Dr. Ronald Witteles discusses common cancer therapies and their ever-expanding list of associated cardio-toxicities while proposing a need to expand the specialty of Cardio-Oncology.
Back to Symposium Page » and our next speaker is Dr Ron with Ellis from Stanford. I have the unique pleasure and fortunate to have trained under Dr Hotels at Stanford during my heart failure fellowship. And it was sort of my first foray into understanding about amyloidosis, cardio oncology, sarcoidosis. Prior to that, I thought this was all something hematologist did. I do remember one of my first questions Thio, Doctor. Jealous in my in the afternoon clinic and amyloid was I don't understand for the life of me the difference between amyloid between myeloma, between Angus, that alone is confusing. So why don't we start there and then we'll get into the types of amyloid whatnot. So I've learned a lot on Bond. The doctor will tell us, directs Elise programs and more recently, is also the editor off the party oncology journal. A really great general when it comes to these topics and sort of a home when you want to look up review papers and what's latest and greatest in this field. So thank you, Taylor, for taking the time to be here on a Saturday morning and educate us on this topic. Thank you, Jay. And thank you both. You and regime for putting this wonderful session together. This wonderful conference I really enjoyed coming last year. And, uh, there's no place I enjoy coming Teoh Mawr for a conference in San Diego. So it's too bad we have to do this virtually this year. But I'm really glad and honored to have the opportunity to participate for anybody who have who may have been at the meeting last year. I talked about cardio oncology in 2019. I promise you, this is not just a rehash with a couple of extra slides that we're gonna cover. Ah, very small amount of the same material. But I've tried Thio focus on a lot of material that we didn't cover last year s O that any repeat attendees will be able to hopefully learn something. So let's get started. So we're gonna really focus on the four cancer therapy specific specific toxicity is listed up top after cycling's her two inhibitors, veg F inhibitors, and particularly on the hypertension associated with them and immune checkpoint inhibitors. Now, one of the things I want to emphasize and I'll point this out at the end is that cardio oncology is an exceedingly broad field eso I've listed three types of toxicities we're not covering, but there's actually many more than those is just impossible to dio in a single talk, and I'll close with some thoughts about the role of a cardio oncologist. So let's start with an three cycling's. These, of course, are very potent. Anti Me A plastic agents for multiple tumors. I've listed some of the common ones. Obviously docks, Robison or Adriamycin is the most common one. They're used for a number of different tumor types, the most common being breast cancer, lymphoma, leukemia and sarcoma. Uh, the mechanism toxicity is has been understood in more recent years. Toe likely largely be mediated via its effects on Tokyo I som race. But with that, there's a significant component of free radical formation and injury as well. That contributes now if we're trying to get a sense of the rates of toxicity, if you turn to the label, you'll read some of the statements I put up there. They say the probability of developing impaired my cardio function is and you see the numbers 1 to 2% of the sort of typical doses of about 300 mg per meters squared and goes on so on and so forth. Upto 6 to 20% at 500 mg per meter squared and they go on. And they say that treatment of dots Robison induced congestive heart failure includes the use of digitalis diuretics after load reduces, such as a sin hitters, low salt diet and bed rest. And such interventions may relieve symptoms and improve the functional status of the patients, so we should probably not be taking this too seriously to begin with. Hopefully, most of us aren't prescribing bed rest to improve the functional status of our heart failure patients. But on the other hand, if we look at the actual numbers of top, let's see how true those are on the numbers mainly come from this famous or, I would argue, infamous graph. This shows the probability of congestive heart failure on the Y axis and the total cumulative dose of docks Robison on the X axis, and you can see that the numbers are really quite small until you hit a so called inflection point at about 550 mg per meter squared so often hear this number as the maximum dose that people can receive. The problem, of course, is that this publication came in 1979. Before there was really any decent cardiac imaging thio know what the real rates of toxicity were. So these numbers are really based on oncologist making a clinical diagnosis of heart failure. And so you can imagine how much this might be underestimating the true prevalence. So, um, or reason, not even that recent anymore. Look at the data came from this study in 2003 by swaying and colleagues on. What they did is they looked at three and three cycling trials, and the nice thing with it is that they each of the trials had frequent cardiac imaging. Toe look for real rates of important cardio toxicity. You see the definitions of a significant events. Most of the events were what I highlighted an e f drop absolutely f drop of at least 10% going from baseline normal thio abnormal. And if you look at the numbers, you can see that at 300 mg per meter squared, it's not just off its Instead of 1 to 2% it's actually 16% and at 550 mg per meter squared. It's not 6% it's 65%. So the data is literally off by a full order of magnitude. So considering that, let's ask the question, Well, how often should we be? Screening LV ejection Fraction and patients who receive answers? Cyclones and I've listed a bunch of options. Seven different options up there. I Last year I went through these details. I'll just hit the highlights now on you see very, very different ideas. So So where have I come up with these? Well, because each of these strategies are endorsed by major groups and societies as of today on De. So just to give you an example up to date, which is where a lot of people turn, gives a couple of options they say are reasonable. 240 mg per meter squared and then every 50 mg for me to square thereafter or 360 mg per meter squared in every two cycles thereafter. If you turn to the American Cancer Society, they take a different approach. They take the ostrich, stick your head in the sand approach, and they say it. It's almost unbelievable to read this, but this is what the American Cancer Society recommends, patients should be advised to be aware of the potential risk for cardio toxicities and report symptoms such as shortness of breath or fatigue. However, routine screening or testing for cardiovascular disease in asymptomatic patients beyond careful history and physical examination are not warranted. So they're saying, Forget it. There should be no standard cardiac imaging that is being done outside of symptoms, so unbelievable, really. Uh, the European Society of Medical Oncology takes a very different approach, and they take approach of what I would say is overkill. So let's look at their algorithm here. You're They say that if you have, if you're getting answer cycling's and an echo at the end of chemotherapy shows no LV dysfunction, you should still get another echo three months later. And if that shows no LV dysfunction, you should get another echo three months after that. And if that shows no LV dysfunction, you should get another echo three months after that. And if that shows no LV dysfunction, you should get another echo three months after that. And if that shows no LV dysfunction, you should be getting an echo every year, So we have anywhere from Don't do any imaging it all to somebody who has normal findings at the end of their chemotherapy. Who's now getting four more screening echoes in the next year and then an echo every year after that. So talk about mixed messages. Eso If you're in oncologist trying to get a sense of what you should really dio, what are you going to do with this? So my recommendations that I think are guided by the data would be there for anybody getting answer cycling's. They really should have a Baseline F assessment, and then you should do it if they get to 300 mg per meter squared, which is a typical lymphoma dose and every 50 mg per meter squared thereafter. So some patients, for example, patients with sarcoma often get high doses of answer cycling's well. You should really be watching closely above 300 mg meter square, and then, regardless of the total dose, you should be getting one at the end of therapy. So, for example, the dose that's most commonly used when anti cyclones air used in breast cancer is 240 mg per meter squared. Those patients should absolutely get an echo or F assessment in some form at the end of therapy because they have about a 7.5% rate of true cardio toxicity. Using the definitions we gave before in terms of high risk cases, say somebody who starts with a borderline low e f um, there you have a few options you can consider an answer. Cycling free regimen, if appropriate. So, for example, in breast cancer, there's answer cycling free regiments that are usually perfectly reasonable alternative options. Of course, if they already have true LV dysfunction, that it should be goal getting standard heart failure therapy, they should be getting closer monitoring. I wouldn't wait till 300 mg for me to square, for example. But then there's other options that I think sometimes on the cardiology side, we don't think about as much as we should. And so I've listed three of the options besides not giving the answer cycling's at all or changing the dose to reduce toxicity. And that is infusion protocols like the Soma formulations and then the one I wanna highlight the most, which is dextrose oxen. So in terms of prolonged infusion protocols, you know, most anti cycling's air given. Essentially, as Boulis is on board, that's partially for convenience, partially because there was some thought. Maybe you get higher levels and they're more effective against the tumor. But there's now really quite robust evidence over time that if you give prolonged infusions, soem or gradually you limit the cardiac toxicity. So this was from a Cochran review in 2016, and it looked at a number of studies. And what you can see is that overall, you're falling on the left side of the line of equivalent meaning, favoring the longer infusions here to find as a t least six hour long infusions for decreasing cardio toxicity. Not practical to do for every patient who gets cardio toxin, Who's getting an answer? Cycling's but practical and wise to do in a particularly high risk patients. How about life? Isobel formulations? Here's another Cochran review. This formulation and others clearly do seem to lower the risk. The problem is that life Isobel formulations have only been studied in particular tumor types and psychologist tipo here not gonna want toe just take a leap of faith that an entirely different chemotherapeutic agents is gonna have equivalent psychologic outcomes. So unless that light is normal, formulation has been studied for the tumor type. For example, in some of the gynecologic malignancies, usually they're not gonna want to go there. Let's focus on decks. Prozac stain. For a moment, I think this is an under used agent eso. It's a water soluble analog of E. D. T. A. It's a strong iron key later, and unlike Dita, easily passes into cells and in Hibbert inhibits Tobias armories to the history of it is kind of interesting. It was developed in the 19 fifties by the Eastman Kodak Company of Kodak cameras and film. A swell as this other corporation, Ciba Geigy, I believe, is how it's pronounced as a jet fuel additive tech and for textile manufacturing. Andi as they kind of did back then. They tried a lot of things and said, Well, maybe these will be anti India plastic agents as well, but very quickly it was clear that the toxicity was too high on it was abandoned, but subsequently, in different doses, it was discovered that it could ameliorate and recycling cardio toxicity, and it also can ameliorate and recycling extra visitation injuries, which is actually also approved for, But we're gonna, of course, focused on the cardio toxicities part, so there's a few lines of evidence for its my cardio protection. I like looking at this study, which was published in the New England Journal in 2004, and what they did is they looked at Children who had high risk L. L and were getting docks, Robison based therapy, and they studied up with or without concomitant extra boxing. Andi. They defined three different proponent measurements, normal, so undetectable, basically troponin elevated proponent and then what they called extremely elevated troponin. Now, when you're in my world, we might not call above 0.25 of troponin C extreme, but for the purposes of this study that they're trying to differentiate that from really mild elevations. And the protocol again was to give Dr Robison at the standard dose, with or without extra boxing. So this is a really important slide because it hopefully gets at one of the concerns that I called this often have. If I'm giving Dexter's oxen, is it going to lower the anti Nia plastic efficacy of the docks? Robison And this slide would argue No you can see the overall event free survival eyes really identical between the two arms. Um, now this is sort of a surrogate measure of toxicity, but I'd say it's it's a pretty important one, and that is looking at the development of positive troponin during the therapy. So if you look at the second bar graph there that before treatments, you see that there percent of patients who had elevations in the sample was was very low. Azzawi would expect. But as they go on and get docks, Robison multiple cycles of it. If you look at the the bars all the way on the right, you see towards the end of their docks. Robison therapy Almost half of the patients who were getting docks Robison alone had elevations in Proponent versus almost nobody very small under 10% for those who are getting dextrous oxen. And what's more is, if you look at the protection from extreme proponents, you see similar findings. Onda. And so it's telling us it's clearly doing something to ameliorate cardiac injury. Here is ah Cochran review of the evidence of Dexter's oxen for impacting not just proponent positivity, but clinical heart failure and you can see there is no question where this signal lies strongly on the favor of the dextrous oxen are, um how about again this question of does it affect the anti neo plastic efficacy? Well, this is still what gives oncologists, um, pause. So even though technically from Cochran, the Cochrane Review wasn't quite statistically significant, it crossed that line of equivalents. You can see it seems to fall on the side favoring control. Although it was really all driven by that one study by swaying in 1997 Andi again, I think the preponderance of the evidence points against it's really impacting the anti neo plastic efficacy. But if you talk to oncologist, this is why there's sometimes ah, little reluctance. Give it. And you might have looked at the data. I was just sharing and say, Why don't we give it every time? And this is part of the reason for that. But if you look at progression free survival, which is how on college is usually like to look at at response rates, you see right in the middle of between Texas oxen and control, So again I'd say the preponderance of the evidence is it's not really harming your anti neo plastic efficacy, but there's no question that it helps ameliorate toxicity. Overall survival again, crosses clearly crosses one. I wouldn't make much of the very slight trend on the favoring control when you when you look at the numbers. Okay, let's turn our attention to her two inhibitors. So the classic one that we think about is trash to sin mob on this eso understanding this so her two or human epidermal growth factor receptor to the gene was discovered in clone in the early 19 eighties. This is amplified or over expressed in about 25% of patients with breast cancer. It's denotes aim or aggressive tumor and shorter survival. So back before there was trash two's a mob and now other. Her two antagonists, patients who were unfortunate toe have breast cancer that was her to over expressing had a much worse prognosis. So trans Tasman was developed for this reason, and it was a monoclonal antibody. It is a monoclonal antibody against the extra set of the domain of her, too. So the original pivotal trial was here on it was published in 2000 and one in the New England Journal. It was women who had metastatic breast cancer, who all had her to over expression and who hadn't yet been treated for the disease. Basically, they presented with metastatic breast cancer, and their intervention was to get chemotherapy alone or chemotherapy plus trash to Sin Mob, which in psychology world is usually abbreviated h because of its brand name. Um, and if you look at the progression free survival, there's no question it was a home run. I mean, the it's still a bad disease, But but look at the difference that the transfusion have made. And that wasn't quite as dramatic on overall survival. It was still a clear, significant difference in these patients with medicine who presented with metastatic disease. But here was the bad news. So on independent review, they found that the percent cardiac dysfunction was really quite high over a quarter of the patients who got the anthrax cycling's and trashed Susan Mob, which is the bar on the left. The second bar are those who got anthro cycling's without trust. Susan Mob, the third bar are those who got trust Susan have without an three cycling's in the fourth bar are the ones who got neither. And so you can see that the cumulative effect of answers likens interest. Susan have seemed to be particularly bad, but here was the worst news. Eso when you looked at N Y j Class three and four heart failure. So really quite severe heart failure you're talking about one in six of the patients developed this, who got the anthro Cycling and trust is a mob versus quite low rates with all the others. So this presented a really problem because you had this quite effective Antonia plastic agents, but with really unacceptably high cardio toxicity rates when you combine it with an three cycling. So what happened, though, is that oncologists began to understand how to ameliorate the toxicity and the answer waas that if you didn't give them at the same time, but rather first gave the answer recycling and then waited to give the transvestism mob that the toxicity rates were much less. There's good mechanistic evidence for this. I I found this study to be quite informative. This was a small, mechanistic study, but it really tells you what's going on. This was of 10 her to negative patients who got answer cycling's. And then they took another 10 who didn't have cancer. It all and just had chronic heart failure. And what they did was they gave radio labeled. So in nuclear scan trans to Saman, not in treatment doses just to see where where it was taken up. And the patients who had gotten an three cycling's half of them had significant myocardial uptake of transfuse map, whereas none of the chronic heart failure patients did. In addition, they had done prior work showing that if you waited close to a year after the anther cycling, there was very little my cardio uptake. And the implication and this has been better understood with time is that her two is up regulated in the heart in response to acute injury. So if you have a patient who you've just injured their heart with an three cycling, her two is up regulated, and if you hit them at that point with Trask is a mob. You're really raising the rates of cardiac toxicity. So this is what eventually led. Thio actually quite quickly led to oncologist understanding. You have to separate out when you give them, and that's how it's always given. Now this is very important study called hero. This was over 3000 patients who were rant with her two positive breast cancer, who almost all had received previous anthro cycling based chemotherapy. And then they randomized to get stressed to sin mob for a year or observation. Now look at those LVF assessments. Ah, lot 036 12, 18, 24 30 36 60 months. Let's look at the data for the almost 1700 patients who were randomized to trust us a map. So the New York Art Association class 34 rate of heart failure was less than 1% 0.6%. And even if we say let's not just focus on the clinical outcomes, let's focus on the imaging Onley. 3% of the patients had to drop of at least 10% to an E f under 50 kind of a standard definition of cardio toxicity. And that despite nine e f assessments by protocol in the study, and I ask, is that even higher than what you'd expect in the general population? I mean, that rate is so low. That is probably what you'd expect if you just did nine serial echoes on random people. Now this is a nice study, which was of over 3000 patients with her two positive operable breast cancer. And they were recognized me there randomized to three different regimens. A C T, which includes Dr Rubin Generator. Meyssan without trust is a mab a C T H, which includes both or tch, which includes the trash twosome AB, but no answer. Cycling. So you get to see what happens with the three different strategies you can use in a her two positive patient, and you'll note that the median follow up was quite long over five years. Let's keep that in mind as we look at the data. So here is the LVF Cindy Charm, and it's it's It's nice because it shows you that that compared to the tch arm, which has the lowest rate with Tres Susan mob alone, um, it's higher as you get thio anti cycling alone and still higher when you get to the combination of the two. I'm sorry this in the formatting did not did not show. Unfortunately, I'm sorry when they reformatted the slides, it lost its proper formatting. Well, what this shows with the outcomes, I will tell you. I will tell you, uh, verbally. What it showed was the patients. Let me just go back to the different arms. The patients who got a c t meaning the anti cycling without trust. Who's a mob Did not, uh, are there oncological outcomes were unacceptably poor. So what that tells you is, if you have her two positive disease, you have to give trustees mob. But if you compare the a c t A charm versus the tch arm, the anthro cycling's basically saved you over the time of follow up. 20 distant breast cancer metastases. So you did get something out of the anther cycling's, but it cost you about the equivalent number of patients developing N Y j Class 34 heart failure, which is probably about an equivalently bad outcome. So it tells you that a C T H and T C H r probably both reasonable things that you could give for. I heard to positive patient, but what I want to focus on is the tch arm. So the there were four patients in the tch arm of 1030 who were randomized to it who develops grade three or four Congestive heart failure. That's less than one in 1000 people per year. And once again, I would ask, Is that rate higher than what we would have seen in placebo? Probably not So in now. Two different studies. We're seeing that with trash. Two's a mob you're talking about a rate well less than 1% of true cardia toxicity, despite lots of cereal monitoring with echoes. So what have we learnt? If you give answer, Cycling's can competently with trust is mad. There's unacceptably high rates of toxicity. But if you give them sequentially, the though there is some significant cardio toxicity. This could be watched for with routine monitoring and if you get transfused without an answer, cycling. In fact, the rates are extremely low, and routine monitoring is probably not appropriate. But screening recommendations don't reflect this knowledge. So if you look at the trans to smack label, it's still saying to reform Q three months screening with LVF, and that's for everyone, regardless of anti cycling. And again, I would say the data just doesn't support that. What's MAWR? They tell you that you need to do LVF measurements every six months for at least two years following completion of Herceptin. So how Maney echoes is that baseline one Echo form? Or during the one year of trash Susan mob form or after therapy? So a total of nine echoes is what they're saying for everyone, including if they don't get the anti cycling. So I would argue this is screening overkill. And so what this leads to is oncologist vote with their feet. This is an actual study that was trying to support that screening recommendations are being followed. This shows echoes and Mug is in patients who are consecutive patients who were getting trashed to sin mob. To me, this looks like modern art. This is just all over the place, and this is the reality of what happens if you talk to oncologists. This was another study that said, How often are you getting echoes or mug is by looking at actual claims data? And as you can see, most patients got exactly zero. And in fact, the people who got the fewest were actually those who got anthro cycling's. So the recommendations air so muddled that unfortunately oncologist vote with their feet and often just throw up their hands and say, You know, we're just not going to screen at all. So my take in terms of screening for LVF trustees mob business follows for a standard risk patient who's received and recycling and is now going to get transfused. Mab, you should do baseline. You should do post answer cycling and then every three months on trust is a map. And if it's normal, that's it. In a standard risk patient who has not gotten answer cycling's Who's just gonna get transfused? I actually don't think the data support any screening being done. And in the high risk patients where there is, let's say, longstanding, really poorly controlled hypertension or a known borderline or reduced LVF. Then, yeah, it probably makes sense, toe follow them, regardless of whether they're gonna answer cycling. But that's, of course, the distinct minority of patients. There are other her two strategies, such as this one called TDM one. This is pretty neat idea where they are using the her two receptor not as a way of directly targeting the sell by inhibiting it and killing the tumor that way, but by targeting the cell with super site of toxic chemotherapy, which is what the D. M one portion is, and they use the trust. Use a map to just hone in on the cancer cell, and this is just 11 study is an example, with almost 1000 patients, and they randomized them to this agent, TDM one for an alternative regimen and again with frequent LVF assessments, you see that the rate of F drops under 45% was really low in the TDM one arm and, in fact, lower than the alternative on. Yet the arm that did better in terms of treatment was the TDM one arm. So it tells us that even if the patient can't get trust is a mob or has failed, trust is, um there's lots of other good options. All right, let's move on to the next toxicity, which is anti veg F T k eyes, which and I want to focus on the hypertension because it's the most common toxicity. So veg F inhibitors can cause hypertension by a variety of mechanisms, so they change the balance of basic constrictors. Invasive dilate er's in the vessels themselves. They have an effect on end of filial self survival so it leads to increase systemic vascular resistance. And then there's direct effect on the kidneys as well. And it's probably that constellation of all three of these effects that leads to the hypertension. So we did a recent study at Stanford on this. It was a recently published way, looked at data from actually over a decade of patients who had metastatic renal cell carcinoma, and we looked at every single patient at Stanford. You got treated for that with the variety of anti veg F tyrus and Chinese inhibitors, as you see listed there. And we were just looking at the blood pressure measurements, and we were able to take advantage of the robust databases at Stanford and every single time those patients were at in the health care setting and had a blood pressure measurement. We were able to capture that, and we looked at very co variants and, uh, accounted for those. This is a real world population. These weren't study patients. You see that 80% of these patients had preexisting hypertension by the 2017 a C C. H A criteria, but there were generally well controlled at baseline 1 30/77 or so. Here's the change in blood pressure that happened during the therapy, and I should say we had a controlled population as well, which for patients who are getting other therapies that we did not have anti that Jeff activity. So if you focus on those who are getting the single agents anti veg F T k I, you can see that on average they had an increase in blood pressure of about eight or nine systolic and about seven diastolic. Now that's the average over. The whole study period is I'll show you. It goes up a lot higher than that early on. And what showed that this was really data was that when you looked at the control population, they had no change on systolic or diastolic at all. So this is a really, really affect what s'more, if you gave them, if they finished one course and they failed it from a psychological standpoint and you're switching them to a different agents, it didn't really increase your systolic blood pressure further. But diastolic went up by about another additional two points above that Andi. There was a variation between the different agents you can see exited, which is now a commonly used anti VHF tiki. I was the particularly bad one compared to other agents. Now this I know a lot of data. I'm just going to circle the important parts here. This was the change in blood pressure, depending on how you treated them. And I want to point out that before this kind of data, we really didn't know. Are there some agents that are better than others? And what stood out is that calcium blockers and typically and load up in because others, like Delta and Rapid, often will have drug interactions with them but and load up in typically clearly stood out as the best agents. Maybe maybe old Austrian antagonist did as well, but those numbers were too small. The error bars were too large to know for sure, but it didn't bring out Hey, using and load up in in these patients who develop V Jeff inhibitor TK induced hypertension is probably the way todo Here's the time course of the systolic blood pressure changes and so you see it really shooting up in the with the first cycle. And so the average patient had an increase in the systolic blood pressure of 13 millimeters mercury. The reason it comes down with time is because they got treated and diastolic similarly jumps up by about eight or nine millimeters of mercury. Um, all right, I'm getting to note about five minutes to panel discussion. I think I have 10, but I think it goes to 9. 35. But I'll try to move along. Um, so, uh, if we look at hypertension as well, it actually has an important prediction for tumor response. So this is really interesting, actually. So when your patient develops hypertension, you could tell them there's actually some good news with that. So this is an analysis for three trials of patients with metastatic renal cell carcinoma, and they looked at survival based on whether they developed hypertension or not. And it turned out that whether you're looking at systolic blood pressure on the top or diastolic blood pressure on the bottom that, uh, that thesis, Irv I vel was considerably better for the patients who developed hypertension. Why could that be? Probably because it tells you that that patient is sensitive to that anti veg F t k I. Excuse me and and if you look at the next question. Oh, does that mean we shouldn't treat the hypertension? If developing hypertension is a good thing? No, that's not to take away. In fact, the only group who does worse is the group who did not develop hypertension. Regardless of how you treated it, patients did better. So when you see these patients in your clinic, you could tell them Hey, good news. That actually probably means that their cancer therapeutic agent is working, but we need to treat the hypertension to present to prevent what could be bad cardiovascular events. Alright, the last main class I want to focus on is immune checkpoint inhibitors. So Checkpoint inhibitors, of course, have been one of the real major advances in the last few years in cancer therapeutics. Who could give a whole talk about how they work? I'm just gonna hit the main highlights. Three idea here is that the immune system eyes one of the main ways the body prevents tumors from forming on do it. But the body also has checkpoints on immune system so that you don't attack yourself on, so there's a couple of different ways that this is done. One called C T L A for the other called pd one with or it's like an PD l one. And so, uh on Ecologist ultimately developed agents that block these checkpoints to unleash the immune system to attack the tumor. Ah, lot of tumors a lot. A lot of cancers sort of wisely Will will over express these checkpoints to so that the body's immune system doesn't attack it. So we want to inhibit those. Let the immune system attack the tumor. The problem, of course, is that if you're unleashing the immune system, you can get toxicities. Eso g I skin endocrine hepatic pulmonary toxicity, neurologic toxicity, all these air common. So if they can attack those organs, why couldn't they attack the heart? And the answer is, they can, um, unfortunately, as we'll get into it seems fairly uncommon. Amazingly, though, despite the fact that this was a very predictable toxicity, no routine testing for Macro Titus was really built into the trials. This was the first Newman Journal report on this. I think it's probably the highest author to patient ratio ever. 32 authors describing to patients. So 16 toe one, all that being said it was a really good report. Um, they looked at two patients who died. Unfortunately from fulminate my card itis who were getting combination checkpoint inhibitors. Um, they did autopsies, and they found a number of interesting things. Both of them had t cells and macrophages infiltrates. And really, interestingly, the selective T cell populations which were infiltrating the mic Ardian were identical to those present in the tumor and that one of these checkpoints lie against the PD. L one was highly expressed in myocardial tissue. The authors then interrogated the corporate safety databases of the makers of these drugs. Andi found that the rate of drug related severe adverse events of myocarditis that were reported was 0.9% which seems quite low, but with an important caveat. Although if you looked at people who were getting those combination, checkpoint hydrotherapy was quite a bit higher 0.27%. So you may say a 0.27 That's not that. That's nothing. Remember, A. This is presuming that every case gets reported to the corporate safety databases we know that doesn't happen. Be, um 0.27% may not seem that high, but that's the rough numbers one in 400 or so. Well, if 1 400 are getting life threatening toxicity, all of a sudden, that actually does matter. Here was a slide showing the from the journal articles showing the electrical instability the T cell infiltrates. They also went to the same group of authors, went and interrogated the World Health Organization's database of case safety reports and found that other itis is a pericarditis, temporal artery itis and then Nepali. My Algebra Matic, a other auto immune vascular diseases, had much higher rates compared to other therapies with checkpoint inhibitors. We did a screening study at Stanford to say, Hey, could we use troponin too screen? And between September of last year, in April of this year, we screened 174 patients and we did a lot of screening. So I think every every dose of immune checkpoint inhibitor up to the up to the 10th round of its They would get proponent tested and we defined three levels Normal proponent detectable but not above the upper limit of normal in that 30.17 point 55 nanograms per mil leader or significantly elevated above 0.55 I want to emphasize lots of logistical work had to go into this, Andi, because every time a proponent was positive, somebody had to act on it. Here's what we found Most people do not have Proponent positivity is your A Z would hope and expect the ones in purple are ones that did have your opponent. Positivity is but were ultimately determined not to be from my card itis off. Usually it was somebody with supply demand mismatch who was ill for other reasons. But there were 44 specific cases that were picked up of my card itis. And I want to point out none of these would have been picked up without proponents screening that they had not yet reached clinical sexually. And they developed Realtor opponent elevation. So this is in nanograms per leader. You could divide by 1000 to get two nanograms per mil leaders. So this is getting to proponents of 10 in this patients. This is getting to proponent of 12 in this patient. This is getting to the opponent of four in this patient. So these air Realtor opponent rises and all of them had imaging correlates with Emery clear imaging correlates of my card itis. And again, I want to stress that this would not have been picked up without perspective. Proponents screening. So what to do? What to do with this? You know, I'd say screening protocol seems reasonable, but it's early days and Thio put that in place. You really have to have good infrastructure set up. It probably makes a particular role for patients. Get that combination checkpoint inhibitor therapy, certainly, with or without screening. Once you've recognized my card itis, you need to stop the checkpoint inhibitor and institute early therapy. Certainly steroids. You could debate what else should be used. There's many unknowns that remain. When should you biopsy? What's the best treatment? And in a patient like this, could you ever restart in immune checkpoint inhibitor? All right, so in summary, three World of cardio oncology really has a dizzying array of toxicities. This was from a review article in circulation I co authored in 2015, and I show it not so that you can read what's on the slide, but a to show how many different agents there were, but also how quickly the field moves. This slide was immediately out of date by the time or this figure by the time it was published, because we didn't include checkpoint inhibitors because it wasn't yet known. So the field really moves quickly. Uh, who should be referred to a specialty cardio oncology clinic. And this is just my opinion. There's obviously no evidence to guide this. I'd say it depends on the refers comfort and the clinics availability and I list. Uh oh, I'm not going to read through them all, but I list a host of things that for sure a patient should be referred with on. Do you see there is many different things on there and meaning that if you're gonna call yourself a cardio oncologists, you really need to know how to manage these things. I think there's some other ones that are more questionable. Let's say general cardiac care in a patient with cancer, I don't know if that really needs to be a cardio oncology clinic, but you see that host of things that really, really needs to be okay, So in overall conclusion, my takes eso anthro cycling's, I would say the classic form of toxicity on are still a major problem because they've been around for a while doesn't mean that we should ignore them on. I actually think generally under screening occurs with him for trans twos. Mob cardio toxicity is really dependent on whether or not they are also having or had, I should say, after cycling exposure and unfortunately, have this mix of under screening and over screening that I reviewed V. Jeff inhibitor associate Hypertension is very common. It actually probably a good thing in terms of correlating with humor response but needs to be treated with. And I would say, um, load, opinion and perhaps brutal act on should probably the preferred agents immune. Checkpoint inhibitor toxicity is fairly uncommon, but could be deadly, and there may be a role for perspective screening. And again, this is really a complex field with the need for cardio. Oncology specialist uh J. Was saying when he was introducing me, he was highlighting this journal, which I'm privileged to be an associate editor on Jack Cardio Oncology. For anybody interested in the field, Really, what encourage you toe read it. It's a quarterly journal. It's open access so anybody can access that and and really high quality publications and cardio oncology and I'll point out for anybody interested in her or who does work in amyloidosis were also our goal is to also be a real home for amyloidosis research both a Ellen translate written. And with that I will stop, I think right on time and look forward. Thio discussion. Thank you, Dr Exactly on time. A second, maybe 9. 35. Perfect. Thank you. While my slides load up, I think there were a couple of questions from the audience that it's gonna get through quick. Andi think one question productive would tell us, uh at what baseline ejection fraction. Would anti cyclones be? Absolutely Contract indicated for cancer patients. It's a great question. I always worry about the term absolutely contraindicated because everything should be about risk benefits. I think it's really important to have a conversation with the oncologist about just how important answer cycles are for that tumor types. Are there any reasonable alternatives? Eso You know, I'd say if I had to pick a number where I'd probably say we just cannot do it. I mean, I probably below 30%. I don't think there's any any scenario where I'd be brave enough, but but you know somebody's a 35. I'm going to be pretty darn worried about giving any. And again if there's a reasonable alternative we're not going to. And but I would say in anybody with riel LV dysfunction, who needs to get answer cycling's, pull out all the stops, do the infusion of protocol and give extra socks. And, most importantly, question two. If a patient with no cardiac diseases receiving presents to MAB alone, do they need screening with Echo? It's a great question. You know, there's there is what the label says, and that is what I say, so you can choose to follow who you want. The label says that everybody who gets trashed use a map should be getting Q three month echoes, uh, during transfusion therapy and then Q. Six months afterwards, Uh, for for a couple of years again, hopefully I highlighted. I think that's overkill for patients who are not getting answer cycles and who don't have other high risk factors. And I actually don't think that the data supports screening them at all. Doctor tells court another quick question for you that I have in the meta analysis that you showed with and recycling based cardio toxicity. You said it about 300 mg per meter squared. It was actually on the order of nearly 16%. What was the time period? The follow up time period in which that L B F change was noted. Yeah, those those studies were did not, like continue echoes for perpetuity. So usually those were pretty quick. I would say this gets it this question about early in late toxicity of cycling's. And I would say I think it's a misnomer. All anthro cycling toxicity is acute toxicity. It's just that sometimes it doesn't clinically manifest itself until years later. By the time the person's had enough remodeling of their heart to drop their E f, I would say in somebody who has a truly normal eco at the end of their answer. Cycling therapy. I personally don't believe that they that you need to keep getting echoes after that, but it really needs to be truly normal at that point and does the treatment. If the treatment included, you know, if it was left side of cancer, for example, with radiation, does that change your kind of follow up strategy after, Yeah, it does and I with radiation. It's which is a whole other topic, but it really depends what kind of radiation you're talking about. So breast cancer radiation you're talking about the biggest risk is actually of L. A Di disease mid led disease because of what's in the field. Um, but it's, uh, but there are statistically higher rates of lower E f with it as well. A supposed to Hodgkin's disease radiation where, particularly people who were treated a while ago really get the base of their heart blasted and valve disease. Osteo coronary disease and, of course, restrictive and constricted pericardial disease are all common right side of breast cancer. Does not carry for radiation for does not carry any higher risk for obvious and atomic reasons. So the question was 27. 0, so I should a case about this 27 year old patient transferred and cardiogenic shock BT had a genetic mutation e c. D. And then came in with some more BT Later, when you transplant patient to eliminate for the risk, how did you treat? So it's a good question. So basically we treated the patient with anti medication, actually, Way offered an e P study, and the patient was hesitant to get a P study unless he If the medications did not work, he would then go for any P study. So basically on solo and on a beta blocker is what he's on right now and in terms of transplanting to eliminate for the risk. I mean, he's only 27. His contract ladies preserved and other than the arrhythmic event is doing fine. So our goal is Let's try to suppress the arrhythmia, if not by medications. A B A B D ablation, if possible. A supposed to transplanting him at this stage. Given the medial graft, survival is still, you know, 8 to 10 years and he's only 27. We'd like to keep him going as long as possible with his own heart. Before we get to having, uh, saying you need a transfer