Managing cardiotoxicities for RCC treatment – Cardiologist’s perspective

Dr Ricky Frazer – Velindre Cancer Centre, Cardiff, UK

Dr Rebecca Dobson – Liverpool Heart and Chest Hospital, Liverpool, UK

RF: Welcome to this session today on managing toxicities for RCC treatment. My name is Dr Ricky Frazer, I’m a consultant medical oncologist at Velindre Cancer Centre in Cardiff and I’m delighted to be joined by a great friend and colleague, Rebecca Dobson. Hi Rebecca, do you want to just briefly introduce yourself?

RD: Hi Ricky, thanks for having me. Hi everyone, my name is Rebecca Dobson, I’m a cardiologist working up at the Liverpool Heart and Chest Hospital and I run the Cheshire and Merseyside cardio-oncology service. I’m really pleased to be with you today.

RF: Just to bring people onto the same page, we know that for advanced and metastatic clear cell renal cell carcinoma we’ve got a number of treatment options. We use the IMDC criteria to categorise patients to either favourable risk, intermediate or poor risk. The three treatment options across the different risk groups include single agent TKI, tyrosine kinase inhibitor, IO/IO combinations, so two immunotherapy drugs together, and then IO/TKI, so an immunotherapy with a tyrosine kinase inhibitor. 

Now, the challenge that that brings us is that if we’re using an immunotherapy checkpoint inhibitor plus a TKI we may get toxicity from either of those treatments. And the challenge for us is that they can be overlapping toxicities or adverse events, so sometimes there can be a challenge working out which agent is causing the adverse event or toxicity that we encounter. Rebecca, if I hand over to you, maybe just talk us through a little bit about some of the risk factors for developing in particular checkpoint inhibitor cardiotoxicity.

RD: Yes, of course. I think we all get understandably quite anxious about checkpoint inhibitor cardiotoxicity and one of the questions I get asked a lot is who is most at risk. I think the easy answer is that everyone is at risk but we know that there are certain groups that potentially have an increased risk. Those groups include patients who are receiving combination immunotherapy, so two different types of checkpoint inhibitor at the same time. Also patients who have had previous myocardial injury, so things like a previous myocardial infarction, heart failure, previous cancer therapy related cardiac dysfunction, previous autoimmune diseases. Then another group which we don’t know much about but I’m sure will come in the future years, there will be genetic predispositions to checkpoint inhibitor induced cardiotoxicity but we’re not yet clear as to what those genetic factors are. 

In terms of what we can do to try and mitigate the risk of checkpoint inhibitor induced cardiotoxicity, baseline testing is really important and this is for several reasons. One, it enables us to understand the patient’s risk at baseline and pick up potentially previously undiagnosed abnormalities. So, for example, we may have a patient who is seemingly well from a cardiac perspective with no history or symptoms and we would assume them to be low risk. If we then assess them at baseline, take a history, examine them, check some biomarkers, and by biomarkers I mean cardiac biomarkers such as troponin and NT-proBNP. If we do that and then detect, perhaps, an elevated troponin at baseline we may then go on to perform further investigations and pick up something like aortic stenosis, for example. And it’s really important that we know of these cardiac conditions before we start immunotherapy because it will help us tailor our treatment and perhaps even get in there first and perform some cardiac treatment such as a TAVI, for example.

Another reason baseline testing is really important is that we are monitoring these patients quite closely as they receive their immunotherapy. In order to interpret biomarkers down the line we need to know what they were at the beginning because many patients with cancer will have lung disease, will have hypertension, will have cardiac disease and will have elevated biomarkers at baseline. What we don’t want to do is incorrectly label someone with having a cardiotoxic reaction when, in reality, they had elevated biomarkers at baseline. 

So it’s really important that we risk stratify our patients and I’ve put this slide in here to make the point that this is not just for patients receiving immunotherapy, it’s all types of systemic anti-cancer therapy. This little graphic here is from the European Society of Cardiology Guidelines that were published a couple of years ago, just to invite the listeners to have a look at that. You can see it’s stratified by patient risk level and gives you some really clear, nice, simple investigations you can do according to risk and cancer therapy. 

RF: Great. So then, Rebecca, maybe just talk me through what you might look for on ECG and, in particular, I hear about QTc prolongation, what does that mean? Give me the very simple overview.

RD: So QTc prolongation is something that causes understandable anxiety. One of the problems we have with calculating the QT interval is that people do it in different ways. If we just rewind a little bit, in the simplest possible form what we’re trying to measure is the amount of time it takes for the heart to depolarise and repolarise. We do that from looking at your ECG and measuring from the beginning of the Q wave to the end of the T wave. Now that’s easy if you have an ECG like the one on this slide where there’s no interference and it’s a really nice, obvious Q wave and T wave. But we all know that in real life it’s not that easy. 

So little tips that I use, I always look at my ECG and try and work out which lead is the clearest and has the most obvious T wave and I always use that lead. Measure from the beginning of the Q wave to the end of the T wave and then we have to correct that QT interval for heart rate. Now, I use an online calculator to do that, we should be using the Fridericia formula for our cancer patients. So there are lots of apps and websites, it doesn’t really matter which one you use but you can put in your QT interval, you can put in your patient’s heart rate and it will give you a corrected QT interval.

It's really important we have that information at baseline for particular drug therapies because we want to know what it is at the beginning and then we can monitor it closely and assess whether we need to tweak treatments or look at other things like concurrent medications that potentially prolong the QT interval and clearly monitor electrolytes and things like that.

RF: So, Rebecca, let me give you a quick-fire case that I just want to walk through and there’s plenty to cover so I accept that we’ll need to keep some of the answers a little bit brief. So this was a patient, a 58-year-old man presented with shortness of breath, generally unwell. CT imaging showed widespread lung and liver metastases and a large left kidney mass. So the sort of patient I will see fairly regularly. All bloods are normal except low haemoglobin; performance status of 1 and so, based on the fact that he’d presented with metastatic disease and the low haemoglobin, he’d be IMDC 2 and an intermediate risk. Therefore I planned for an IO/TKI combination which would be my standard treatment here.  My first question, maybe just give me your 30-second version, would you consider doing baseline testing here and what risk factors should I ask about in a busy clinic? 

RD: Absolutely, I think we should be doing, or at least thinking about, baseline testing in everyone but certainly someone of this age because any 58-year-old man is going to have an increased risk of cardiovascular disease. So, yes, we should absolutely be taking a history from our patients, asking about symptoms. So he may not have any past medical history of hypertension but he may have symptoms of chest pain, breathlessness, things like that. So I would definitely take a history asking about cardiovascular symptoms and obviously a past medical history as well. 

RF: Okay, and then just in terms of baseline testing, just remind me. So ECG?

RD: Yes.

RF: BNP and troponin or…?

RD: Yes, it depends on where you work and what resources you have available but every patient should be having an ECG because this is freely available. We should be measuring cardiac biomarkers in all of our patients as well, so troponin, either a troponin T or a troponin I, and an NT-proBNP. Now, international guidelines recommend that all patients have an echocardiogram as well, I don’t think that’s realistic at the moment.

RF: So I was a well-behaved medical oncologist on this occasion, did an ECG and cardiac markers at baseline and they were normal. Things were going well but then pre-cycle 3 we did routine blood pressure which we would do before each treatment and the blood pressure is elevated. They’re asymptomatic, feeling otherwise well. So I guess the question here is how should I approach this increased blood pressure in a patient who is on this combination?

RD: Really good question and I think this is one of my bugbears is that I feel that we all, cardiologists and oncologists, probably undertreat hypertension and we’re all very quick to explain it away and say, ‘Oh, the patient is anxious, they’re in pain, they’re stressed, they’ve waited three hours to be seen, they couldn’t get a parking place.’ But actually we know that many of these drugs will cause hypertension and if we get in there early and treat that hypertension we are reducing the risk of future cardiovascular events but also future cardiotoxic events. So this graphic is again taken from the ESC Guidelines and you can see that a lot of these drugs have a very common effect of causing hypertension and we shouldn’t be afraid to treat that.

So I often get asked, ‘Well, what do I use? What drug should I use to treat my patient’s high blood pressure?’ So standard anti-hypertensives with the only caveat being to avoid non-dihydropyridine calcium channel blockers, the main reason for that being that they can potentiate the effects of VEGF inhibitors and actually make the hypertension worse. So just your standard ACE inhibitors, angiotensin receptor blockers, diuretics, bearing in mind that many patients will require more than one agent to control their blood pressure. 

Also important to remember that because we’ve caused the hypertension by giving them the VEGF inhibitor or the TKI, we need to anticipate that blood pressure drop when we stop their systemic anti-cancer therapy and make sure that we don’t leave them on lots of anti-hypertensives because of course they’ll get a hypotensive rebound.

RF: That’s a great reminder, thank you. So let’s move forward in this case. So if we then think about, as we said, those baselines were normal, we’ve managed the hypertension, but now the patient presents feeling unwell with palpitations and dizziness and there’s a little bit of fatigue, as I remember. ECG showed new fast AF and we commenced them on rate control. But I guess I’m left with the question is this just AF, could it have happened anyway, am I blaming or am I thinking about this being a TKI or an immunotherapy checkpoint inhibitor related toxicity and do I need to immunosuppress the patient?  So the first question, I guess, for me is I never know what the threshold is to get on the phone and have a chat with you, Rebecca, so thoughts?

RD: This is a really tricky one, isn’t it? You’ve picked a tricky case here which is something that we see all the time. Is this just a cardiac problem or is this a cardiotoxic problem and, if so, which cancer therapy has caused the problem? Now, in terms of the symptoms that I think worry me more, it tends to be patients who you’ve tried basic things. So you’ve got your patient with fast AF, you’ve given them some bisoprolol, you’re not getting anywhere, they’re still in fast AF. So you might give them some digoxin and they’re still in fast AF. That would worry me, if you’ve got someone with fast AF that is resistant to rate control, that’s the sort of patient you definitely should speak to a cardiologist about because probably it’s not just an arrhythmia, there’s probably a cardiotoxic reaction going on that is going to require that multidisciplinary involvement.

RF: That’s really useful. OK, so my next question, once I’ve spoken to you and I’m a little bit worried, is what investigations should I do. Very simply, for an oncologist, why should I do each of those investigations?

RD: It’s important to remember to do the basic, simple stuff first because I often get phone calls saying, ‘Can I have a cardiac MRI scan?’ and the patient has had one ECG and not very much else. So serial ECGs are really important in terms of investigations because we know that in patients who are having or perhaps developing something like checkpoint inhibitor induced myocarditis, they may start with fast AF but then they may develop T-wave inversion and then their QRS broadens and then they get some ST change. So serial changes in an ECG are very helpful in helping us work out what’s going on.

Echocardiograms are also helpful, particularly if you are working somewhere where you can’t get an MRI quickly. So an MRI scan may give you an alternative pathology, you may see a big pericardial effusion, you may see a regional wall motion abnormality and realise that actually this is an acute coronary syndrome type of picture rather than a myocarditic type of picture. Ultimately, a cardiac MRI scan is the only investigation that is going to answer the question is there myocardial oedema or not. So usually these patients end up having an MRI scan and that’s for two reasons. One, because, yes, we want to know if there’s oedema so that we can treat that. But it’s really important that we know there isn’t oedema as well.

So the last thing I want to do as a cardiologist is get this wrong and give you the wrong diagnosis. So cardiac MRI is the gold standard radiological investigation; it needs someone experienced to interpret that because these are subtle changes on an MRI scan. So using your MDT and making sure that you’ve got someone with some expertise in looking at MRIs of these patients is really important. 

The other thing to say is we’re increasingly finding a lag between the patient’s presentation and the radiological findings. In those circumstances what we tend to do is monitor the patient safely for a bit, a couple of weeks, and repeat the MRI scan. We often find at that second MRI scan that the patient has evidence of oedema. So if you get a normal MRI scan and you’re still suspicious don’t assume that the MRI scan is right and you’re wrong.

RF: That’s really useful. So, Rebecca, these are the trends that I’m tending to see. Now, I accept this isn’t an exact science but just give me the very simple understanding around this global oedema, BNP, troponin discrete.

RD: We’re certainly seeing different patterns, both on the MRI scan, and different elevations in terms of biomarkers. So some patients, and I’d say probably most patients, present with very high NT-proBNP levels. So we’re talking about tens of thousands but they have fairly unimpressive troponin. So where I work we use troponin T and the upper limit of normal is 14. So we see patients with troponin of around 20, 30, 40, which is much less than you’d expect in someone with myocarditis. But when you put them in an MRI scanner you tend to see global enhancement and global raised T2 values to suggest that there is myocardial oedema throughout the heart. 

That is in stark contrast to the other group of patients who tend to present with relatively unimpressive NT-proBNP levels but very high troponin levels, so in the thousands. When we scan these patients they tend to have more discrete areas of oedema, just affecting one or perhaps two parts of the heart. You might say, well, so what? What difference does it make? The main thing to remember from this is that if you have a patient with an unimpressive troponin, it can still be myocarditis. So many people, including cardiologists, will say, ‘Well, the troponin’s not high enough, it can’t be myocarditis,’ and it can be. 

RF: That’s super useful. OK, so this patient’s troponin was quite high, BNP maybe not as impressive, ECG I had the AF, ECHO was normal and MRI was consistent with myocarditis. So accepting now that we’re concerned or we’ve got good going evidence that this could be myocarditis, what happens next? The real question I want to know is there a role for steroids?

RD: Absolutely. So this has been a real sea change for cardiologists. In the past whenever I’ve looked after patients with myocarditis it’s been infection related or COVID related or something like that. Or young, fit people who’ve had a throat infection and then developed myocarditis and those patients tend to get better with supportive care, they just need to rest and they do not require any additional treatment. Which is not the case in managing patients who have got immunotherapy-induced myocarditis and we know that it's really important that we get in quickly with high doses of corticosteroids. Which makes us all feel a little bit uncomfortable, certainly as a cardiologist it makes my colleagues, my pharmacy colleagues, very uncomfortable. Patients need much higher doses of IV methylprednisolone, initially to try and dampen down this immune reaction. Then, obviously, there are other immunosuppressants that we can add in as appropriate.

RF: The one thing I really need to lean on the cardiologist for is the supportive care management and, in particular, I hear about the four pillars of heart failure and, accepting that that’s a lecture in itself, what kind of supportive care do I need to be thinking about?

RD: It’s a really good question and I think the first thing to say is none of us should be managing these patients unilaterally on our own without the expertise of other specialties. So certainly in Liverpool when we have patients with myocarditis the radiologist is involved, the oncologist is involved, I’m involved, pharmacy are involved. It’s a real collaborative approach to these complex patients. 

From a cardiology point of view, as you say, it is supportive care, there’s no cardiac drug I can give that is going to treat the myocarditis. But if the patient has an arrhythmia, like our case here, then we would treat the arrhythmia. If they have pericardial involvement, so they may have pericarditis and have some chest pain, or they may have a pericardial effusion, you would consider colchicine, you would consider a pericardiocentesis if it was indicated. 

If you have patients with left ventricular systolic dysfunction, and it’s important to remember that 50% of these patients will not have left ventricular systolic dysfunction, but if they do then you would consider your standard pillars of heart failure treatment. So ACE inhibitor therapy, beta blocker therapy, mineralocorticoid antagonists and SGLT2 inhibitors. And trying to get patients escalated on these treatments quite quickly is challenging but it just magnifies the reasons why we should be managing these patients collaboratively.

RF: That’s fantastic. So in terms of an oncology perspective, Rebecca, I’m often using ESMO guidance or ASCO guidance, or UKONS and the Immuno-Oncology Clinical Network, IOCN, have created some guidance around baseline testing and you and I were both involved in that. If you could give me one cardiac resource or website or organisation, what would it be?

RD: I think it’s really difficult because this is very under-recognised amongst cardiologists. So I would say I would use the ESC guidelines. As you’ve already mentioned, the IOCN are developing a whole series of resources and guidelines and consensus statements that are going to be really helpful. I would use all of the guidelines that you’ve mentioned and then I would add in the ESC guidelines as well.

RF: Fantastic. So this patient, we thought that it was likely myocarditis induced from immunotherapy. We treated him with high-dose steroids, they improved and actually the cancer responded well and we decided not to rechallenge. I’m going to follow this patient up. I just wanted your final thought on is there any role for cardiologists to see them again?

RD: I think it depends on how the myocarditis has affected the patient. So if they’ve been left with irretractable arrhythmias or heart failure, for example, then absolutely that’s a patient I’d want to see in my clinic so that we can help manage their symptoms and work with the oncology teams to guide their immunosuppression. If you have a patient, and luckily we’re seeing more of this, who has recovered really quite nicely from their myocarditis and they’ve not got any ongoing arrhythmias or heart failure or any symptoms, then that’s not someone I really need to see. But it’s a very much case-by-case basis. So if someone has ongoing cardiology symptoms that you or the patient are concerned about then, yes, I would definitely ask a cardiologist to follow the patient up. 

RF: Fantastic. So, just to conclude, we’ve covered a case here, a kidney cancer case that’s on an IO/TKI combination. We’ve talked about some of the potential symptoms that we should be asking patients about, some of those baseline tests. We looked at the presentation and we’ve talked about investigations that might be useful and here the cardiac MRI added a lot of value. We talked about immunosuppressive treatment but also supportive care management. Then finally we’ve thought about follow-up, certainly with oncology but also potentially for a role of the cardiologist as well. 

So on that note, Rebecca, I just want to say a massive thank you for joining us today. Thank you for enlightening me on things that I find quite tricky and I look forward to seeing you again soon.

RD: Thanks very much.