osteomyelitis, again, in a skeleally mature dog, and that is a draining tract and a history of a penetrating wound or prior surgery or prior trauma or something like that. In the absence of those two factors, the likelihood of a bacterial osteomyelitis is actually very, very low, and that's an important thing to keep in mind.
Then there are other few things that we can see that can cause bone lysis again in little dogs, we can see leg calferthhe's disease, that's avascular necrosis of the femoral head. We can see bone cysts, we can see traumatic osteonecrosis. So these are actually quite rare, compared to those other differentials that we went through, and again, osteosarcoma being at the top of the list.
So if we have a radiograph of a limb that looks highly suspicious for a neoplastic process, I would argue that the very next thing that we want to do as soon as possible is actually get some radiographs of the lungs as well. And we definitely recommend 3 views of the thorax, so 2 laterals and, and of course a ventral dorsal projection. And very, very few dogs will have radiographically detectable metastasis at presentation.
It's only about 7% of the dogs that we see. However, those dogs have again a dismal prognosis and sort of the, the therapeutic choices that an owner make is likely to be very different in that dog with with gross pulmonary metastasis compared to a dog whose thoracic radiographs look fine. But again, an important thing to remember is that about 90% of dogs with this disease do have metastasis in their lungs.
It's just below our limited detection. It's microscopic at the time of presentation, which is why we certainly feel like local therapy alone is generally suboptimal in a case like this. So, I can usually look at a radiograph and again based on signalment, based on history, based on radiographic appearance, feel pretty comfortable about whether I think a lesion in question is osteosarcoma or not.
However, there are certainly circumstances where maybe there are some components that don't read the book quite right, or we have an owner who wants absolute certainty about, about what they're dealing with before making choices. And there, of course, some kind of sample of the lesion is totally appropriate. So this can be done through various kinds of surgical biopsies.
We will most commonly use the jam sheety bone core based technique. There are also larger samples that can be obtained either from an open surgical biopsy with curettes or ranjus, and an instrument called a Michelereine, which is actually quite large. It looks kind of like a drywall saw that you can actually use to get very, very large cores of tissue out of there.
But really in the last 5 years or so, we've moved towards doing cytology as our first line of defence when we are trying to sort of confirm a diagnosis of osteosarcoma. So this can be done either with radiographic guidance or with ultrasound guidance, especially if you have a very, very firm or a lesion that doesn't have a lot of bony destruction. Sometimes ultrasound can be very useful to find a soft spot in the bone into which a needle can be guided.
And often we'll be able to get a diagnosis of mesenchomal neoplasia or sarcoma with a fine needle aspirate, but they may not be able to say for certain whether it's an osteosarcoma versus some other kind of sarcoma. And that's actually where alkaline phosphatase staining can be very useful. So this is a cytochemical stain that can be performed on the aspirates that have already been obtained and even already been stained, that can potentially confirm that diagnosis.
One of the helpful hints when we're talking about sampling these bony lesions, that's actually very different from how we're trained when we're talking about getting samples from most other kinds of neoplasia, is we wanna aim actually for the dead centre of the radiographic lesion. When we're talking about sampling an osteosarcoma, whether it's worth via biopsy or whether it's via cytology. And that's because actually the periphery of these lesions are often really primarily made up of reactive bone.
And as a result, again, if that's what's sampled, we're likely to get back a diagnosis that's simply reactive bone or something like that. So again, the exception to the rule, we really do wanna shoot for that dead centre of the lesion. I do usually forewarn owners about a couple of things when we're doing a surgical biopsy just so that they're aware.
So one of them is certainly increased pain, so we may wanna, in addition to warning the owners about that, increase our analgesia, which we'll talk about in a minute. So, there's a very, very, very small risk of inducing a pathologic fracture from a biopsy. I think that risk is considerably less than 1%.
But it is not zero, and it is certainly worth something that's something to bring up to the owner. And then there's between a 7 and 10% chance of a non-diagnostic biopsy, and that's very important for the owner to know about. So it doesn't seem to matter which technique is used or the, the skill of the operator.
It's just one of those dumb luck things. So one time out of 10 or so, the small number of cells that we sample, whether it's via biopsy or via cytology, simply are not representative of the disease process. So these pieces of information, talking to the owner about them ahead of time can actually be very, very helpful and help avoid any hard feelings or, or complications or misgivings after the procedure.
So as far as treatment of osteosarcoma goes, really there are two issues that we need to find a way to deal with. And one of them is usually the factor that brings the dog in in the first place, which is, which is the fact that they have a painful limb, they're lame, they're uncomfortable in certain circumstances, and they might not be sleeping well, they might not be eating well, etc. So dealing with that local disease is certainly problem #1, and then problem number 2 is dealing with the potential for metastasis.
So as far as dealing with the local disease goes, there's actually a number of different options that we'll talk about, but certainly the simplest thing that we can probably offer is some kind of symptomatic pain management. And that can come in a lot of different flavours. So we'll usually start with an NSAID of of some type.
I don't think the choice of NSAID really makes a lot of difference, so you can use your favourite. Some people are very fond of opiates, so, in previous lifetimes, we used to use a lot of tramadol, but again, there is accumulating evidence that it may not be a particularly good analgesic in dogs. So more recently, we've actually moved to using a lot of gabapentin as our second line treatment after NSAIDs.
We also found The mantadine to be useful in some dogs as well. And then we can use paracetamol with codeine, things like that as well as necessary. Usually by the time we're in the, in the kind of territory where we'd be talking about owners, about fentanyl patches, we're also seriously having talks about quality of life and euthanasia.
And then we also have a nice tool in our armamentarium called the bisphosphonate drugs, which I'll talk about sort of toward the end of the talk as another palliative option to consider. Really, I would argue that in the vast majority of dogs with osteosarcoma, the best local treatment that we can offer is amputation. And this is something that we actually do quite commonly, even in here at Colorado State University, where we've sort of pioneered all these alternatives to amputation.
We actually spend most of our time trying to talk owners into the procedure because it's so well tolerated and quick and comparatively cheap and easy. However, an important thing to really be aware of for owners to know is that amputation alone. It is generally associated with disease control for an average of about 4 months.
And the reason that they run into problems is again as a result of lung metastasis. So it's a wonderful palliative measure. The pain control is instantaneous, and it does not come back in that affected leg, obviously, but again, we are talking about short term gains when it's used as a single modality by itself, and that's obviously very important information for the owners to have.
I, I kinda like to highlight this picture. This was actually one day, at the clinic back when I was a, a resident at University of Wisconsin-Madison. Where we had 123456 amputees that all came in on the same day.
But actually one of the major things that I think is an important take home for this is that you can see we've got relatively small dogs. We've got large and giant breed dogs. We've got front legs, we've got back legs.
We've got some dogs that are very, very skinny. We some got some dogs that are a little bit heavier, and really all of these dogs are very, very good candidates for amputation, and again, In a consult that I do for osteosarcoma with an owner, I would probably say a third of that entire consult is trying to dispel some of the myths that owners may have about amputation and how their dogs are gonna do. And really it's, it's quite remarkable how well most of these dogs do, in fact, get along with three legs.
So as I mentioned, however, really local therapy is only part of the story. And really what we need to do in order to do best for our patients is to combine that with some kind of additional medical therapy to see if we can address that microscopic disease that's all too present in the lungs of these patients. And really I think at this stage, the closest thing that we have to a standard of care for this disease.
It's probably the drug carboplatin. So prior to carboplatin, there was another related drug called cisplatin that was used quite commonly and actually worked very well, but it was really unpleasant to give both for the patient and for the technicians. So carbo actually became quite inexpensive a few years ago, and now it's really become an excellent substitute.
So generally we give a dose of carboplatin every 3 weeks for between 4 and 6 treatments. And, and I'll show you a little bit of details about 4 versus 6 in just a second. So here's a study that Doctor Phil Bergman did now 25 years ago, comparing carboplatin and cisplatin and actually showing that the outcomes are relatively similar.
And again, an important thing to keep in mind here is if you sort of draw a little imaginary line over from this 50% survival mark, you can see you're looking at median survival times in the neighbourhood of about 325 days with the addition of carboplatin. So that's almost 3 times as long. As patients who receive amputation by itself.
So it really does seem to make quite a significant difference in the outcome in these patients. Another drugs that's been studied for the postoperative use in these patients is doxorubicin, which, as most of you know, we use for all kinds of neoplastic diseases in veterinary medicine. And there's a little bit of, of kind of confusing information out there about doxorubicin.
So the very first study that was looked at was actually in 1978 and reported very, very Little to no activity with doxorubicin. But then two subsequent studies you can see here in 1995 and 2007, actually reported outcomes that were considerably better than amputation alone, but, you know, at least in one of them, perhaps not quite as good as what's been reported with carboplatin. So I think the take home with these two more contemporary studies does do suggest that Doxorubicin probably does have some benefit.
So if we're in a situation where for one reason or another carboplatin can't be given, I do think that doxorubicin is probably an appropriate substitute to consider. So a study that Doctor Laura Selnick, who is one of our surgical oncology fellows here at Colorado State, performed, actually looked at about 470 dogs who had been treated here at Colorado State University for osteosarcoma with a combination of amputation and some kind of injectable chemotherapy. And here you can see how this data broke down.
So there were 4 different 5 different protocols that were looked at. So carboplatinx 4, carboplatin x 6, alternating carboplatin and doxorubicin, doxorubicin every 2 weeks, and doxorubicin every 3 weeks. And statistically, there was no difference between these groups in terms of their outcomes.
But what you can see is numerically it actually appeared that the dogs who received alternating carboplatin and doxorubicin might have done slightly better than those dogs that received some of the other protocols. But again, keep in mind. There was no statistical difference here.
And again, we really remain fans of, of carboplatin x 6 in our patients at this point. Again, numerically, ever so slightly better than carboplatin x 4, and that really allows us to consider doxorubicin later if necessary, and we'll talk about that in a moment. So I just talked a lot about median survival time.
So we have a median survival time of 4 months with surgery alone, median survival time a little less than a year with surgery plus chemotherapy. Obviously, the way that we establish these medians and the way that I explained them to owners is that half of the dogs do better than the median. Mark and half don't do that well.
And obviously, it's impossible for us to look at an individual dog and know for certain which side of the average mark they're going to fall. But there are a few things that we can use that do help us to make it a little bit of an educated guess about what side of the average mark a dog might fall on. And really, the big three that are very easy to, to apply in practise are serum alkaline phosphatase.
So when we do our sort of routine pre-surgical blood work, we get alkaline phosphatase on that chemistry profile and actually about 1 in 7 with osteosarcoma does have an elevation in their alkaline phosphatase, and those dogs as a group tend to have outcomes that are significantly worse than those dogs who have a normal alkaline phosphatase. Another that's actually been shown in multiple studies is a location at the proximal humerus. So as a group, dogs with proximal humeral osteosarcomas do tend to also fall on the short side of the average mark.
And the last one that's quite interesting that again you get for free on your blood work is monocyte numbers actually. So it appears that dogs that have more than kind of the average number of monocytes, and the cutoff we generally use is 0.4 times 103 per microliter.
So dogs that have more than 0.4 monocytes as a group tend not to do as well as dogs that have less than 0.4 monocytes.
And this holds true for both disease-free percentage and overall survival. So, what do we think is going on here? We actually think that these monocytes, when they're floating around in the blood, are actually called into the tumour, and they become tumour associated macrophages.
And this particular kind of macrophage actually supports and promotes tumour growth and metastasis. So the more of them there are floating around in the blood, the more of them have the potential to get into the tumour and again promote this aggressive behaviour. So as I mentioned, we, we do try very hard to talk owners into amputation.
But there are some honest to God contraindications. So, severe and progressive neurologic disease, severe orthopaedic disease. So we're not talking about some, some degenerative joint disease in their hips, or even a prior cruciate rupture if it's been repaired, but really, really severe orthopaedic disease.
I guess I put morbid obesity on the list as well. One might think that prior amputation of another limb is a complete showstopper, but I have seen a couple of two-legged dogs in my career that have actually done very well. And then again, of course, the owners just not being able to wrap their brains around the concept of a three-legged dog is another one that would need to be sort of considered at some point as well too.
And thankfully, there are some alternatives to amputation that we do discuss with owners if a dog falls into one of these situations. And so one of them, which was really pioneered here at Colorado State University, is what's called a surgical limb salvage procedure. And this is really something that only works at the at the distal radial site.
And the way this procedure works is actually the diseased bone is actually removed surgically, and it's replaced with either an allograft, so a bone from a cadaver dog, or a metal spacer, and these are available commercially. And then, the carpal joint is fused, and you can see one or sometimes two giant plates are actually put that actually span that joint. And this is actually a procedure that's, that's quite successful and procedures like this are actually the standard of care in humans with osteosarcoma thanks in part to the work that, that's Dr.
Withroe did here in dogs back in the 80s and 90s. But Some things to keep in mind are some caveats. So this is a very, very expensive procedure.
So here at CSU we're generally looking at 7000 to $9000 US. It's a procedure that does require an enormous amount of expertise. So this is not a procedure that's going to take place in general practises.
This is not a procedure that most surgical or orthopaedic specialists will have ever performed. So this is really something that's limited almost exclusively to fellowship trained surgical oncologists. And the complication rate is actually extremely high.
It's north of 70%. And again, the big complications that we can see from this procedure include bacterial infection, local recurrence, and hardware complications as well. Infection is by far and away the most common complication that we see, so more than half of the dogs will actually develop a chronic smouldering bacterial osteomyelitis at the site where this limb spare is performed.
But a very interesting observation that one of our former fellows made is that if in fact we have a dog who develops a post-surgical osteomyelitis, they live twice as long as if they don't. And this is actually not a result of of Any kind of prevention of local recurrence or anything else like that, metastasis is actually prevented in these patients, which is really quite remarkable. And this is just a quick, a quick slide to show you that actually the same thing seems to be true in humans as well.
So the incidence of postoperative bacterial osteomyelitis is much lower, but the effect on outcome and at least in this one study is exactly the same. And we actually were able to here at CSU model this in mice as well. So if you give mice bacterial osteomyelitis and then grow tumours on them, you can see significant reduction in osteosarcoma growth as well.
And it really seems like this is dependent upon monocytes, macrophages and NK cells. So if you took those cells out, actually, you lose the, the beneficial effect of the bacteria. So it seems like it's a stimulation of innate immunity that, that is responsible for this.
So again then a question I suppose becomes, well, is there a way that I can utilise this information in my practise? So, should I be purposefully infecting all of my patients with bacteria in order to sort of get this, this improved survival outcome? Well, I certainly wouldn't sort of Advocate for that at this point.
But there are some, some approaches that are being looked at or have been looked at that almost do that. And actually, one of them was this. This is a drug that was called LMTPPE, which is actually a synthetic bacterial cell wall product that was looked at in dogs for the prevention of metastasis for, for quite a long time back at University of Wisconsin.
And this is really the culmination of, you know, kind of 10 years of work on this slide. So you can see dogs that receive amputation alone are here, median survival time around 4 months. Dogs that receive either cisplatin or MTP have median survival times around a year.
Dogs that receive cisplatin followed by MTP have a median survival time of around 18 months. So significant prolongation and survival. So MTP is not available in the US for the treatment of dogs or humans.
It actually is available in the EU for the treatment of humans with osteosarcoma. It's sold under the brand name Mepack, and it is frightfully expensive, so it probably be, I, I think one reference I dug out suggested 40 to 60,000 pounds to treat a single dog. So not something that that most owners are going to be able to afford unfortunately.
So, another alternative to amputation that we can discuss that's actually much more readily available is what's called palliative radiation therapy. So this is a form of radiation therapy that really any, any specialty practise with a radiation machine is able to deliver. So obviously, the local practises won't have radiation at all, but if you work close to a referral practise, That has any kind of radiation, they can offer this form of radiation therapy.
So, fairly high but safe doses of radiation are delivered in kind of an indiscriminate fashion, relatively infrequently, and again, doesn't require any special CT scans or computers to, to do the planning or anything else. And it's somewhere between 1 and 4. Daily or weekly treatments depending on how it's done.
It's relatively inexpensive, at least here in the States, and 75 to 90% of dogs will experience significant improvement in their comfort level following this radiation therapy, which lasts for a median of 2 to 4 months. This can be repeated if pain recurs, but there is an evidence of a pathologic fracture, although it may not be as effective the second time around. Something that we and others have been exploring more recently is a technique called stereotactic radiation therapy, which actually involves the delivery of very, very high doses of radiation in an exquisitely targeted fashion to the tumour, while avoiding damage to the normal tissues in the area.
And again, down here when we're talking about an osteosarcoma in a limb, the normal tissues we worry the most about are, of course, the skin in the region. And again, this is a heat a colour wash heat map. So you can see red is the highest doses of radiation that are being delivered very specifically to the tumour, and blue is actually the skin, which is getting a very, very low dose.
So, it's possible that getting these larger doses of radiation, in addition to providing pain control, can actually kill the majority of tumour cells that are down there, can have a better analgesic effect. And actually, there's some evidence to suggest that the very, very rapid cell kill that can occur with stereotactic radiation therapy could also stimulate the immune system and that, of course, has benefits for potentially systemic tumour control as well. Another advantage of this procedure over a surgical limb spare is that actually there's very, very low risk of infection and any anatomic site can be targeted.
It's not relegated to only, for example, the the distal radius. Any of the appendicular sites and most axial sites of occurrence. Can be targeted using stereotactic radiation therapy.
So, at least at CSU the way this procedure is generally done is that a CT scan is acquired of the limb, and then the images from that CT scan are actually put into the planning computer to aid the radiation oncologist in designing the plan. So again, very high doses are administered to the tumour but not to the surrounding tissue. That generally takes 24 to 48 hours.
And then 3 doses of radiation therapy are then generally administered on consecutive days, weekdays, that is. We'll generally give a dose of zoledronate, which I'll mention in a second, either at the time of or before the first treatment, and then carboplatin is given with the one of the 1st 3 treatments as well. And then they go on to get more carboplatin afterwards.
So very, very recently, just within the last month or two, the group here at Colorado State University wrote up the 1st 123 dogs that have been treated with stereotactic radiation therapy, and the likelihood of good lameness control is about 84%, and this persists for a median of about 6 months or so. The fracture rate was 40% in this group of patients, and part of that probably has to do with again the devitalization of the bone in the area. Part of it probably has to do with the, the really profound improvement in lameness that these dogs have.
So they no longer favour that limb, and as a result, again, increased activity may be increased risk of fracture, and when combined with chemotherapy, the means survival time is about 8 months or so. The biggest prognostic factor for outcome was the size of the primary tumour. So the bigger the primary tumour was, the lower the survival time.
Smaller primary tumours were associated with better survival time. So, what about this 41% fracture rate? Is there anything that we could do to potentially mitigate that?
Yes, in fact. So one of the things that's been learned is that the degree of cortical lysis of the bone on CT scan is actually very predictive of fracture. So, the best, candidates for this procedure are those that actually have relatively minimal cortical lysis on their CT scan.
And again, we can take a look at the CT scans and potentially either steer owners away from stereotactic radiation therapy as an option, or at least make sure that they're adequately informed about the risk based on how those radiographs and CT look. So after our, our local therapy and whatever form that's going to be is done after our chemotherapy is finished, what do we do then? So generally, we like to recheck these dogs every 2 to 3 months for good physical examination, potentially lameness examination, go over for new lumps and bumps, a set of chest X-rays, and if we're doing some, one of these limb sparing procedures, we would certainly get limb radiographs on those rechecks as well.
So why do we do that? Why do we want to look so carefully at these dogs after The the sort of definitive therapy is complete. Is there more stuff we can do?
Yes, in fact, there is more stuff that we can do. So one of the possibilities is surgery. So if in fact we do see a dog who develops lung metastasis, there are certain dogs that are actually very good candidates for, for surgery to remove those metastases.
And the dogs that are the best candidates for this are dogs whose tumours have been controlled for a reasonable amount of time, and, and normally our cutoff is about 10 months since we've treated their primary tumour. They need to have a manageable number of metastases and for us, that's usually no more than 2 or 3. And a slow rate of progression.
So how do we measure the rate of progression? This sounds strange, but actually what we generally do is, if we have a dog who comes in for a routine recheck, and we see pulmonary nodules on their radiograph, if metastasectomy is a possibility, the first thing we'll do is send them home for a month. And then just simply repeat those radiographs and ask, well, how, how much has the disease changed?
And if change has been fairly minimal, we would definitely consider that dog a good candidate. But what we're trying to pick out are those cases where what we saw the month earlier was just the tip of the iceberg, and now a month later, their thorax has just exploded with metastasis. And those dogs obviously would not have benefited from from any kind of surgical intervention.
And again, with proper case selection, median survival time is about 6 months with surgery alone, which is, you know, a fairly substantial percentage of what their initial disease-free period probably was. So this is with surgery alone. We would quite commonly recommend additional postoperative chemotherapy in these patients, and generally a different agent.
So if they started with carboplatin, we would think about doxorubicin after surgery. They started with doxorubicin, we would think about carboplatin, etc. What about medical therapy?
So there medical therapy options for managing pulmonary metastatic disease that's big enough that we can see it? So we very rarely will see meaningful tumour shrinkage in dogs with measurable pulmonary metastatic osteosarcoma that receive conventional chemotherapy. However, there's a subset of dogs that definitely will benefit in the forms of growth arrest, so we can see their tumours stop growing.
And again, in this context, in a dog with advanced stage disease, I would consider that to be a victory. So we're very happy with stable disease as an outcome in these patients. And with that goal in mind, I won't hesitate to recommend postoperative or I'm sorry, so chemotherapy to try and control those pulmonary metastases.
Then there's a drug that most of us have probably heard of at this point called palladia. So palladia is actually approved for the treatment of mast cell tumours in dogs. However, there is accumulating evidence that it may work for some other kinds of tumour as well.
And actually one of the tumour types where there was some initial evidence of of potential activity was actually metastatic osteosarcoma. So in the initial report, which was actually kind of a low quality survey-based retrospective study, one partial response was reported and 10 out of 23 dogs had stable disease, which persisted for an average of 24 weeks, which sounded pretty good, but again, not the highest quality data. So subsequent to this publication, we actually performed a prospective study looking at Palaia by itself in dogs with metastatic osteosarcoma.
And actually in our hands, only 3 dogs out of 17 had stable disease, and the median progression free interval was only about 60 days, so it really had very little activity by itself. So when we talk about using palladia for the treatment of this disease with measurable pulmonary metastasis, generally we don't use it as a single agent. We'll talk about combining it with some other things.
And one of those is is this particular drug, this drug called losartan. So losartan is actually a blood pressure medication and it works by blocking angiotensin receptor. So that's how it works as a, as a blood pressure medication.
But it actually turns out, in the interest of time, I'll just say, it can also block monocyte migration into tumours. So I told you at the beginning, we think that monocytosis in the blood is a bad thing because these monocytes can actually get into the tumour tissues and promote tumour growth. Losartan, as sort of a byproduct activity, not its primary activity, can actually block that activity and actually keep monocytes out of tumours.
And in multiple, multiple mouse models, you can actually slow the growth and metastasis of different kinds of cancer with losartan, given to mice. And actually in dogs who have received a combination of palladia and losartan, it does appear that the likelihood of seeing meaningful tumour shrinkage is higher, and the duration of of their disease control is higher than when palladia is used by itself. So generally, we'll talk to owners about palladia plus losartan, with or without the addition of metronomic cyclophosphamide as well, when we're talking about the medical management of of .
Pulmonary metastatic disease with these oral agents. Another drug that you may have heard of, was a vaccine that was actually made from a modified live Listeria that actually we think probably worked, if it worked at all, a lot like the way that drug MTP or an infected bone works by sort of non-specifically stimulating the immune system. And this was actually a product that was available for a short period of time here in the United States for the treatment of dogs with osteosarcoma.
However, it was removed from the market as a result of several reports of the culture of live Listerial organisms out of the dogs. In some cases, many, many months after treatment was complete, and the attendant zoonotic risks that are associated with that. So it's unlikely that we will see this product resurrected in the future, unfortunately for dogs with osteosarcoma.
So the final thing that I'll mention are these bisphosphonate drugs, which again can be very, very useful as a palliative measure in some dogs with osteosarcoma. So many of you may be familiar with bisphosphonate drugs. They're most commonly used in humans actually for the treatment of postmenopausal osteoporosis, but it turns out that they can actually be very useful for the palliation of of malignant bone disease in humans.
And there has been some work looking at this class of drugs in dogs as well. So I won't spend a lot of time on this just to say that if you dump enough of these drugs into a petri dish, you can inhibit the growth of canine osteosarcoma cells, but it's really not clear whether the amounts of these drugs that are required to inhibit growth in a petri dish are achievable in dogs. So there may or may not be a direct anti-cancer effect from these drugs.
However, there is some evidence that they can definitely actually improve pain control in some dogs with osteosarcoma. So a study that's now going back about 15 years using pomidronate, which was given at the dose and schedule you see here, a 2-hour infusion at a dose of 1 to 2 milligrammes per kilo. About a third of patients had subjective improvement in their pain, and the average duration of that pain control is actually quite long.
It was in the neighbourhood of 6 or 7 months. And actually those dogs that did have pain control improved also appeared to have decreased bone destruction and actually increased bone mineral density, so perhaps a reduced risk of fracture. And oh, it's not clear, oh yeah, monthly.
So this is given monthly, it tends to be extremely well tolerated. And more recently, there's actually a newer generation more potent bisphosphonate drug called zoledronnate, which can be given, which may be better, and actually has the benefit of being able to be given as a 15 minute slow IV bolus instead of a 2 hour infusion, which actually is certainly much easier for the staff. Neither of These drugs are cytotoxic agents, so the personal protective equipment and other protective measures that are required for chemotherapy drugs are not required for this class of drugs, so they actually can be used quite safely in a general practise situation.
And again, this drug also appears to be associated with quite profound reduction in these bone turnover biomarkers and again subjective improvement in pain in, in quite a decent number of patients as well. So, we recently have been looking at a drug that's actually a combination of a bisphosphonate drug with chemotherapy. So this is actually a chemotherapy drug that is conjugated to a bisphosphonate drug, so that high doses of chemotherapy are delivered actually directly to the tumour tissue.
And this is the drug I mentioned at the very beginning, NBC 11. And here's this one particular dog where you can see really significant improvement in their lameness after the administration of NBC 11. Very profound reductions in these bone turnover biomarkers and some evidence based on, on PET imaging of very significant reductions in metabolic activity in the tumour again after administration of this drug.
And this drug has actually been through phase one clinical trials in humans with a variety of different kinds of malignant bone diseases, and Again, they saw a significant number of patients benefit both clinically and with reductions in the metabolic activities in their lesions, and we're certainly excited to see this drug continue to be developed on the human side. We're currently involved in studies looking at a next generation version of this compound with a more potent bisphosphonate and a more potent chemotherapy drug as well. And with that, I'm gonna close this session out, and this is actually very apropos for today, given how cold it is.
And I, we have just a few minutes to actually open up the floor for any questions that anyone might have, and I thank you very much for your attention. Doug, thank you so much for some fascinating insights into where osteosarcoma is going and these bisphosphonates are certainly an exciting prospect into into the future of what we can do for our patients. So thank you so much for your time.
Folks, just before we start, looking for any questions, I haven't had any come through. Just a quick reminder that we are about 10 days away from our virtual congress of 2021. The exciting news, of course, is that this year, it is a whole week long.
And, Pam is just Drop the link into the, the chat box for you to, to click on and go and have a look at it. Members are automatically registered, which is great news. And you have the potential of 100 hours of CPD in that week.
So it really is a fantastic, event to be looking forward to and I'm very honoured to, to be able to say that I am part of that and I will be chairing some of the sessions of it, but 100 hours in a week, that is absolutely fantastic. And there's gonna be loads and loads of stuff that you can pick and choose from, lots of different streams that you can have a look at and, and see what interests yourself. Doug, the, one of the interesting things that you were talking about in my mind is, is this whole thing of big heavy dogs with amputations.
And that is something that we've always kind of been told to, shy away from, as it were, because especially if it's a front leg, yet you seem to be having good success with this. Yeah, we certainly do. As I mentioned, we, we tend to offer amputation for all shapes and sizes of dogs.
My, again, our, our former director and my former mentor Steve Withrow used to say if, if they're walking well on four legs, they're probably gonna walk just fine on 3. And really, really, that is quite true. There's actually a UK based study that was done maybe 15 years ago or so, a survey of, of owners of canine amputees that actually looked at quality of life and owner satisfaction with the amputation procedure, and they actually found that age of the dog, size of the dog, front leg versus back leg had no impact on owner's satisfaction, and owner satisfaction ran around 93%.
So the vast majority of owners were extremely satisfied with the quality of life of their, of their dog after amputation. And again, none of those things mattered. I will say, however, and this is, this is certainly an important caveat to that is, I, I do agree that it does take the, the really big dogs who have a hind limb, or sorry, who have a front limb amputated, maybe a little bit longer to get going afterwards than the little, you know, toy poodle who's jumping around.
The evening of surgery. So that is something that we do prepare owners for. So those, those giant breed dogs, especially those that are getting a front limb amputated, certainly may require a bit more assistance for the first couple of weeks.
And one of the things that's really brilliant is the number of sort of commercial tools that are now available for that. So I don't know if you have them in the UK, but here we have these things called help them up harnesses. Which are wonderful, and they come in all different sizes and colours, and, and they can be a really wonderful resource during that immediate postoperative period, the first few weeks, while the dogs are regaining their balance and, and building up their muscle strength and things like that.
So the end result is almost always the same, but you're absolutely right. It does take a bit more time with the, with the really big dogs with the back, with the front leg. Yeah, I think that's because all your toy poodles and Chihuahuas are used to spending half their bouncing around on their backs.
That's right. Has come up with a fantastic question. Can early castration increase the incidence of osteosarcoma in large dogs?
So that's a really great question, and actually the, the data out there is is somewhat mixed. So there are some studies in certain breeds. And the first one I think that was done was Rottweilers actually that did suggest a slightly increased risk of early castration, sorry, of, of osteosarcoma in Rottweilers specifically that were castrated early.
There appears to be some information in some other breeds. I think golden retrievers is another one that's been looked at now. That may suggest the same thing, but one of the things that's very challenging about those types of epidemiological studies is they're making fairly broad pronouncements based on a very small number of cases and controls.
So it really does need to be taken with quite a, quite a bit of a grain of salt. That being said, When it comes to the castration side of the picture, I think there are very few downsides to waiting a bit, before castrating a, you know, before castrating a young dog. The, the ovarian hysterectomy side of the story is a bit more complicated, and I don't think I really have time to go into it.
But, with the castration thing, I think, I think there are enough potential benefits, musculoskeletal and, and potentially neoplasia prevention to say it's, it's probably worthwhile to wait a little extra. Again, not nearly so cut and dried with the girl dogs though. Yeah, yeah.
I remember that first study you were talking about, I remember reading it or first of all, hearing about it and being told there was a 50% increase in the incidence. And then when you read the study, it was because it went from 2 dogs to 3 dogs. You go, well, I guess technically that is 50% increase.
Exactly. So that's that's why it pays to the studies, right? Yeah, exactly.
Yeah, yeah. That's fantastic. Doug, that's all from our side.
It is just left up to me to thank you once again for all your time and to wish you well over the freeze that's coming shortly to you. It makes me feel a little bit bad when I say I'm feeling cold here at at sort of -7. So, but Thank you for your time and to all of the people that joined us tonight.
Thank you so much. I hope you've enjoyed tonight as much as I did, to my controller in the background, Pam, thanks for making everything happen. And folks, please don't forget to do the survey for us on the survey monkey that pops up when we close here.
It really is. Important that you realise that this is your channel. This belongs to you and it's your feedback which allows us to know what you're after and what lectures and everything else you want us to put on.
So take a little bit of time, fill in that survey, monkey, and let's hear from you. Doug, thanks again and good night to everybody. Thanks again, everyone, and enjoy the virtual congress next week.