Hello everyone, it's Anthony Chadwick from the Webinar vet, welcoming you to our 11th annual virtual congress. Who would have believed in 2013 when we had, 300 people registered that 1110 years later we would have nearly 20,000 registered. So thank you so much for registering.
Our mission has always been to make veterinary education more accessible and more affordable to vets throughout the world, and this congress is, as you know, free to attend live, but there is an option to buy the recordings either during or after the congress. But I'd like to thank, The sponsors who've made this possible as well as our own team for pulling it all together as well. Please do share on social media about the conference using the hashtag VC2023.
And let people know about it and let your friends know about it, tag them into the posts. Because it would be great if we could hit the 20,000 mark on this our 11th year, 11th annual conference. As well as oncology, which we're going to be looking at today, and thank you so much for HTE for sponsoring this particular symposium.
We'll also be looking at antibiotic stewardship, and tomorrow we're going to be looking at how we're going to regenerate the veterinary environment, how can we become more sustainable. We've also got sessions on nutrition, exotics, clean path, diagnostic imaging, anaesthesia and cardiology, so hopefully something for everybody. Let's get on with tonight.
We're very fortunate tonight to have two fantastic speakers on oncology, who I'm sure are well known to most of you. Our first talk today is going to be given by Professor Doug Than, who's going to be talking about 10 recent advances in veterinary oncology. He's gonna look at how er this is helping with some of our treatment outcomes as well.
Doug is one of our most popular speakers at the webinar best, and I've been lucky enough to get over to Colorado and every time I speak to Doug, the sun is always shining and it's always 70 degrees. Well, he tells me today it's a bit dull and not quite so warm, so I'm sorry for that, Doug, but, really looking forward to Doug's presentation. Doug is, as I said, the professor of oncology at CSU.
In fact, it's the Barbara Cox Anthony professorship. Doug has published widely in the area of veterinary oncology. He's had over 150 peer reviewed articles, 20 book chapters, and he is co-editor of the journal Veterinary and Comparative Oncology.
Doug, I'm really looking forward to your talk as always and over to you. Great. Thanks so much, Anthony.
It's really great to be here as always. I realised that, I think the last time I actually gave a top 10 list talk for the webinar that was around 10 years ago. So not only is it 10 recent advances, but it's 10 years since the last one, which seems very fitting.
So I think without further ado, we will go ahead and get started with these 10 things that I think are are worth. Having all of our listeners sort of keep in mind, either for things that may be available as we speak, or things that may be available in the very near future. Very quick, conflict of interest disclosure, the things that you can see in red there are things that I will be mentioning very briefly today.
So just keep in mind, about what, what you're seeing there. So here are the 10 things that I think we'll try and cover this evening. So we'll do a brief update on receptor tyrosine kinase inhibitors.
This is actually a topic I covered 10 years ago, but we certainly do have a lot more information. Then we'll talk about three new drugs that have sort of varying degrees of regulatory approval in different parts of the world. We'll do another update on stereotactic radiation therapy.
We'll talk about, something that's actually very, very exciting and has revolutionised cancer therapy on the human side, called immune checkpoint inhibitors, which will be coming to a veterinary clinic near you quite soon, I think. And then we'll briefly touch on a few things that are a bit more controversial, including two alternative or complementary or herbal products that are seeing an enormous amount of use, at least here in the states. We'll talk about a new concept called personalised medicine and, and the potential issues with that, and then talk about some new blood-based cancer diagnostics that are coming online.
I think we'll have time to just chat about one of those in the interest of time. So, for starters, let's just do a little bit of a review of, of the receptor tyrosine kinase inhibitors that are currently available, which in the UK include palladia and Massib. So I think for a very long period of time, sort of coming up on more than 10 years, we've all been very familiar that latia and massive that do have activity as single agents for the management of canine mast cell tumours, and this is due to the activity that they have.
Against a receptor tyrosine kinase called CIT, which is a protein that sits on the surface of the cell and signals into the cell and helps to direct cell activity. But one of the things that has been very obvious for quite a long time is that both of these drugs actually have targets other than kit. And what we've learned in the last 10 years is actually that there may be quite a bit of activity in other kinds of cancer, especially with palladia, that may be mediated at least in part through.
Inhibition of signalling through these other receptors. And again, the two that you see listed there, Vega receptor 2 and PDGF receptor, are actually both very, very important for the growth and maintenance of new blood vessels. And as a result, some of the activity that we see in these non-mast cell tumour targets may actually have to do with the inhibition of blood vessel vessel growth, which is necessary to provide nutrients and oxygen to tumours, of course.
So what do we know now that we didn't know 10 years ago? Let's just go through some of the recent data. So one of the things that that I just mentioned is actually there's quite a few papers in the peer reviewed literature and again all these references, I think, you know, these references are not in your proceedings, but again, there's a large number of tumour types where we now have evidence of anti-tumor effects, and these include a variety of different kinds of carcinomas, insulinomas, and gastrointestinal stromal tumours, again, among, among quite a few others, and this is obviously very exciting.
So what does this anti-tumor activity look like and, and how does it compare to what's observed in dogs with mast cell disease? So it is a bit different, actually. The response rates that we generally see in most of these non-mass cell tumour indications are quite a bit lower than what is seen with mass cell disease.
So with mass cell disease, we generally quote response rates in the neighbourhood of about 40% or so. Those are more like in the 20% range from most of these other indications and what you're seeing here on the right is just a dog with a just huge metastatic lymph nodes from the, from an anal sac tumour that's actually had quite a nice response to palladium. A more common outcome and an outcome that we would actually consider to be quite acceptable in these patients with advanced disease from a drug like peladia would be stabilisation of the disease.
So, if we think that seeing actually meaningful tumour shrinkage is the best thing, certainly we think that being able to administer a pill at home and make the tumour stop growing is a very acceptable alternative. And the average amount of time that this disease stabilisation occurs for, if it occurs, is actually variable from patient to patient and and tumour type to tumour type, but I think a reasonable expectation might be something in the neighbourhood of 4 to 6 months of control on average. In some cases it can be quite longer than that.
In some cases it's considerably shorter. One of the other things that's changed is that the early studies with palladia for non-mast cell tumour indications really suggested that there may be a role for this drug for the treatment of metastatic osteosarcoma in dogs, and this was based on kind of a, a, a fairly poor quality survey-based retrospective study that was performed. But two subsequent studies, one which was a prospective study and one which was another retrospective, really suggested there was very, very, very little activity of palladia when it's used by itself for metastatic osteosarcoma.
However, there's a paper that just came out earlier, or early last year that combined palladia with a blood pressure medication called losartan. And losartan's been used for a very, very long time in both humans and to a lesser extent in dogs for blood pressure management. But it turns out that very high doses of losartan, about 10 times the dose that you would find in a veterinary formulary, are associated not only with blood pressure control if necessary, but inhibition of monocyte migration, and monocytes are generally immunosuppressive and very tumour promoting.
So if you can keep them out of the tumour. You may have an anti-tumor effect, you may have an immunomodulatory effect, and when combined with palladia, actually, it appears to be much more effective than palladia by itself and actually very, very well tolerated. Despite these very high doses of a, of a, of a blood pressure medication, we don't tend to see a lot of issues with hypotension.
So an interesting combination that is continuing to be looked at, here at Colorado State University, and elsewhere. One of the other things that's changed in the past 10 years is that we've learned a lot more about the safety and efficacy of palladia in cats. And you can see there have been a large number of papers published recently looking at the safety of palladia in cats and several studies that have tried to look at the efficacy for varying diseases as well.
From a safety perspective, actually this is actually quite a good drug. It appears to be better tolerated in cats, if anything, than in dogs, which is very exciting, but that really the only disease where there's really solid evidence of anti-tumor effects is mass cell neoplasia in cats. And actually the response rates in cats do appear to be perhaps a little bit higher than what's been observed in dogs, again, about 70% or so.
And I think the durability is probably similar to what's reported in dogs. Generally responses last an average of 4 to 6 months. So much like on the dog side, it's certainly not something that is a substitute for surgery.
It's not a cure, but it's an incredibly useful tool in our arsenal, and again, it does appear to be quite well tolerated in most cats. We also learned a lot more about using palladia in combination with other medications, and intuitively we would think that this is something that could be beneficial because palladia and these other medications work in such different ways. And in fact that really seems to be the case that because they work in different ways, for the most part, combinations appear to be relatively safe and well tolerated.
However, it's important to know that some dosage reductions of the conventional chemotherapy does seem to be important, and the reason for that is because of additive neutropenia when Palladius combined with other myelosuppressive chemotherapy drugs like the ones you see listed here. One really interesting combination is this combination of palladia and viblastin, both of which appear to have efficacy by themselves, and in combination may have superior efficacy to either agent alone based on a couple of small studies that have been reported, which is quite interesting. Another thing that's been looked at recently is this combination of palliative radiation therapy, so just once a week outpatient radiation therapy doesn't require any sophisticated treatment planning, and palladia, and this is actually quite an efficacious combination with response rates in the neighbourhood of about 80% or so and median progression free intervals around 10.5 months.
So this is now our sort of treatment of choice for locally advanced unresectable mast cell disease in dogs, because again it's very well tolerated and actually appears to be relatively efficacious in this high risk population. There's a very, very recent study from this institution actually that came out last year that suggests that one possible exception to the good tolerability might be if a significant amount of abdomen, abdomen is actually in the radiation field. So it appears that there may be an enhancement of radiation therapy adverse effects in the case of abdominal radiation.
And the other part of the body appears to be fine, but again, you may need to be a bit more judicious with your radiation dosing if there's a lot of abdomen in the radiation field. There's also some work that's been done looking at combining palladium with metronomic chemotherapy, in this case, cyclophosphamide, and both drugs appear to be very well tolerated if they're used at the full doses, and there's some evidence of additive effects on the immune system if both of them are used together. So that's something that's worth considering as well.
One of the real gaps that remains in our knowledge is how efficacious drugs like palladia or masia that are when they're used in the post-operative setting, either in high risk tumours to try and delay or prevent metastasis, or in in completely resected tumours to try and delay or prevent recurrence. We really still have a big hole in our knowledge as far as what we can tell owners about their efficacy in that context. So for that reason, I tend to generally not utilise these agents in the postoperative setting.
It's not because they, I don't think they work. It's simply because we really don't have a good idea about how well they work that we can communicate to an owner. And furthermore, we don't really have a good idea about how long to use them for.
Palladia has been looked at postoperatively in some non-mast cell tumour cancers, including osteosarcoma and hemangiosarcoma, and the data from both of those studies was actually negative, so it did not appear that the addition of palladia to conventional surgery and chemotherapy improved the outcome in either of those two diseases, unfortunately. This is a piece of information that's the subject of quite a bit of debate. So should I be doing sophisticated genetic testing on the tumour before I decide whether to use palladia or massive?
So, interestingly, my opinion is that the answer to this question is different depending on the drug. So for palladia, I would argue that the bulk of the data does not suggest That kid mutation status can be utilised to predict who's going to benefit from palladia and who is not, and this is based on actually several prospective studies that fail to, that have failed to suggest that there is an improved outcome in dogs whose tumours actually have an activating mutation in kit. In fact, in some of the studies, it's been rather the opposite.
So in other words, kit mutant tumours do worse with palladium. The opposite, however, may be true with Massive in that there seems to be the biggest difference in outcome in those dogs whose tumours do possess an activating mutation in kit. So why the difference?
These are different drugs. They interact with the with the kit protein in different ways and actually massive that was specifically designed to target mutated kit protein, whereas palladia wasn't. So I think depending on the drug that you're planning on using, doing this kid mutation testing could be valuable, could not.
So complicated, but but I think that's really where the, the state of, of kid mutation testing is in this particular context for trying to pick a drug. So we're gonna move on here. And next, very, very briefly, we're gonna talk about a new tool that we have in the US that has conditional approval from the, the US Federal Food and Drug Administration called Leverdia.
So Levertia is a very interesting drug. And it works in an incredibly cool way by inhibiting a protein called exporting one. And as this little cartoon describes, exporting one is a protein that sits on the nuclear membrane, and whose job is actually to pump proteins from the nucleus out into the cytoplasm.
It turns out that there's a large number of so-called tumour suppressor protein, again, whose jobs are to inhibit cell proliferation, inhibit other characteristics of cell malignancy that can only do their jobs if they're in the nucleus. And if they get pumped out of the nucleus, it is as if they've been inactivated through a genetic mutation or something else. They simply can't do their job, and that's a way that tumour cells can become more aggressive.
And in fact, most human tumours where it's been looked at have higher levels of export in one than normal tissues do. And for some tumours, the higher the level of export in one, actually the worse the outcome is for the patient. So a very, very, very interesting target and a drug that targets this pathway is actually approved in people for the treatment of multiple myeloma and some low grade lymphomas.
In dogs, there is some evidence of efficacy in lymphoma, and again, that's what it's currently approved for. So, the dose you can see there, it's given twice weekly as an oral medication in this group of patients, about 60 patients or so. The overall response rate was about 35%.
However, the median response duration was only around 18 days. And again, there certainly were some adverse effects that were observed using this medication. So again, this drug does have conditional approval for use in the United States, and it is a drug that is being used in some patients for, for treatment of lymphoma.
However, I have to be very honest, it's really not tremendously efficacious. I mean, I would argue that we see outcomes at least this good from corticosteroids. So, again, great concept for a drug, really interesting target.
I'm eagerly awaiting some future studies that may help us figure out how to use this drug better. So are there some other tumour types where it may be more efficacious? Can it be used safely in combination with other treatments?
Can it be used after remission has been induced as a form of maintenance therapy? I think these are all very, very interesting questions, and I'm really hopeful that some subsequent studies are going to be performed that will help us to really get a better understanding about how to utilise this drug. The next treatment that we'll mention is a drug called rabiphozidine, which is referred to in the United States as tinobia, and Tinovia has full approval in the United States for the treatment of lymphoma in dogs.
This is a drug that I know, can be obtained through special licences on an individual, one-off case by case basis in the UK. I certainly have colleagues who have done that before, but again, you can't order a large stock of it and keep it on your shelf. You know, for when the next lymphoma patient comes in, that I'm aware of.
So, this is what's called a false nucleotide. So it's a drug that looks a lot like the DNA base pair guanine, and when it's incorporated into DNA, it looks funny, so that when the replication machinery comes by, it actually causes strand breaks at the site where these funny looking guanines are incorporated. And this particular drug.
Is actually a pro-drug, and it turns out that lymphocytes have the machinery that's necessary to convert the pro-drug into the active form more so than most other cells in the body, and rapidly dividing lymphocytes, for example, those that are in lymphoma incorporate more of the drug because they're dividing rapidly, and that's where a therapeutic index comes into play for lymphoma in dogs. So it's given as a 1 mg per kg IV infusion over 30 minutes. We try very hard not to give it faster or slower than that, and it's given just once every 3 weeks.
And if things go well, we plan to do 5 of those treatments and then quit and monitor those patients. So Tannovia can be associated with some adverse effects. Gastrointestinal effects, like we sometimes see from other chemotherapy drugs are most common.
Neutropenia is rare, but it can occur, and there are a couple of more unique adverse effects that are observed, including a cumulative dermatopathy. So it doesn't occur after a single dose, but after several doses we can start to see some hair loss, erythema, etc. And a very small percentage of dogs can experience a delayed, presumed idiosyncratic pulmonary fibrosis, and that can be fatal.
So in a small in all of the studies that have been done in over 600 patients, the incidence appears to be about 4%. About half of those cases appear to be associated with fatality. The other half either are were a radiographic finding only or an nerosy finding only, but still something that owners definitely do need to be aware of.
So there have been a lot of studies performed using this agent that have been published in the peer reviewed literature. I'm not going to read them off to you, but again, you can find most of these in PubMed very, very easily. I am going to highlight just a couple that, you know, are of particular interest.
One of the ones that we'll talk about is the registration trial that was performed recently for Tannovia in the United States that led to its full approval by the FDA. In this study, dogs were randomised on a 1 to 3 basis to receive either tenovia or placebo. And then as soon as they developed the criteria for progressive disease, which is, you know, fairly minimal increase in size of the lymph nodes, they were able to be removed from the study and receive any other therapy that the owners wanted to pursue.
So ethic, a very ethical study design, but as you can see, the primary endpoint which was progression free interval was met, and the dogs receiving actual tinovia did about 4 times better than the dogs that received placebo. Looking at objective response rate, the objective response rate in the Tenoia treated dogs was about 75% versus about 5% in the dogs that were treated with placebo. So, that was an all comer study that actually looked at dogs with B cell lymphoma, T-cell lymphoma, dogs that were very heavily pre-treated, dogs that had had no previous treatment.
One of the groups of dogs that has been studied a bit more intensively for this particular medication is a group of dogs with a B cell lymphoma specifically that have failed one previous line of therapy. In this group of dogs, Tannovia appears to be a very, very active drug with objective response rates in the neighbourhood of about 75% and median response durations in those dogs that experience a response of about 6 months. And I would argue that this actually compares very favourably to most of the other rescue drugs that have been looked at.
And this is the context in which we at here at Colorado State tend to useadia or sorry, Tannovia the most frequently. Is in that first relapse setting in dogs with B cell lymphoma. Another very interesting indication that's been explored, however, is looking at a combination of tannovia.
And doxorubicin, given in an alternating fashion once every 3 weeks. So they come in, they get tanovia. 3 weeks later they come in and they get doxorubicin.
3 weeks after that, they get more tinovia, etc. Until 3 of each drug is given. And actually, quite interestingly, the data that's been generated now in 2 independent studies looking at this alternating combination.
Suggests outcomes that are really quite comparable to what's been reported with chop-based chemotherapy. So this is interesting and potentially very useful for those owners, for whom the number of visits is a major limiting factor in being able to pursue therapy. So again, with this particular protocol, you're looking at a total of 6 treatments versus something in the neighbourhood of 12 to 16 treatments with a conventional top-based chemotherapy protocol.
And I think Owen may get into more details about Chopp chemotherapy in the next hour. So I'm gonna kind of leave it here for now, and just say something to think about. We're certainly hopeful that this is a drug that may become more widely available elsewhere, sort of, North America in the not too distant future.
So the newest kind of drug in our arsenal that's different is this drug called tilinol tiglate, which is also called Stelfanta, and selfanta is approved actually both in the UK and the rest of the EU. So this is an injectable medication that's actually derived from the seed of an Australian rainforest plant, and its approval is actually for the intralesional treatment of canine mast cell tumours. And it's actually quite interesting.
So, again, it's approved by the EMA and it's also approved by the VMD, the FDA, the Veterinary Medicines Authority in Australia and Swiss Medic as well, so fairly broad, approval around the EU. So the indication, at least in the United States, is for cutaneous mast cell tumours anywhere on the body and subcutaneous mast cell tumours below the elbow or hock. They could be of any grades, but they need to be non-metastatic, and they need to have a total tumour volume of less than 10 cubic centimetres.
And there's a special formula that the drug manufacturer cubiotics has people use, which is indicated on their website. And the reason for this is very, very large tumours, the amount of material that needs to be, needs to be injected may be associated with systemic adverse effects, and the larger the tumour is, the larger the giant hole that you'll see occur on the dog, which we'll get to in the next slide. So again, this is a drug that works effectively by licing the tumour and what you're left with is a crater where the tumour used to be.
So, a full thickness ulcer. Develops at the site, that's the injection occurred. And one of the things that's actually quite remarkable about this drug is how well, these lesions tend to heal with no intervention.
So very contrary to everything we've all learned about wound management, the manufacturer is very adamant that these wounds not be debrided, that these dogs do not go on antibiotics, that the wounds not be bandaged, and hold on to your hats, that these dogs not wear an Elizabethan collar and actually be allowed to lick the, lesion. So a little bit of auto debridement. And despite all of these very counterintuitive strategies, the majority of these lesions heal up quite remarkably well.
However, there certainly are some exceptions to that which we'll get into. So how well does this drug work? So in the, randomised placebo-controlled study that's been performed with Taelenol tgney.
The overall response rate is about 75% after a single injection. Again, compared to a couple of partial responses in dogs that receive placebo. And when you follow those dogs out for a year, about 90% of those dogs, are remain disease-free at the 1 year mark.
So if you sort of multiply those two numbers together, it gives you about a 2/3 likelihood of being able to do a single injection, have a complete regression of the lesion that persists for at least A year? We don't know what happens beyond a year just because the studies haven't been done to look at that. So as far as adverse effects goes, wound formation at the site, of course, is very, very common because that's the way the drug works, and there can be associated injection site pain and lameness that's associated with it.
Those are the most common adverse effects that are seen and that are significantly different from what was observed in placebo group. Another interesting thing is this is a drug that is being looked at for some other indications, including some other canine tumours, and actually has been looked at for some equine tumours as well. So there's one initial study that's just looked at two horses, one with a squamous cell carcinoma and one with a sarcoid, I believe, and in both of these horses, again, there was quite a nice response that was observed.
Anecdotal experience suggests that horses may have more systemic adverse effects from this drug than, than dogs do, so some additional medication is necessary, and I certainly in the interest of full disclosure, do need to, to let people know that. Despite the fact that the majority of these lesions again heal up quite well after injection, there have been some catastrophic, types of ulcers that have occurred in a very, very small percentage of patients. So ulceration that sort of tracked up the limb, toward the lymph node, degloving type injuries that have occurred to distal limbs, a small, small number of which, have ended up resulting in amputation.
So the vast majority of these heal up with time. But there have been a few very serious and really inexplicable serious ulceration that have occurred. So I think this is a very interesting drug.
I do think that it will end up finding a niche for the treatment of quote unquote small tumours and tight spots, but my honest opinion is that for the majority of cases, blade excision is going to remain the standard of care and it's gonna remain much more simple. Moving on, the last time we gave this lecture, I also very briefly mentioned the concept of stereotactic radiation therapy. I do think it's worth revisiting again because again we have quite a bit more information about its efficacy, and I do know that in 2019, what I believe was the first SRT facility opened in the UK, up in Edinburgh.
So this is something that is now at least somewhat available to the owner who is willing to travel. So the idea behind stereotactic radiation therapy is to use very, very sophisticated treatment planning and immobilisation of the patient to deliver extremely high doses of radiation in a very, very focused way that allows avoidance of a lot of the sensitive tissues that may be present in the radiation field. So, for example, the skin, internal organs, brain tissue, eyes, etc.
And really this has allowed what used to take potentially 3 or 4 weeks of daily treatment to be accomplished in something like 1 to 5 daily or every day, every other day treatments. So a shorter total treatment time. A smaller number of anaesthetic episodes and, again, potentially, being able to do the radiation therapy for some tumour types that, it was very challenging to do before, abdomens, for example, brains, thoraxes, and, and, reduced incidence of adverse effects effectively.
So it's really quite, quite an exciting change. So as we mentioned, some of the advantages here are things that we talked about already an ability to treat a variety of anatomic sites where conventional radiation could be difficult, fewer anaesthetic episodes, some evidence that maybe there could be a different kind of biologic effects when radiation is delivered in this way versus with conventional fractionation. So actually very interesting idea.
This is a fancy little chart called a dose volume histogram that actually allows you to really see graphically the amount of amount of radiation that you're capable of delivering into the tumour. So the tumour is in these sort of reddish colours here and all of the tissues that you're trying to avoid the skin, the eyes, the brain, and the more delineation or distance there is between the tumour and everything else. The more of a therapeutic index you have and the lower potential for serious side effects.
So this is what stereotactic radiation therapy allows you to do, which is actually quite exciting. So the two diseases where we have the biggest databases for efficacy are osteosarcoma and nasal tumours, and both of these have come out relatively recently. So here you can see over 100 patients with osteosarcoma that have been treated here at Colorado State.
Pain control is generally excellent with this treatment. Most of the dogs have a functional limb, following the procedure, although, the eventual rate of fracture in unselected cases is about 40%. But half of those cases occur fairly quickly after radiation therapy.
Another half can occur in a delayed fashion. And in more recent times, we've actually become much better about predicting fracture risk based on the imaging characteristics of the tumour and either steering owners away from stereotactic radiation therapy as an option or just making sure that they're adequately informed of the risk before they undertake this procedure. Outcomes you can see in median survival time of about 8 months is really within the range of what's reported with amputation and, and carboplatin-based chemotherapy.
And the rate of local recurrence is actually very low. It's less than 10%. So local tumour control actually appears to be quite good using this modality.
And again, the other tumour type where we have a very, very large number of patients that have been treated is nasal tumours, and this is a data set that comes out of North Carolina State University. Again, about 130 patients or so. Almost all of the patients treated with this modality improved clinically.
And a median overall survival time of about 18 months is reported, and this is effectively equivalent to what's reported with other less targeted and more highly fractionated radiation delivery platforms. So, quite similar outcomes with again a significantly reduced number of treatments that are necessary. There's a large variety of other tumour types where there are at least small retrospective studies that have been performed demonstrating some amount of efficacy and generally quite good tolerability for stereotactic radiation therapy.
Again, I'm not going. To read this list off to you. They are listed in the proceedings, although I don't think I have all the references in there.
My reference list was already 2 pages and I needed to stop somewhere. But again, you can see quite a few different kinds of tumours where there's some evidence of efficacy. Anytime you're using radiation therapy to treat a big tumour, I think the likelihood of true cure is probably unlikely.
But we can definitely see long term what we call durable palliation or, you know, tumour control that lasts for many months or even longer than a year for some of these diseases. So moving on, our next topic is going to be immune checkpoint inhibitors, and this is actually something that's again very, very exciting on the human side and starting to trickle into the veterinary side as well. So, pretty much all over the world, immunotherapy has become sort of the 4th, tier of, cancer therapy in humans along with surgery, radiation therapy, and chemotherapy.
And these drugs to a large extent work by releasing some of the breaks that tumours have put on the immune system, allowing the tumour to recognise the tissue as foreign and reactivating those immune cells to make them actually more efficient at at helping to eradicate or control these tumours. And I have a little graphic of this that I'll show you in a second. These are some of the names, at least in the United States.
They may go by similar names in the UK and the EU, they may have different names. These are all monoclonal antibodies that are specifically for use in humans that we can't use in our veterinary patients. However, there are some exceptions.
So here's just an example is, you know, tumour cells by nature have evolved a variety of different mechanisms to hide from the immune system. And one of the mechanisms by which they do this is through again the production of a variety of these immune checkpoints that have the potential to basically cloak the tumours from the immune system and being able to interfere with the binding recognition of these immune checkpoints allows the tumour to become visible to the immune system again, which is quite exciting. So the two, the two molecules in green that you see on the right side of this slide, CTLA 4 and PD1 and also it's ligand, which is called PDL1, are the parts of this checkpoint, milieu that they are actually approved products that are targeting.
So there are human-approved drugs that target both CTLA4 and PD1. But as you can see, there's a very large number of other checkpoints that people are working on to potentially target for future therapeutics. So as you can see, All kinds of responses are being observed with these medications in humans, in patients with what were previously untreatable diseases, so advanced metastatic melanoma, lung cancer, kidney cancer, bladder cancer, a variety of other cancers, and one of the things that's become incredibly interesting about this class of drug is that for the first time, at least in the United States, these drugs are available and they actually approved, not for a specific type of cancer, not for a specific histotype of cancer, but for a type of cancer that expresses something called microsatellite instability.
And microsatellite instability is basically a phenotype that increases the number of DNA mutations that are present in the tumour tissue. And the more DNA mutations are present, the more foreign antigens are expressed by that tumour, and the more unusual that tumour looks to the immune system. So, in fact, any tumour that demonstrates microsatellite instability, irrespective of its histotype is eligible for treatment with these drugs and for reimbursement by health insurance, which is actually quite exciting.
What do we know, very, very quickly, obviously, we can see some side effects from these types of medications, and the majority of side effects that we observe are autoimmune in origin. So pneumonitis. Skin changes, autoimmune anaemia, etc.
Most of these can be dealt with via immuno immunosuppressive therapy quite readily and interestingly, it does not appear that the use of immunosuppressive therapy to deal with these adverse events. Diminishes the outcome of these patients. So it seems like once the immune system is reactivated to recognise the tumour, the use of immunotherapy treatment to treat side effects if it's carefully titrated still preserves the ability for the immune response to persist to the tumour, which is quite interesting.
So what is known about these kinds of inhibitors in this pathway in dogs? So in vitro, actually people have developed antibodies that target both PD1 and PDL-1, and actually the other one I mentioned CTLA4, and you can see that the use of these antibodies in vitro are associated with enhanced proliferation of T cells and enhanced secretion of pro-inflammatory molecules like interferon gamma. So suggesting that again blockade to this pathway can make T cells work better in dogs.
So, there are 2 companies that actually have products that have been evaluated in tumor-bearing dogs, not in a petri dish, but actually in patients. So there are 2 antibodies that have been looked at in Japan, one that targets PD1 and one that targets PDL-1, and Merck, has, an antibody that targets PD1 that actually has conditional approval from the US Department of Agriculture, although it has not been released for sale yet, and additional studies are ongoing. And there is another company that actually has a CTLA4 antibody where clinical trials are going to start very, very soon.
This is just one little piece of information from one of the studies that was done in Japan. So the upper right, that what you're seeing here is a graph that's called a spider plot, and basically this is looking at change in tumour volume over time, and these are individual cases that you're seeing plotted here. So you can see, you know, the majority of animals progress fairly rapidly.
There's some that can have stable disease in occasional cases for a long period of time. And then there are some quite dramatic objective responses that can be observed. This second one is what's called a waterfall plot, and this is just a way to look at best response.
So what's the maximum amount of tumour shrinkage that was observed? The lower this curve gets, the more of a response that's observed. So again, in this small study, there was an objective response rate of about 20% or so, which, again, in dogs with advanced melanoma.
Where really there are no other good treatment options. It's quite interesting. It remains to be seen what the optimal targets are for this, kind of antibody-based approach, but we're all eagerly awaiting the release of this, so it's something that we will have in our arsenal in the future, I hope.
Moving on, I'm gonna cover these next two in one. So these are two sort of herbal medications that are used all the time in our veterinary patients, at least over here in the US, and I do want to talk a little bit about them because of how frequently we see them being used. I have no idea if that's the case in the UK, but I guess I'll start by saying this is actually the whole concept of sort of complementary and alternative medicine is something that one of my colleagues here in, in, in Colorado studied quite a while ago via some very, very large surveys that were performed.
And what she discovered is about 60% of owners were giving some type of alternative or complementary medication to their dogs, in many cases, unbeknownst to their primary veterinarian. And you can see one of the top ones was supplements. Followed by dietary intervention, prayer, vitamins, I would argue that that's also a supplement.
And then herbals and botanicals. I think this number is considerably higher now than it was at the time this survey was performed about 15 years ago. But just an example, I don't know how many patients you guys see like this, but this was one dog who came in on all of these medications, some prescribed, but a lot of them, sort of self obtained to try and treat their dog's cancer.
So let's talk specifically about the two that at least I see use the most. One is a drug called Yunan bio, which is a Chinese herbal concoction that is purported to have an effect on bleeding. And this is something that we see used very, very commonly in dogs with hemangiosarcoma to try and prevent a bleeding episode, dogs with nasal tumours, to try and prevent a bleeding episode.
So what do we actually know about the efficacy of unumbile? So you know, at least as of 2017, had been looked at in a total of 5 different studies. Some of these were in normal dogs, some of these were in dogs that had tumours or dogs that were undergoing other kinds of procedures, but I think the really the take home message is, for the most part, there was no evidence of any improvement in any measure of coagulation.
In the majority of these studies that were performed in the one study that actually looked at a tumour population, this top one up here, Yunan bio, with or without aminocaproic acid, had no effect on symptoms, the time to another bleeding episode or overall survival when it was used in dogs with cardiac hemangiosarcoma. So I think the take home message is really there is no data suggesting that unabio has any effect on coagulation or that it really has any utility in improving bleeding or any other aspect of, of quality of life in dogs with cancer or any other disease. One of the other sort of disturbing facts that's recently come to light about Unabio is that the company that manufactures it has recently been accused of trafficking in pangolin parts, and pangolins are a protected species, so this is obviously unethical and illegal, which I would argue is another reason to potentially not consider utilising this medication in your patients.
So, that's my short stump speech about, about union bio. Now, let's move on to CBD. Colorado, for those of you who don't know, was one of the first states in the United States to actually legal legalise cannabis products.
And, so they may have been a little bit ahead of the curve as far as the, the use and sale of CBD, which again is supposed to be a non-psychoactive form of, of cannabis. And in fact, there is some literature out there. Suggesting that CBD in its pure form can have an anti-proliferative effect in canine cancer cells.
And here you can actually see some of the studies that have been looked at where, you know, you are able to put enough of, of this drug into a petri dish to inhibit the growth of more than 50% of the cells for a lot of these tumour types. So that's, of course, very, very exciting, but then the question becomes, that's great, you know, it, it takes you know, 10 mcg per mL of CBD to inhibit tumour growth by 50% in a dish, how much CBD can I possibly get into a patient? So the highest doses of CBD that have been looked at in dogs were actually in a study using it for seizure control.
And in this case, the dose that they were using a very, very pure CBD oil was 2.5 milligrammes per kilo. And that was a dose that did seem to have some effect, complementary effect on, on seizure control.
But the highest plasma concentrations they saw in any of these dogs given this very high dose of CBD was 1 mcg per mL. So you can see significantly less than the amount that needed to be incubated with the cells continuously in order to have any kind of anti-proliferative effect. So really I think it's almost impossible to put enough CBD into a dog to have a direct anti neoplastic effect.
So, how much will it cost, at least in the United States, to give a drug that isn't gonna do any good? So, here's, here's just a couple of little back of the napkin calculations I did going from the top 5 websites that came up when I did this search. So you can see the costs are between $200 and almost $500 a month for that dose of 2.5 milligrammes per kilo BID.
So, again, I cannot discount the possibility of other treatment effects from the use of these drugs. So for example, anti-inflammatory effects, analgesic effects, but I would argue that there are much better established and more efficacious anti-inflammatory drugs and analgesics that could be considered for this population. So, I don't think this is gonna stop any owners from wanting to consider utilising these medications.
They do appear for the most part to be relatively harmless, but there's really no possibility based on the data that we have currently that they're going to have a true anti-tumor effect in any patients. So, last two things I want to talk about very, very briefly are this concept of personalised medicine and the concept of blood-based diagnostics. So there are now two companies that are offering sort of personal medicine screening in the United States, and I'm sure that they're going to be happening in Europe in the not too distant future.
So these are outfits that will actually take a piece of tumour from a paraffin block and then sequence the DNA for a small number of genes and then generate a report that is going to theoretically tell you which drugs might work best to treat this particular canine tumour. In the case of this company Phytocure, they actually will sell you the drugs to treat the tumour. In the case of this other company, which is called Vi Animal Health, they simply generate a report.
That suggests some drugs that might work, but they don't provide the drugs at all. They simply give, give the report. So this is an interesting idea.
I think that these companies are capable of measuring what they are actually measuring. But here's what we know about this approach in people, and I think this is really in informative. So in these huge, huge studies of almost 6000 patients that have been done in humans, where they have a vast database of mutations and drugs to choose from and correlations between drugs and mutations and all those kinds of things, only 25% of patients who were enrolled in this study to do personalised medicines were able to be matched to a drug, and only a third of them, so 8% total actually derived clinical benefit from this drug.
So if we think that we have a a prayer of doing any better than than these dismal results that have been reported in humans, I think we're fooling ourselves. So I, I think this is really, really interesting, but it's a great example of just because we can, doesn't necessarily mean we should or we know, or know how to utilise the information that's being generated. In the interest of time, I'm gonna skip through, these other little bits.
But I will say that one of the other really, really big issues that we have in our dog patients is the fact that we don't know how to give all the drugs that are being recommended. So most of these targeted agents have not been formally studied for safety or pharmacokinetics or efficacy in dogs. And as a result, we don't have any good evidence that the doses that are being recommended are going to do any good for the patient.
And there's a really interesting paper here that I would encourage you to check out if you're so inclined. Wei was the first author from Frontiers of Veterinary Science just a month or two ago, suggesting that at least one of the drugs that was being prescribed from one of the US compounding pharmacies had zero bioavailability in patients, and it had been prescribed for years for the treatment of some cancers based on this targeted therapy concept. Very last thing I'm going to mention is this concept of liquid biopsy.
This is something that's available here in the US and it will be available in the UK. I know people are working on it. This is very hot on the human side, and the idea is actually a similar kind of DNA sequencing approach, but it's being done on blood instead of being done on tumour tissues, trying to use it as a way to actually detect cancer potentially early.
So there's a very, very large study of about 1000 dogs that has actually been performed using one of these, modalities, which is sold by a company called PETDX. And here are the results. If you break them down by tumour types.
So there's some tumours where actually this test is very good at being able to detect cancer, and others where it's really not, but here are the tumour types where you really need some kind of early detection test because there aren't tumour types that present obviously or are hard to diagnose. So very interesting, but again, for a lot of these tumour types, the, the sensitivity is actually pretty low. And another interesting thing is that when you are using this test to detect small non-metastatic tumours, you only detect about 20% of them.
And I would argue that these are the tumours that you would want to detect with a screening test, so that you can act on them early before they become big or spread. And I think additional work needs to really be done to figure out how to optimise this test and how to use it best. It will be coming to the UK and the EU, but I think we need to do a lot more work to figure out how best to use this whole idea of, of blood-based diagnostics before we can really talk to an owner and, and feel like we're giving them good advice.
And with that, I'm, thank you for your attention. I'm really happy that everyone was able to hang on. I see we have, over 1000 participants.
That's great. And maybe we have time for just one or two questions before we have to move on. So once again, thanks very much.
Happy to answer a question or two if Anthony thinks there's time and there's interest. No, that's fantastic, thank you so much so that was really great. Sylvia's asking, asking, does Steelon to work in mammary tumours?
Interesting question. I, I have a feeling that that's one of the tumour types where it's being looked at, but so far the only data that's been published is for mast cell disease in dogs and for those, those two equine tumours. More information to come though.
We've also got somebody asking, there seems to be an increasing talk again of electro chemotherapy in combination with intralesional systemic administration of different chemicals like cisplatin percutaneous tumours. Is this truly a growing area in oncology as well? Yeah, so I think that this is something that is being looked at more specifically in sites where radiation therapy is not available.
So the information that we have is really based on some some relatively small studies. But does suggest that it certainly may have a role in sort of delaying or preventing recurrence or for palliative management of once again, potentially small lesions that could be in locations that are difficult to do surgery on. So we'd love to see more information, especially from some prospective studies.
That are looking at that modality, but we certainly are seeing it as an alternative to radiation therapy in, in some cases where radiation therapy is simply not available. Thanks. It was interesting when Mazy that came out, I actually was asked to look at it for AP and you know, found that it wasn't terribly effective, but Albert's asking a question, .
Hi Doug, what do you think about the new application for oloitinib in canine cutaneous epitheliotropic lymphoma? Yeah, that's an interesting one. So I think, the, the information that we have so far is that it may have, its biggest role in the management of cutaneous lymphoma associated pruritus, much like the way it's used for the treatment of adiy.
But we certainly do know that the pathway that's targeted by alocitinib, can have a role in supporting tumour growth for certain kinds of cancer. And so I'm really curious to see some additional work done, not only for cutaneous lymphoma, but potentially for some other tumours that rely very heavily on Jackstat signalling. So once again, not as much information as we'd like, but more to come and stay tuned for that channel as well, looking at it even more.
So, thank you so much for this session. One of my other favourite lecturers, Mike Willard who's at Texas A&M or, or was, used to say, what I taught you 10 years ago was a lie. I, I'm not gonna say that that that's really true, but it's amazing how much progress we've made in the last 10 years, so looking forward to 2033.
Oh, looking forward to it too. Happy to do a reprise in about 10 years. Thank you so much, Doug, take care, and we're looking forward now to Owen Davis is going to come on, Owen is going to be talking about the latest treatment for canine lymphoma.
We've obviously, talked a little bit about that in the first session. Lymphoma is, obviously a very, Common disease that we see, but I think as we realise over time, we realise that it's, it's probably not one particular disease but a group of diseases, lymphoma and lymphocytes can act in many varied in different ways. So actually trying to find one treatment that fits all is really, really difficult, so is it more than just chop and cocker.
Owen's gonna talk about that in the talk today, he's going to talk about the different types of lymphoma and how we can treat them more appropriately as we understand their disease mechanisms. Owen is an RCBS, an American and European specialist in in oncology, and he works presently at the Highcroft Veterinary Referral Centre in Bristol. So Owen, it's over to you.
Great, thank you ever so much, Anthony, and to the team at Webinar Vetts, it's absolutely great to be back. My thanks also to our generous sponsors of this session. And I have no relevant conflicts of interest.
So ladies and gentlemen, tonight it's all about a dog called Maisie. Maisy's vet wrote me this email asking for some advice on her case, and she's very kindly allowed me to share that with you tonight. So I'll introduce her.
Maisy is a 10 year old female neutered cockapoo with a history of ATP. Presented to a colleague a couple of weeks ago and at a vaccination they incidentally identified enlarged lymph nodes. She was a little bit quieter but otherwise OK.
She was treated with antibiotics to which there was no response, and in the week between antibiotics starting and the recheck, the lymph nodes had grown significantly, and another lymph node at the back of her leg was enlarged. Cytology from the lymph nodes came back as large cell lymphoma. OK, so that's a history.
And we've got some good questions here. We are asked, please can you tell me what the best treatment protocol currently is and how much survival would that bring? Maisie's owner is happy in principle to treat Maisie with chemotherapy, but wouldn't want to put her through too much and wouldn't want to risk any side effects.
We've also got some very important constraints here in that Maisie's difficult to handle and would be difficult for chemotherapy without injectable sedation. Their owner has specifically requested an oral protocol and said it will have to go in food because Maisy can't be tableted. And as if that is not enough, costs are a big concern.
So some very, very pertinent points here. And with the very generous permission of the vet, I'm going to frame this webinar on my response. Let's start with question one.
What's the best treatment for a case of lymphoma? Well, the short answer is, it depends. But we're gonna do the long version now.
You see, if you take canine lymphoma as one big group, then the treatment protocol that is best known and best characterised is a CHOC protocol. And for those of you who are not familiar, CHOP is an acronym. It it's 4 drugs, cyclophosphamide, C, doxorubicin H, Vincristine O, and prednisolone P.
So you're already learning that oncologists can't spell. Now a COC protocol typically runs for 5 to 6 months and it may seem quite complicated, but it doesn't have to be. The most common version of the COC protocol and the one I favour is the Madison, Wisconsin version, and it involves week one in Christine.
Week 2 cyclophosphamide, week 3, then cristine again, week 4 doxorubicin, week 5 off. And then you repeat it 3 times. In the first cycle, you give a tapering course of prednisolone, and in the 3rd and 4th cycles, you can drag out the intervals between treatments for 2 weeks if you want to make it a bit less intense and that doesn't harm the overall benefit.
So it's, it's not very complicated really. Now back to Maisie, shall we treat Maisie with a chopped practicol? The CO protocol has been studied in lots of groups of lymphoma of all different types of dogs.
And actually, nothing has been shown in such groups to be any better. So should we treat her with that? Well, in my opinion, I'd like some more information first.
Particularly I'd like to know the type of lymphoma. OK. Now, as a spoiler, I will tend to treat different types of lymphoma differently and there's more to come on that later.
I'd also like to know the stage of disease if I can, because on occasions involvement of certain body parts, for example the brain or the bone marrow, will mean I'll add in different drugs. And I'd also like to know some comorbidities. And I think this is something that's often overlooked because lymphoma dogs are after all middle aged to old usually.
And the possibility of them having other things going on is actually quite high. Maisy is half cocker spaniel, and cocker spaniels can get chronic hepatitis. And what do we know about that disease?
Well, it can often fly under the radar for ages until the very end stage. If she's got chronic hepatitis and if she has issues metabolising certain drugs, then they may either not work as well in the case of pro-drugs like cyclophosphamide. Or they may not be excreted as well in the cases of drugs like vincristine or doxorubicin, and that can be very dangerous if a dog's not excreting the drugs, you effectively will overdose her.
So before talking about a protocol, I would like a lot more information. The bigger point here though, is that the best protocol for a dog is the one that he or she responds to. And sometimes I find we get a bit hung up on the idea of a protocol being a recipe to treat the disease, and we need to stick to it like we're baking a cake.
We can't possibly go off that. And the ideas of protocols like that are good for research in groups of dogs, and they're good for very rapid emergency procedures. But for management of a chronic disease over a course of months, I think that can be very unhelpful.
So we need to regularly at each visit, assess how those lymph nodes are going down. And if they're not going down enough, particularly if they haven't gone away to normal size after a cycle of the CHOC protocol, we need to be thinking about changing. Either changing it all or adjusting it to try to give this dog every chance of getting into a complete remission.
Similarly, if our dog is having unacceptable adverse effects, we need to be thinking about changing to avoid these. So it's not very often that I do a straight Cho protocol, I will often make changes like this because of comorbidities, and in many cases, I don't use CO protocol from the start. So this is my first key point and possibly my most important key point of the evening.
Protocols are a guideline, OK? Please adapt them to your patient. Back to Maisie, Maisy's vet has asked a very good question, what would be the adverse effects of the treatment?
Let's discuss these now. When I'm talking about chemo with an owner, I'll say that all cytotoxic drugs can cause gastrointestinal upsets, and they can suppress blood cells, cause myelosuppression, and they'll do these to varying degrees depending on the drug in question. When we're talking about vincristine, it's actually very, very light on the bone marrow.
The limiting factor is often GI upsets, particularly at the higher doses, but these are rarely severe. So in general, Vincristine is really well tolerated. Occasionally you can get a peripheral neuropathy.
And where I've seen that or seen that to a clinical extent, tends to be in animals who have another reason for a peripheral neuropathy, for example, diabetics. A cyclophosamide is a bit like the opposite, OK, gastrointestinal side effects of the dose we use are rare. Myelosuppression.
It is more the thing with cyclophosphamide, but that still is quite moderate at the doses we use. However, some dogs get sterile hemorrhagic cystitis. And although that's rarely a life threatening event, it can be really, really painful, so we need to check urine before and after it's used, looking for microscopic levels of blood.
And if we see these we need to rule out infection. If we rule out infection, then we change that drug. And finally, doxorubicin.
We all, many of us know that doxorubicin can be cardiotoxic and toxic to the heart. And that scares us, quite rightly, we want to avoid things like that. But I will tell you that getting to the dose that will cause cardiotoxicity is often quite hard to do.
It's a cumulative effect, but you do need to give quite a lot of the drug, particularly if the heart is normal to start with. The biggest and often understated issue with doxorubicin is that it's very good at causing gastrointestinal upsets. And in my hands, this is the reason why the drug is stopped or the dose reduced far more than any cardiotoxic effects.
So Maisy's owner has made quite an extreme statement that she wouldn't tolerate any risk of adverse effects. Do you remember that? And what can we do to minimise this risks?
Well, the first thing we could consider is that is dosing conservatively, just give less basically. Now when we talk about dose of a chemo drug, we need to think that the effect of the drug is proportional not just to the amount you give, but also the interval between dose, OK, this is the dose intensity. And it might seem prudent to reduce the dose if a dog has a very easily upset gastrointestinal tract or if the owner is particularly risk averse, for example.
Well let's explore that. Now, the risk of adverse effects is roughly a sigmoid curve like this. And we tend to be working at the doses we give in the middle part of the curve where it's very steep, OK?
So you can see if I reduce the dose intensity a little bit, I will reduce the effect in terms of side effects a lot. So why don't we do that? Because of this, OK.
Now the risk of adverse effects is a shadow of the clinical effects on the cancer. So, if you start here, say. And you reduce your dose.
You will not only reduce the risk of adverse effects a lot, but you'll reduce the benefit of the drug a lot too. So there can certainly be very appropriate times for dose reducing, but please don't take that lightly. The second thing you could do to reduce the risk of adverse effects is check if your dog is a carrier of the MDR1 mutation, or more correctly, ABCB1 mutation.
Now this is something we've often heard of because it's well characterised in collie dogs, making them sensitive to drugs like ivermectin. But you can get it in a lot of other rural breeds and herding breeds. One consideration here though is that if I was to ask all the British people in the audience, what what do you think of when you think of a collie.
I might bet that all of us, including me, is thinking of him. Now a lot of the research on this particular mutation was done in America. And I understand that when you ask a lot of Americans what they think of when they think of a collie, they think of him.
Different breeds So in this study that was done in the UK we found that the prevalence of the mutation in the black and white border collie was extremely low, but the prevalence in the rough or smooth collie, which certainly in the southwest of the UK is quite a rare breed, was very high. Other breeds which you want on your radar would be the Australian shepherd mutations very prevalent there. And then you've got the Shetland Sheepdog and the old English sheepdog too.
And if you want more up to-date information on what breeds can be affected, I'd encourage you to look at the Washington State University website. It's a really good source of information, but I guess the key point I'm making is, at least in the dogs I see in my clinic, the likelihood of them carrying this mutation and being oversensitive to drug is actually quite low. So is it justified to test all of these guys?
The 3rd quite practical tip I could have in reducing adverse effects is considering starving actually. Now, starvation will decrease things like IGF one and blood glucose and in a clinical trial of women who are being treated for breast cancer. They found that when they starved themselves for 2024 hours before each treatment, they had a significantly reduced incidence of adverse effects.
All kinds of adverse effects, not just gastrointestinal. Than when they didn't start before treatment. And the effect was so profound that many of the women continued to starve for 24 hours before chemo when the study finished.
OK, and in this study here, it's been tried in dogs and nausea went from 53% fed to 7% fasted and anorexia 60% fed, 7% fasted and lethargy similarly. And another study with doxorubicin in dogs, vomiting, 67% fed, 10% fasting. And of those who vomited when fed, you could abrogate this effect in 80% when they were subsequently fasted.
Now on a practical level, you know, these dogs have got cancer. Do we want to starve them for 24 hours once a week? I'm not sure I do.
However, if a dog has had a particularly bad tummy upset with one drug, you could always consider starving them when that particular drug is used again in the future. And that's how I make use of this effect. So I think with Maisy's owner, who said, I won't tolerate any adverse effects, well.
Perhaps we need to rationalise this and manage her expectations a bit better. In general, the risks of chemo are low and the severity if they occur are pretty low as well. We also use plenty of other drugs like I've listed here, TMPS, phenobarbitone, carbimazole, cyclosporin, non-steroidal drugs.
These can all have very, very serious side effects too. So it's a bit like driving in a car. The use of these drugs is not risk free.
But it can certainly be done in a way such that the risk is low. Moving on to our next question. Maisy's bets are asked.
If we use a treatment for the, the sake of argument, the CHOC protocol, what survival will it bring her? Let's look at this. Now as I say, the CHOC protocol.
Is the best established and well-known treatment for canine lymphoma. And there's a number of studies where it's been evaluated in a group of dogs with lymphoma of no specific type. So you could look up a survival time in this study, 251 days.
In this study, 51 weeks, and there you go. But I suggest you don't, OK. Because look at this, in the 251 day study, a third of them had rescue therapy.
And when you drill down into it, the, the work of the CHOC protocol, the disease free interval it created, was only 204 days or 142 days, depending on how well they responded to that treatment, significantly less. And in the 51 week study. The actual time where the disease was controlled was 36 weeks, and for the remaining time the dogs were just palliated.
So another key point here. When we're talking about a chemotherapy protocol, we need to look at disease free interval or progression free survival. The overall survival is the sum of the DFI or PFS from the each from the induction protocol and from each rescue protocol as well.
These studies also show something else though. And another reason why looking at average survival times can be misleading. Look at the range of survival here, 3 to 1700 days.
And look at the range of survival here, less than 1 week for over 225 weeks, over 4 years. Absolutely huge. And I'm going to illustrate this further with 33 Labradors or Labrador type dogs who I have treated in my clinic.
And I've chosen these because they're all similar in breed. They also have very, very committed owners and they were not impeded by funding or any issue other than the disease limiting their treatment. Let's look at bisto, 10 year old male neuter, labradoodle, multicentric lymphoma.
Excuse me, induced with a COC protocol. Got in remission when it came back again, rescued with the COC protocol. When the disease came back CO protocol, Lomustine LSpiaginase again.
Finally, Rabehozidine and prednisolone. And overall Bto lived for 3 years, 3 months from diagnosis. Let's look at Nina.
One year old, yeah, one year old, female entire Labrador, multicentric lymphoma. Again, started the COC protocol, started a clock protocol, Raoidine Pred, DMAC, Verdinex and Pred and had. 4 months.
4 month survival. And then you've got Lenny, an eight year old male neuter Labrador, multicentric lymphoma, and you know what, just didn't treat him. And then after 2 years we gave him carammicillin bread and after 4.5 years he was put to sleep because he couldn't get up one day.
The disease was still under control. So why is this? When I ask this to a group of people in a room, sometimes people say, is it due to the disease stage?
Well, you know what, they're all stage 5. And I'll have a brief digression here, just to talk about staging a bit more. You see, these are the 5 stages of lymphoma.
Stage 1 and 2 are considered quite rare. Stage 3 is generalised lymphadenomegaly, with 4 is liver and spleen involvement, and 5 is involvement of the blood, the bone marrow, or extranodal tissues. OK.
And if you want to stage a dog, you could do all these tests here. Quite expensive, quite exhaustive. That's When it comes down to it, most dogs are stage 5, OK?
And to put it simply, the harder you look for disease in the bloodstream or the bone marrow or the extranodal tissue, the harder the more likely you are to find it there. So staging rarely changes prognosis, it has very, very little effect on the prognosis and it rarely changes the treatment. I do think it's worth doing and I do offer it in every case.
Because it's important to pick up concurrent disease. If you've got a middle aged to older dog, you wanna know if your dog has chronic hepatitis in the case of a 10 year old cockapoo. You want to know if your dog has a big splenic tumour that's about to rupture and bleed in the animal where you're talking about possible 2 year survival.
OK, you also want to know where the disease is to start with, so you can monitor it better. Whether it goes into remission or not, you know where to find it. So staging is important to monitor treatment and pick up these comorbidities, but it rarely changes prognosis or the treatment you give.
Digression over. I'm asking you why my 3 Labrador dogs had different prognoses. And we said stage, not really a player.
What about T cell or B cell? What about that? What do you think?
Well, bisto is a B cell disease. Nina was a T cell disease, so perhaps we're getting somewhere now. But then Lenny was a tea cell also.
So the key point here is lymphoma is a big group of very different diseases. This list on the right of your screen is are some of the lymphoma types that are available to you. OK.
And in human medicine they have about 60 odd types of lymphoma. The human classification has been shown that it can be applied very, very accurately to canine lymphoma. And so the what we know is probably 20 or 30 different types of lymphoma are currently characterised in dogs, it could be all 60 actually exist.
Now I haven't got time to talk about all these tonight. What I can tell you is that these are the 6 most prevalent types of lymphoma. And if you look at a survival curve here, the Kaman myograph.
Just to explain that if you've got 100% of dogs alive up here, 0% alive here against time on the X axis, it will follow that the groups with the best survival will have a curve that stays near the 100 for longer, in other words up here, those with the poorest survival will have a curve that gets down to zero sooner than down here. So Lenny, the Labrador who lived 4.5 years, had the type of disease in this blue line here.
Poor Nina was this black line here. And this though was this red line in the middle. So different types of lymphoma have different prognoses.
How do you find out the type of lymphoma you've got? Well, if you've diagnosed on histopathology, it's easy, you just ask your pathologist. They'll need to do immunohistochemistry as well, but that should be fine.
I don't know about you, but I don't really like to take a lymph node out of a dog when I've just diagnosed lymphoma, not unless I'm trying to confirm the diagnosis. I often diagnose based on cytology, and I can show you the the trick which we can use here. Is that out of these 6 different types of lymphoma, which are the vast majority, 3 of them are aggressive, rapidly developing high grade diseases.
3 of them are indolent, slowly progressing, low grade diseases. Three of them are B cell. Three of them are TSA.
So when you plot the grade against the immuno phenotype. You'll see that there's limited options. If you have a high grade B cell lymphoma, then you can consider that to be a diffuse large B cell lymphoma.
Similarly, a low grade T cell lymphoma is likely to be a T-zone lymphoma. And you've got two options in the other two categories. But actually the difference between them is often not of clinical level significance.
Or if it is, you could sometimes use clinical features of a case, for example, where the disease presents in the body to be able to tell the difference between the two. So we need grade and we need a you know phenotype based on cytology. How do we get the grade?
Well, actually, you get good quality fine needle aspirates, send them to a good clinical pathologist, and they should give you a good indication. Grade is principally determined by the proportion of cells in mitosis. And here's a cytology sample here and you can see some mitosis going on.
Often some quite abnormal mitosis like that one as well. How do we get the immuno phenotype based on cytology? Where you could take some further fine needle aspirates and send them for flow cytometry.
Or you could get the PA test run on the slides that are already at the lab. The power test because of what I've just said, is often much more attractive. But I'm afraid it's less accurate.
Flow cytometry is a brilliantly accurate way, with a high agreement level with histology. The PA test kind of agrees in 70% of the time, and that's at the level where it's probably going to get it wrong one time in 3. So I would favour repeating pine needle aspirates and sending them for flow cytometry.
So let's explore our Labradors in some more detail. This though was a high grade B cell lymphoma. We consider that as a diffuse large B cell lymphoma if we had histo, OK?
And this is the most common type of multicentric lymphoma in the dog. But this type of lymphoma, well, short protocol is considered standard of care. Runs for 1925 weeks usually, and at the end of the treatments, the treatment is stopped if they're in complete remission.
Excuse me. And then you just palpate the nodes monthly. Well, that's what I prefer to do to make sure they remain under control.
So The average disease-free interval with a shock protocol is in the order of about 8 months. And the average survival, which remember includes rescue therapies, is in the order of about 14 months. But sometimes these, these dogs are doing very well and their survival is affected by the owner's finances because it's frankly just getting quite expensive to keep treating these guys.
If funding is available. About a quarter of them will still be with us for 2 years. My final point with this type of lymphoma is that if they had been off treatment and finished the CO protocol a few months ago.
And the disease comes back. It's often not drug resistant. Often these guys relapse because they're just undertreated.
Now, why do we undertreat them because we don't want to make them ill. And I think oncology is in general is a very ethical and ethically police discipline. In humans, about 70% of people with non-Hodgkin's lymphoma are cured, but they do endure an awful lot of side effects to be cured.
OK, so I think we've got the balance right. I think we don't want to be treating these guys any harder or else, you know, some of them may even perish due to the side effects, but in a lot of cases like this, they relapse because they haven't had enough chemo to stay under control longer rather than the disease evolving and becoming drug resistant. And the implication is if one of these guys has come out of remission and not been on treatment for some time, I would suggest trying the original treatment again.
And seeing how they respond and you might find that a lot of these guys you can just repeat the first induction protocol. Now I'll introduce a character who you haven't met before. This is Clyde and Clyde has the most common high grade T cell lymphoma or peripheral T cell lymphoma in brackets not otherwise specified.
And this is an aggressive disease, I'm afraid. About 25% of these guys will be hypercalcemic and very ill. It will develop drug resistance faster and the remissions will be far shorter.
In my hands, the average survival of these guys is only 6 to 9 months. The very best survivors will live to about 12 or 13 months, but rarely longer than that. You usually have to keep them on some form of treatment for most of their time, and when they relapse, it usually means that the tumour has evolved drug resistance and the the treatment that you used on day one won't work, you're gonna need to go to a rescue therapy.
So with Clyde then, and his lymphoma, do we treat him with chalk? Well, he could do. But we're learning more and more, and that the T cell lymphomas seem to respond less well to doxorubicin.
In this study, for example, the response rate was 50%. In half the dogs, the doxorubicin have no benefit. We also See that T cell lymphomas may respond better to low mustineine based treatments, particularly in this bottom study, the average disease free interval, Was over a year, and the average survival was getting on for a year and a half, which is absolutely brilliant.
So these studies were using a LO protocol and that's the way it's normally called LAPP. I move the P when I refer to it, so I call it a plot protocol. And it is thus.
In Christine day one. They must see day 8. And day 15 off.
And you repeat on the 3 week cycle. You give Procarbazine in the last 2 weeks orally at home and prednisolone usually all the way through. A brief digression to discuss adverse effects here.
Lomustine can be quite good in a way because it rarely causes gastrointestinal upsets. It is actually one of the most dangerous drugs we use though, and don't be lulled into a false sense of security. It can cause quite a variable level of myelosuppression.
In some dogs that can be quite severe. It is also hepatotoxic. And the hepatotoxicity is, is so cumulative do on dose, but it can also be idiosyncratic.
So there is no dose of lousine that would be considered safe, it all has some risk of idiosyncratic hepatotoxicity. Procarbazine, generally well tolerated, but gastrointestinal effects seem to be the biggest thing with that. We're back to the story, OK?
So Clyde has a high grade peripheral T cell lymphoma. There's plenty of oncologists who choose to initiate a COC protocol as the best established treatment and change if the response was poor. Personally though, I tend to use the Lomasine based protocol I've just shown you since it's cheaper and it involves fewer intravenous injections.
These guys aren't gonna live as long, so I'd like to minimise the the needle sticks that they have. Now Nina, the dog I showed you, a poor little dog who only survived 4 months. And despite an awful lot of treatment, Nina also had a high grade T cell lymphoma.
This was the most aggressive form, the T lymphoblastic lymphoma. And in humans, this is now categorised along with the acute leukemias, it's kind of like an acute leukaemia that chooses to occur in the lymph nodes rather than the bone marrow. And thinking of it along the lines of acute leukaemia gives us a a kind of hint as to how aggressive the disease is and how well these guys don't do.
It's often a mediastinal distribution of disease in young animals, very often they're hypercalcemic. It is often has innate drug resistance and it acquires drug resistance quickly, and I think you're doing well if you can get these guys to the 34 month mark. So it's not, not very common, but it is the most super aggressive type of T cell high grade lymphoma.
So a key point here, just to emphasise that the high grade peripheral T-cell lymphomas develop drug resistance more rapidly than the high grade bees, they're also less responsive to doxorubicin. And you have this subset, if you like, this lymphoblastic T-cell lymphoma, which is even worse. On a happier note, let's look at Lenny, because Lenny also has T cell lymphoma and did very well.
Now we've start, only in the last 10 years or so really we've started characterising the T cell lymphomas better because we always noticed that there would be a few dogs with T cell lymphoma who did extremely well and defied all the odds. And with the advent of flow cytometry, we can now identify that these have different markers on their neoplastic lymphocytes. OK?
If you look at the graph here, this grey line represents the majority of dogs with T cell lymphoma, and they have an aggressive disease. But this small group of dogs here. Had a much less aggressive disease and you can't really calculate an average survival time for them because they all remain alive.
And you can see that their markers on the cell surface are different. And this is T-zone lymphoma. It's an indolence in lymphoma, indolent being the opposite of aggressive.
These guys often present clinically well. But they can involve a very high disease burden. Often they have large lymph nodes and a huge spleen, and they may have circulating cancer cells.
Sometimes you pick it up accidentally at an early stage, but very often they're coming in with a high high stage of disease. These zonal lymphoma can have in some cases a very characteristic cytology with this kind of hand mirror morphology of the lymphocytes like that. But the best way to diagnose it, which actually beats histology, is on flow cytometry.
It has quite a funky expression of markers. Tzonal lymphomas will not express CD45, but all white blood cells should. They should express B cell markers, of course T cells don't.
They have high MHC2, which they wouldn't normally have, and they can have a variable levels of CD4 and CD8 which you normally find one or the other on a T cell. So a very, very unusual flow cytometry marker expression. What if we were to treat Lenny with Chock protocol then?
What would happen then? Well, in my opinion, that would be a mistake, OK. Systemic multi-agent chemotherapy has never been shown to be beneficial in Tzoal lymphoma or any other indolent lymphomas.
And I think one of the problems here is that chemotherapy depends on having a large proportion of cells within the cell cycle. The chemo drugs may kill the cells directly in the cycling. Or even if they affect the cells when they're resting, the lethal effect is not gonna be realised until the cells later start to be cycling again.
And with the indolent lymphomas, there's just a much lower proportion of cells that are in the cell cycle, in other words, a lower proportion of cells that are susceptible. So how do we go about and treat these? I can give you my my suggestion.
Things you'd need to consider would be at first do no harm. If you've got a happy healthy dog and you've diagnosed a disease with a slow course, do we really need to treat? But then against that, you've got to consider that the disease is less responsive to chemotherapy, and it's not gonna be as reversible as a lot of the high grade diseases.
If we get a response to medical treatment, it tends to be slow, and the shrinkage of the lymph nodes tends to be partial. So you have to consider the whole patient, consider the age, state of welfare, and whether there's clinical signs related to the disease. My suggestion then would be to stage very thoroughly.
And here's a reminder of the staging I do. Bloods, urine. Image thorax, image abdomen.
Take fine laperates of liver, spleen and other enlarged or abnormal structures. Normally for staging, you'd consider a bone marrow aspirate, but often these guys have lymphocytosis, so you can see that there is haematological involvement to start with. So he staged thoroughly.
If there's stage 1 or 2, that's just one node or a region nodes. How about considering surgery or radiation? Pull the nodes, radiate the nodes.
That's not gonna be so practical if they're generalised or above. So in that case I'll watch things and treat if there's clinical signs. The normal medical treatments I'd employ would be cloambicillin Prep to start with.
And you've got to measure these nodes very carefully because the change in them is not gonna be very dramatic. It will usually be quite subtle. So I'd measure several nodes and have the same person measure them again monthly ongoing.
I'd look to restage every 3 to 6 months and revisit these questions above. Now we're getting better with lymphoma diagnostics and we're diagnosing more and more indolent lymphomas. And T zone is the most common indolent lymphoma, but others are available, for example, marginal zone or mantle zone or follicular lymphoma.
Now follow a largely similar approach. But the ones beginning with M, like the marginal mantle zone, you they could present as a splenic mass. And if that's the case, disease is nowhere else, you could consider splenectomy and get a good disease free interval on the back of that.
The one thing I would warn you about though is that nodal marginal zone lymphoma, as opposed to splenic marginal zone lymphoma, is actually more aggressive. So although it definitely is an indolent lymphoma on histology, it doesn't behave like that, and I'd encourage you to treat it more like a high grade B cell lymphoma if you see this. So that's one exception.
So my key point then, indolent lymphomas are great to recognise, and many do not need treatment until they're very advanced, but beware of the nodal marginal zone lymphoma though. OK. So we've got some other constraints in dealing with our little cockapoo called Maisie, haven't we?
For a start, costs are an issue, aren't they always? And when costs are an issue sometimes you have to be a bit flexible and go a bit off-piste. The first thing I'd consider to treat Maizey properly but trying to do it as cheaply as we can is just cut the dox of rubicin out.
We could use a COP protocol, cyclophosphamide, vincristine prednisolone. And that's actually pretty cheap to buy the drugs at least. The one I favour is a discontinuous cop involves 8 weeks of treatment, 8 weekly injections of incristine, oral cyclovhosamide at home, oral pred at home, and then if everything's under control at the end of the 8 weeks, just try to maintain it with oral chlorambuil, methotrexate and pred, OK?
And it's jack of all trades, master of none. It can be used for the T cell or the B cell cases. And in a high grade B cell lymphoma at least, it will give you kind of like half 2/3 of the disease free interval of a shock protocol night.
But it's cheaper and it's easier. Some people ask me, if I start with a COP protocol, is that going to undermine the dog's prognosis? And we don't know for certain, but in a small group of dogs, it doesn't look that way, OK?
If you look at these survival curves here, the blue line which hits the bottom first were those who dogs who just had a cot protocol and no rescue therapy. The red line is those who just had a hock protocol and no rescue therapy. But this green dotted line here, which was not significantly different from one Cho protocol was those he had cock to start with and were rescued with doxorubicin later.
So from this group of dogs, at least it looks like those who had a cot protocol alone but then received something including doxorubicin later, they had just the same survival as if they'd been given the doxorubicin upfront. So why don't you just try the doxorubicin? It cut out the vincristine and the cyclophosamide.
You could use doxorubicin and red. And again, the average disease-free interval in a high grade B cell case is actually similar, 4.5, 5 months.
It's less intense as well. Although it is a more expensive drug to buy, but you'll have to see the dog less frequently. And for the doxop protocol, I would just give doxorubicin day one.
And repeat, day 21, day 22, etc. With alongside a tapering course of prednisolone. An even cheaper protocol involving just oral drugs would be lousine orally alongside prednisolone.
I don't like that so much, you don't tend to get the lymph nodes into remission. And it does risk the adverse effects and the unpredictability of lousine. And a cheaper agent still would be prednisolone that you could use on its own.
People often ask me the dose of this, I don't think it matters. I would just start quite high at 2 migs per gig-ish, and as the nodes are shrinking, taper the dose down to the minimum dose that will keep the side effects under control. And the other aspect of how it all dog Maisie is that she's very difficult to handle.
And to discuss this further, I'll introduce you to Darius. Another of my patients, a 6 year old male entire German shepherd dog. He was 55 kg of pure rage.
Now we all know dogs who have to be muzzled when they come into the clinic, and that's fine, but Darius was something else. He behaved like a police attack dog or a security dog. He wasn't one of those.
He lived in a flat with his owner, who he was very, very, very protective of, and the owner had to stay at home and her dad and her brother had to bring the dog in. And it was a load of stress having this dog in each time because he would be lunging at people in the car park, restrained by these chains and two muzzles, etc. So I think, I think you're getting the drift.
He was a very, very extremely aggressive dog. Have a think, how, how would you treat him? Well, rightly or wrongly, this is what I did.
After speaking to our anaesthetist, we arranged for him to have some anxiolysis with gabapentin and trazodone before coming in. And to treat him, I thought we would use doxorubicin and lemustine in alternation. Now this isn't a treatment that has a lot of evidence behind it at all.
It's just me acting out of first principles. I'm just thinking what's the fairest thing for the dog and for the owners, the most affordable, the most practical for the staff, etc. So I can't give you a very reliable disease free interval.
It just seemed the most appropriate. We certainly didn't think it was fair to have this dog in weekly for treatment. So in day one, he'd come in with gabapentin and trazodone on board, that usually did very little.
He was injected with a meatomidine, brophenol and ketamine. When he was asleep we placed an IV, we got the bloods, we gave him some fluids, then we gave him doxorubicin, then we woke him up and sent him home. Day 21, we gave him gabapentin and trazodone, and with a lot of luck, and we got some blood from his back, back leg.
They, suffered fa and we dispense some oral lunosity to go home. And then we repeat it. And actually we got 6 cycles in.
And he had 9 months remission based on that. And then the disease relapse. How do you want to treat him now?
Now both doxorubicin and lamustine can have cumulative effects, so I didn't want to give too much more. Doxorubicin can cause cardiotoxicity, reustine liver toxicity. So what could we do?
Well, you might well have heard of this already this evening. We use Tanavvi, CA1 as it used to be called. This is Rabahozidine.
And here in the UK this is something that you can get with a special import licence from the states. So this drug has the advantage of being given every 3 weeks, so it's another 3 weekly treatment, I thought it was appropriate. It's certainly been evaluated as a single agent alongside prednisolone.
And that's what we did. We got a complete response and we got 5 months remission. And overall Darius lived for 17 months.
I'm not gonna say too much about this drug because you guys have heard a lot about it already. It's certainly an interesting drug, and I think it's a very useful drug to have in the toolbox. I tend to use it in the case of relapsed B cell high grade lymphomas like Darius, mostly.
And the response rate is that 75% responses occur in relapsed B cell lymphomas. And out of those 45% are complete responses. That is where the nodes go away to their normal size.
And that's really quite impressive. Now, to be fair, in this paper, I'm not sure if all these dogs with relapse B cell lymphoma had drug resistance, OK? It might have been that if you tried them with Vincristine, they might have responded.
But still, that's quite impressive. And the progression for his survival with his 5 injections was in the order of 6 to 7 months. You can if you want, use it for naive B and T cell lymphoma 2, and response rate is just below 90%.
You can, if you've got a naive B cell lymphoma, then the response rate is just below 100%. And out of those 60% complete responses. The T cell, naive T cell lymphomas don't do quite as well.
The response rate's more like 50% and complete responses in 22. So I think it's a useful tool in the toolbox. As Doug was saying, you've got a risk of pulmonary fibrosis in about 5% of dogs.
I've never seen that, but in the cases I've treated, but you can get a dermatopathy in a lot of dogs, possibly up to half the dogs, and that seems to be cumulative. This is some of the dermatopathy I've seen in my clinic. I've never seen this bother the dog.
Or the owner particularly, but they can look a bit scruffy like that. And one thing that I have used this in a few times is in combination with doxorubicin, because this, as far as I'm concerned, will reduce the chance of adverse effects from both drugs or the the cumulative adverse effects from both drugs, that is the cardiotoxicity and the dermatopathy and things. So it's another, another 3 weekly drug that we can add into our arsenal for things like that.
And very finally, At the bottom of our email, we learned that Maisy's owner had specifically requested an oral treatment for her dog. What can we think of there? Well, the first thing I'd have to say, if owners request oral treatment, we need to counsel these people and rationalise their expectations.
If you want an oral treatment, sure, we could do that, but it's not gonna be half as good. No durable remission will be obtained. You'll be lucky to get a few months in most types of lymphoma.
The other thing is that you've got to be aware of exposure to people. We can't allow people to crush or break cytotoxic pills. Medication needs to go down without touching the sides, and that if you've got an animal who can't be pilled, and they're talking about crushing meds to put in food, then it's not really appropriate for oral treatment.
It might be safer to have the dog in and consider injectable treatment as much as the owners may not want that. But the options you've got would include bread and lemaine as we've discussed. You could talk about prednisolone cyclophosamide.
Prednisone on its own. Or possibly with a bit of persuasion. You could use something like a lock protocol that will have lots of oral medications, so the owners feel like they're playing a good role in the treatment and it will have an intravenous treatment every 3 weeks or so.
Finally, I'll mention burden exor. This is Liverdius CA one that Doug touched on before. And I'll show you some results from the clinical trial in dogs with naive or rela relapsed B or T cell lymphoma.
In naive lymphoma, only about 40% of dogs responded. And stayed under control for about 40 days. In relapse lymphoma, it was a similar proportion responding.
But only lasted about half the time, OK? Interestingly, out of the 7 T cell lymphoma cases, 5 of the T cell lymphomas responded, which is interesting. But we need to see a lot more data on this before we can shout about it.
But I've put it up here because it is an interesting drug and our clients go on the internet and read about it and often ask us about it. It is an oral treatment for lymphoma, it has got its place, but the results are just not very good in a single agent setting. Why was this drug marketed when the results are on the face value, not so, you know, not so encouraging.
I expect it's because we'd like to do trials combining it with other things. And a lot of small molecule inhibitors, which includes the thyrosine kinase inhibitors in human medicine, are given as part of the multi-agent cytotoxic drug protocol. So I'll be very excited to see more results coming out with this drug when it's combined with other things or used in different ways, and I expect it will be a very useful drug in due course.
But for single agent use for lymphoma. Perhaps not top of my list. In summary then, There is no best treatment for lymphoma per se.
I hope I've shown you that subtype in the lymphoma will allow you to determine the best treatment and likely prognosis for each case. Staging lymphoma will allow you to identify comorbidities and form a baseline for monitoring, but it's unlikely to change the prognosis or the treatment. For your high grade lymphomas, especially the B cell cases, then the COC protocol is the benchmark treatment.
You can use it for the T cell cases too, but they may benefit from a low mastine based treatment. If you've got a difficult patient, consider a 3 weekly treatment interval and use things like doxorubicin, or ostine, or rabahozidine or a combination thereof. For people on a budget, consider the COP protocol first, or doxorubicin single agent.
If costs don't extend that far, you could talk about lomtine or prednisolone. Or the indolent lymphomas, consider not treating surgery or radiation therapy for early stage ones and consider carambisil pred if they're more advanced. And remember that there's no durable oral treatment for lymphoma, but use of a protocol with fewer IV injections would probably be the best compromise.
I say big thank you to everyone I work with every day. Thank you ever so much to you guys for listening tonight. Thank you to the webinar vets for asking me to speak, and my thanks once again to our generous sponsor, HT Vet.
If you've got any questions, I'll do my best to answer them. Thank you, Owen, that was really good. We'll come to some questions just before we do that, just wanted to let everybody know that tomorrow we have our sustainability summit.
Something that we've all got to be interested in is the future of the planet because we can't really practise very good medicine if there isn't a planet anymore. So we will be meeting up at 2 till 5 to discuss regenerating hope in the profession, all the good things that are happening, but how can we quicken things up? That will also include the Green Awards.
We've got an award for the green vet personality and the green practise as well. So you'll be very welcome to come to those. And then in the evening at the same time, 7 till 9, George of Woods League will be speaking about alternative diets, the good, the bad and the ugly, and management of obesity, and that's in a session that is being sponsored.
By Royal Cannon. As I said, thank you so much to HTE for sponsoring this event. People have been asking about certificates, you will get a certificate, you can download that yourself if you want the certificate.
If you want to see the recordings, then there is a charge for that, and I think Dawn has put the URL to go and look for it. I think it's 79 pounds plus that for the whole conference, which is not 10 hours is on the video, but 16 hours. And We are hoping to get base accreditation on that.
It is pending at the moment, they are taking their time. The price of it will go up to 99 pounds at the end of the congress. So if you do want to have those hours to look back at again, then it's well worth considering buying the the the Congress recording 16 hours.
80 pounds, it's about a fiver an hour, which is, I think really good, really good value. I found, Owen, with both of those sessions, there's so much new stuff and good stuff that I can take so much in, but actually to be able to go back. And revisit it, to have that sort of video library when you see your next lymphoma case is then very useful to just think about some of these new treatments which I must admit I hadn't heard of, so it's great to see some new treatments coming out in this disease, and I think as, as you said, you know, it's not a 10 years ago we said maybe it was a one disease or we could treat it in one way, whereas as we're learning to, to differentiate the different types of lymphoma.
Then we'll almost certainly get better results or be able to tell people what to expect because prognosis is a really important part of helping clients make decisions, isn't it? Yeah, absolutely, yeah. So I think that is everything as far as announcements.
Do, let people know and please do, tag on social media if you've enjoyed this session and tag some of your friends on. And if you really enjoyed it, you want to leave a testimonial, you can on the site or or directly with me on LinkedIn, so if you're liking what we're doing, we're. We've had well over 1000 people on tonight trying in our mission of making veterinary education more accessible and affordable to vets all over the world.
It would be great if you could put in where you're listening from. I believe there's over 100 countries that will have registered vets from 100 countries have registered for the event and nurses. So it will be great to see where everybody is listening from, and perhaps a a photograph of where you are in the world on social media would be fantastic.
Thank you again to HDe for making this session possible as well. So let's see if we've got some questions. I'll move closer.
You can look at my pictures of African mammals, the zebra and the . I think it's a sable antelope. Oh no, it's a kudu.
I think you've seen a kudu there, oh no, you've seen the zebra and the what's the other one? It's a rhinoceros, I think, isn't it? Oh no, I think he's seen the two middle ones, sable antelope.
Anyway, less of this, let's ask some questions, . Owen, Sylvia's asking, do certain lymphomas do worse with Preds only? I remember being told that at university as well, Sylvia, so I don't know what your thoughts are on that, Sylvia.
Oh sorry. I, yeah, no, I, I think if you, there's a couple of things there. If you start treatment with a with a high grade lymphoma with prednisolone and you get the disease into remission.
You are applying a selection pressure, if you like. If you think in terms of evolution and natural selection and survival of the fittest, you're given a, a weak treatment that will kill some of the lymphoma cells but not others, and you will set up a situation where if the lymphoma happens to evolve resistance to drugs. Then it will be highly beneficial.
That's always the case for treatment with other cytotoxic drugs as well, but they'll just kill more of the cells. So if you pre-treat with prednisolone, you get into remission and you get the disease recurring, it will often be resistant to a number of drugs because the mechanism of resistance is expression of this multi-drug resistance pump that will extrude not just prednisolone but a lot of other drugs from the cell. So that's the pre-treatment issue.
There's some of the indolent lymphomas and I think cutaneous epitheliotrophic lymphoma as well. Have suggestions that if you treat those or treat them with steroids, they'll do worse. And that's not just a treatment with steroids thing, that's treat them with anything.
That comes from retrospective studies where the dogs who had treatments did either no better or did actually worse than those that were left untreated. And on the face of it, it may sound quite compelling, but you've got to think that that there were vets like you and me making decisions to treat these dogs or not to treat other dogs. And the ones who were treated were probably more advanced and had worse clinical signs.
And so the treatment there may just be an indicator of more advanced or more severe disease rather than being an inherent negative prognostic indicator. Oh, an epitheliotrophic lymphoma is one of my er sort of interesting diseases that I followed as a dermatologist and it became quite personal when, The histopathologist diagnosed my, my own dog had some lipuliodermas which I cut out and being a good dermatologist, I sent them out to, to be biopsied, and they came back as epitheliotropic lymphoma, but he, he then lived for a long time. I, in the end did just put him onto steroids and in fact he, you know, the lymphoma wasn't what killed him.
So. When I spoke to the pathologist about this, I think this was where you begin to understand, you know, is the lymphocyte inflammatory, or is it neoplastic, is it reactive? And there is a real spectrum of how the lymphocyte is reacting as well, isn't it, because when I used to see epitheliotrophic lymphoma, it was usually dogs that were falling apart, you know, in front of me and actually Lumustine, er, you know, had some good effect there.
And even using Masivvet sometimes also helped. So again, there's a continuum of a lot of these diseases, and I suppose as you saw with your middle case, some of them perhaps never get noticed because they almost don't need any treatment either. Yes, yeah, absolutely.
And I think with the epitheliotrophic lymphoma cases, they're often picked up quite late. Yeah. The, the disease is quite indolent, so that's another type of indolent lymphoma has a very long time course.
And if you do happen to happen upon them quite early, then yeah, you can get a very good outcome. Hm. Brilliant, we've got Martin, I think one of our old colleagues from er Liverpool.
Is there still a role for L asparaginase in the treatment of canine lymphoma as a precursor to chemotherapy, and Richard has asked the same question. Yeah, no, I think that's a good question. Yeah, I just wish I had more time to, to talk about that really.
If you use asparaggenase as a precursor to chemotherapy, then what it's not going to do is improve your emission time or disease control. OK, it's not going to get you a better survival. What it will do though is knock down the disease quicker.
And if you've got a hypercalcemic dog who's having dysrhythmias and muscle fasciculations or a dog with a big mediastinal mass and can't breathe and needs oxygen, or a dog with zero neutrophils and it's in danger of going septic. You want to get them better as soon as possible. So the rapid knockdown of the lymphoma with asparaginase is really, really useful as an in these emergency cases.
The other thing is if you've got a dog who needs to go to theatre for a big surgery and has also got lymphoma, you want to treat the lymphoma, but giving steroids and cytotoxic drugs is not a great idea if you're gonna do a big operation on them. Well, you can control the lymphoma with use of asparaginase as well. So I think it's a great drug, it's a really useful drug and I tend to use it in those scenarios when for some reason chemo is not appropriate, but you need to treat the disease or if you're in the emergency setting.
Thanks, Owen, we've got a question here. We always love cats on webinar best. I know we can't go into too much time with this, so maybe you're just a quick snippet.
Tatiana's asking, are there any novel treatments for intestinal lymphoma in cats? Yeah, it's another good question, Tatiana. I'm very sorry to say I don't know of any novel treatments for intestinal lymphoma in cats.
In general with feline lymphoma, and there's no established best treatment, cop is often just as good as chop for a lot of treatment, so no, I'm, I'm not aware of that. And just looking where people are listening in from, so we've got Ilona in Ukraine. I hope everything is as good as it can be for you there, Ilona.
Maria from Uruguay. Alfredi from South Africa, Somebody else listening in from Argylehi in Scotland. So people listening in from from all over the world.
So thank you so much for letting us know about that. Really interesting point, Owen, that I think you brought up about the how starving can reduce some of the unwanted side effects. Was that within Christine?
That was Bencristine and doxorubicin in dogs. It's been shown in people with a lot of other drugs. So lamucine, does that have a, a better effect as well, starved?
Yeah, I can't, can't see why it wouldn't. If you, if you starve your your, your cells are battening down the hatches, and they're better able to deal with stresses of all kinds, whether that is cytotoxic drugs or low blood glucose or hypoxia. So the, the cells are bracing themselves, whatever's gonna hit them, and if that's lousine rather than doxorubicin, I, I think their response would be no, not really much different.
But I'm not aware of any prospective studies of that. I'm just speaking . From what seemed logical.
Owen, thank you so much for for staying on that little bit longer there. I think that's most of the questions. If we've missed any, I do apologise, but we're a quarter of an hour over, so you've been really kind to stay a little bit longer.
Thank you. No problem at all. It, it, I think both sessions have been really excellent and it, it's fabulous to see how oncology is coming on, you know, I lost one of my relatives, a few weeks ago to oncology, to, to cancer, so obviously it's still a, A disease that we need to tackle and defeat, but there's obviously fantastic progress going on, so, and interestingly, you know, we can learn, doctors can learn from vets and vice versa.
So thank you for all of the fabulous work you and of course Doug are doing and Doug's still on. Thanks ever so much. Thanks for inviting me.
Cheers and thank you so much for HTA for sponsoring this particular session. As I say, please do comment and leave notes and pictures on on your various social media channels with hashtag. At VC 2023, as I said before, tomorrow's session 2 till 5 is on sustainability.
It's entitled regenerating Hope. We all need a bit of hope in these trying times. And then tomorrow evening, some great nutrition lectures from Georgia Woods Lee on alternative diets and obesity as well.
So hope to see you tomorrow at these lectures and it's good night from Liverpool and the webinar vet. Bye bye.
