CASE ANALYSIS – WHY CANCER SURVIVORS NEED TO BE WARY OF CARDIAC DISEASE

Let’s start with a case because this is what happens every day when we are in our outpatient or inpatient clinic. This was a 49-year-old female that came to see us because she had breast cancer in 2004. At that time, she had right radiotherapy and chemotherapy, and in December of 2013, she started with heart failure, dyspnea on exertion, weight increase, and lower extremity edema. She was seen at a peripheral clinic and started on guideline directed medical therapy, with ACE inhibitors, diuretic and metoprolol succinate. 

When she came here and had the physical exam, she had JVP, so she was in S3 gallop and was in frank heart failure. In the digital clip of her echocardiogram – normally, this should be like a doughnut squeezing quite well – but the ventricle is dilated in this short axis view and barely contracts. And this apical four chamber view shows the same scenario, which is very dilated ventricle, barely contracting. And here with some secondary mitral insufficiency. 

THE UPWARD TRAJECTORY OF CANCER SURVIVOR HEALTH DOES NOT PROTECT THEM FROM CARDIAC DISEASE

So, this case illustrates what can be happening in these patients with breast cancer, lymphoma, or other malignancies that receive chemotherapy. Why does this happen? The population, if we projected to 2060, the longevity is increasing, and the population is aging more and living more. And there are more and more cancer survivors every year. Survivorship increases, and the mortality is decreasing year by year.

Around 2010, we see that the proportion of patients in these age groups, which are greater than 65, greater than 85, or 75 to 84, is very small. But as we move and for now, for 2020, it's around 18 million. And this is projected to be around 28 million by 2040. 

And the biggest proportion of the patients are those older than 65. And what was happening before? Cardiology and oncology were looking at different areas, and now together, we look at the same horizon because the patients needs are first. We're trying to take care of the patient, protecting their heart while they are taking their journey through their cancer treatment and recovery. 

WHO IS AT RISK FOR CARDIAC DISEASE AMONG CANCER SURVIVORS? 

Among different age groups, 0 to 19, 20 to 39 are very small, but the biggest are 40 to 64 and greater than 65. These two encompass around 75% of patients. And if we look at all these groups, it's going to be around 95% middle-age or above, 2/3rds of them are elderly. 

If we look at it by site, breast cancer patients and hematologic, mainly lymphoma patients, had a high lifetime cardiotoxicity of 5.3 million. This is in 2014. How about if we look at it now for 2019? We see males all the types of cancers, but I want you to concentrate mainly on the left, on non-Hodgkin's lymphoma and leukemia. In this group of patients, it's around 800,000 patients. For female, breast cancer patients and non-Hodgkin's lymphoma again, it's around 5.2 million. 

If we take into account all sites, it's close to 10 million in both genders, but the ones that receive more cardiotoxic chemotherapy are non-Hodgkin lymphoma and leukemia in men, and females breast cancer and non-Hodgkin lymphoma and some leukemia as well. If I were to summarize this, by male, non-Hodgkin lymphoma for 2019, it will be around 650,000 patients, while for female, it's around 4.1 million. 

The projection for 2030 is going to be around almost 900,000 for male and around 5.3 million for women. So, we think that the cardiotoxicity is around 5%. That is quite a lot of patients that we have to care. We never know which patient is going to suffer cardiac toxicity.

HOW DO YOU MONITOR FOR CARDIAC DISEASE RISK?

The basis of the monitoring for now is ejection fraction. This just shows Her Majesty the ejection fraction that we can look by different methods. But that's the gold standard to follow these patients. And if I were just to show in the next five slides a nice correlation of different methods for ejection fraction, this comes from a group of breast cancer patients that were followed for one year. At the end, there were only 100 patients. But the caveat is the following. 

Here you are, you came to your hospital, you have breast cancer. They're probably trying to recruit you for around 50, let's put it at 30, different studies that want you to be in their study. And then you're going through chemo and then somebody comes along and asks you, “Hey, I want to image you with three different modalities at three different time points.” So, it's very difficult to recruit patients. 

This is what they found. This is comparing real time 3D TTE, so echocardiography in 3-D and MRI. And the correlations are beautiful, above 0.83, 0.88, and you can see in the bottom the Bland-Altman, where there is not too much difference between the two methods. Again, this one is 3D echocardiography with CMR at baseline at the left, six months at the middle, and 12 months at the right. 

This is comparing MUGA, so the one that we used before, which was nuclear medicine with MRI, and again nice correlations on top, ours of above 0.88 and the Bland-Altman at the bottom again, quite tight. So, nice correlations. And this is comparing MUGA with 3D echocardiography, and you can see, again, nice correlations. 

So. whatever method you use, as I was showing you before, you can interchange between one and the other, or hopefully, follow them during their treatment. But what we think is easier is to do it with echocardiography because it's portable, non-ionizing, the patient will not have radiotherapy or any X-rays involved, and it can be easier done and just leave MRI for special cases. 

HOW DO YOU DEFINE CARDIAC TOXICITY IN PATIENTS? 

If you look at the oncology literature, there could be around 10, 15 definitions. This is what was published six years ago: “Cardiac toxicity is defined by a drop in ejection fraction of greater than 10 percent to a value less than 53. If this occurs, you repeat it in two or three weeks. If there is a doubt, you can use cardiac MRI.” 

Then, the Europeans decided to do their own definition and they said, “OK, let's do a drop of greater than 10 percent to a value of less than 50, again close to the previous one, to repeat in two or three weeks.” So, if we look at the rates of congestive heart failure, this was a very interesting study that we did here in Olmsted County. Olmsted County is a place where people live for quite a while, so we're able to follow patients that were consulted to two different hospitals, either Olmsted Hospital or the Mayo Clinic. 

In this case, we followed close to 1,400 cancer patients with 1,400 controls for 25 years, and we gender and age match each cancer patient to controls for all the co-morbidities. And we saw that beginning from the first year, patients with cancer had higher incidence of heart failure. And this small magnification that's there is just to show that from, just from the get-go, cancer patients had higher incidence of heart failure. 

CANCER PATIENTS WITH DIABETES ARE EVEN MORE AT RISK OF CARDIAC DISEASE

When we looked at the group with diabetes, this was even more pronounced. You can see already a divergence of more incidence of heart failure. When we looked at the dose of anthracycline, definitely it was greater than 300 mg per meter squared. But we looked at this again, just to whether we would recommend no anthracycline or yes anthracycline. And again, we saw the same curves. 

So, the pattern that's been repetitive in these patients is, if you receive anthracycline, you will have a higher incidence of heart failure. And what's happening then? That thing is that doxorubicin therapy is more malignant than the cancer itself. The mortality due to doxorubicin therapy is similar to ischemic heart disease, as well as the peripartum cardiomyopathy or other diseases. 

We're dealing with a real entity. It does happen. And this is what we're trying to avoid with finding early cardiac toxicity and cardio protecting these patients. So, what happens to trastuzumab? So we've talked about anthracyclines, type one toxicity. Type two toxicity, the majority is due to trastuzumab used for breast cancer patients and esophageal cancer patients. And in this nice slide, courtesy of Stephen Ewer, more than 10,000 patients and around 11% had a drop of EF of greater than 10 percent. 

The nice thing about trastuzumab, it's irreversible while anthracycline is nonreversible. These patients, around 2.5 percent, went to Class III and Class IV heart failure, but around 11% had cardiac toxicity. And this is what's happening. More malignant than cancer is the five year survival following your first admission for heart failure after chemotherapy, and this is particular in breast cancer patients. 

CASE ANALYSIS – WHY A NORMAL EF CAN BE MISLEADING

So let's look at another case. This is 62-year-old male that came with a new diagnosis of lymphoma. Past medical history of hypertension, diabetes. Physical exam was unremarkable. If I show you the same cut as the first patient I showed you, you can see that this is a happier ventricle. The doughnut is contracting better. And this patient had normal EF, and as well on this four chamber view, you can see it contracting better. 

If we were to do a biopsy on these patients with normal EF, this was done some years ago, even sometimes left ventricular biopsy, even though the majority of the time we do RV biopsy, if we were to grade what we find in the pathology slide from grade 2 to grade 3 being where we see apoptosis, the generation of the myocytes of normal interstitium to grade 2, 2.5 or 3, if we were to do serial imaging in these patients, we will find in this pathology slide replacement fibrosis. 

And if we were to look at the MUGA scan and the echocardiogram in these patients, the EF is normal. So, besides that the EF is normal, I showed you the pathology slides where there is already abnormalities in the interstitium. There is fibrosis, and this is what takes the patient down the path of cardiac toxicity and development of heart failure. And this is more pronounced with anthracyclines. 

WHAT IS ADVANCED CARDIAC IMAGING?

So, this is where we come with the concept of advanced cardiac imaging, and this is the same case I showed you before. If I were to show you now something called strain imaging, this is just for showing purposes, but you can see the beautiful three curves in the top left, top right and bottom left. And then the nice bull's eye at the bottom right, where you can see it all red. All the values are normal. 

And with this technique, what we do is we cut the left ventricle in 16 pieces, and we measured the deformation of each piece. And then we can, with that, define what it is. In this patient in particular, we had to the left of the screen that baseline and to the right of the screen what happened three months after therapy. And comparing the two bull's eyes, the right one is very abnormal. And this patient had a normal EF, but the strain was abnormal. 

With this, we introduce the concept of strain imaging in these patients. And what I want you to be confident is in the lab that you're sending these patients for their echocardiogram, that they can do strain imaging well. And I thought I could just use this systematic review where we have different types of strain compared with sensitivity and specificity. 

This is more or less the same scenario that I showed you before. A patient comes a baseline to your left, normal strain. First follow up, abnormal with normal EF. Second follow up, abnormal strain, abnormal EF, but nothing was done. And this is to look at sensitivity and specificity. 

HOW GLS WILL HELP YOU SAVE YOUR CANCER SURVIVOR PATIENT

So, in this systematic review, they looked at different changes in global longitudinal strain with different sensitivities and specificities. In this case, above 75% sensitivity and specificity, which could help to diagnose cardiac toxicity. So, we're using this method. In patients with normal EF, when it is abnormal, it can tell you down the road when the EF is going to drop by greater than 10 points, either to a value of less than 53% or less than 50. 

And you can see the different combinations of strain and in some cases with troponin as well because these patients, as they change their contractility, despite that the EV is still normal, they can leak troponin, and that's telling you that the myocardium is being injured. And this as well with two different authors, same thing, same scenario. Different cutoff values of GLS, global longitudinal strain, with troponin or without, and you can see the sensitivity and specificities all around from top to bottom. 

And again, other two authors with same scenario. So, what this is telling us is, hey, we can probably be proactive. We'll image our patients, we'll follow them with echocardiography, but we have a tool now that can tell us when that myocardium is suffering, and we can be proactive after it. 

WHY THE TIMING OF THE EF DROP IS CRITICAL

This is one of our studies with breast cancer patients that received anthracyclines and trastuzumab. It showed EF that dropped at the end of T2, but during T1 in the different colors; green, yellow or orange, we can see different types of strain will change and could tell us that the EF was going to drop. This was more or less the sensitivity and specificity with the area under the curve. 

So, same scenario. We have different authors, we have our own data as well, showing that this method is reliable as long as it is done in a good echocardiographic laboratory. And this is with lymphoma patients. These were followed for more than one year. After one year, the EF droped, but before one year, at six months and nine months, we could see this signal either by global longitudinal strain or other types of strain that the cardiotoxicity was going to happen. 

THE 2 TYPES OF CARDIAC TOXICITY

What is the appropriate monitoring for these patients? There are some nice guidelines that were published in 2014 for this that I will encourage you to look at, and this is what happened. So there's two types of cardiac toxicity. Type one in the main scenario here is with chemotherapy related to anthracyclines, the doxorubicin, the epirubicin, et cetera, as well as the mitoxantrone. These patients have irreversible damage to their myocardium, so we have to be very careful when they're administered to be able to monitor them appropriately to avoid cardiac toxicity.

And here we have type two cardiotoxicity. The main chemotherapy agent here is trastuzumab, but here we also have the tyrosine kinase inhibitors and monoclonal antibodies, which the majority of them either finish in MAB, monoclonal antibody, or NIB or VEGF inhibitors that we're using more and more in lung cancer, melanomas, et cetera. So, type two toxicity, which is reversible in the majority of the patients. 

CLINICAL JUDGEMENT AND RISK FACTORS OF CARDIAC TOXICITY

We also have to use our clinical judgment, and our best clinical judgment in these patients is the risk factors. For anthracycline induced cardiotoxicity, we looked at the type of anthracycline, doxorubicin; the total dose, it's greater than 200 mg per meter squared, yes or no, and I'll show you the algorithm later; the type of administration, continuous infusion or not; if the patient is having concomitant radiotherapy; and the risk factors on the right; age, very young age, younger than 15 or older than 65; female gender; pre-existing coronary disease or any cardiovascular risk factors as diabetes, hypertension, hyperlipidemia. And definitely also African-Americans are at higher risk for developing cardiac toxicity. 

REGIMENS FOR TYPE 1 TOXICITY

So, for type one toxicity, we begin with a baseline echocardiography with 3D ejection fraction preferred, but you will just use whatever ejection fraction is the most frequently used in the laboratory where you are referring the patient. Strain imaging and troponin. If the EF is greater than 53%, and the value of global longitudinal strain is normal, and the troponins are negative, you do a follow up echocardiogram after the completion of therapy and six months after. 

If the patient gets to the maximum of 240 mg per meter squared of anthracycline, and he's continuing to receive this chemotherapy, like sarcoma patients or some breast cancer patients that had a previous lymphoma, or the other way around, lymphoma patients that are now having breast cancer, every 50 mg per meter squared you have to follow this algorithm. Or, if the EF is less than 53%, there is a drop in global longitudinal strain or the troponins are positive, we should suggest a cardio-oncology consultation or cardiology consultation if you don't have a cardio oncologist next to you. 

So what happens if the patient is receiving anthracyclines and now he's going to have trastuzumab? So, this is type one toxicity with the initiation of trastuzumab. We do a baseline echocardiogram again. If the value of the EF is above 53%, and the troponins are normal, and the GLS is normal, we follow up every three months during therapy and six months after. If there is a drop in EF or drop in GLS or positive troponin, cardio-oncology consultation. 

REGIMEN FOR TYPE 2 TOXICITY

What happens with type two toxicity? So, type two toxicity, as I said before, trastuzumab, all the tyrosine kinase inhibitors, VGEFs, so all these monoclonal antibodies as well that are getting more and more used for lung cancer, melanoma, et cetera. So, we do baseline echocardiogram with EF, GLS, or global longitudinal strain appropriately and troponins; and, if the EF is normal, the troponins are negative, and the longitudinal strain is normal, we do follow up after one month with TKIs and VEGFs and then every three months during therapy. 

But, if the EF is abnormal, there is abnormal longitudinal strain or positive troponins, again, cardio-oncology consultation. And here, for trastuzumab, we also take into account other risk factors that can potentiate its toxicity to the heart like prior chest radiation or that the patient had anthracyclines before, as well as age, older age, hypertension, diabetes, coronary disease, cardiomyopathy of any sort, or arrhythmias. 

So, once we initiate trastuzumab, again going through the algorithm, we do the baseline echocardiogram. If EF is normal, there's no troponin or GLS is normal, we do follow up after three months, and then, if the patient continues with trastuzumab every three months, or if there is abnormal EF, dropped to 53 or less than 50 if you want to follow the Europeans, with abnormal GLS or troponin, we do a cardio-oncology consultation. 

HOW DO WE DO EARLY DETECTION OF SUBCLINICAL LV DYSFUNCTION? 

If there's a drop of 10 points of the EF to less than 53 or less than 50, we name this chemotherapy-related cardiac toxicity. If there is a relative drop of the GLS as compared to baseline, if it's less than eight percent, there's no evidence of cardiac toxicity. But if we were going to use the GLS only, if there's a change in three percent, three absolute percent value, then there is subclinical dysfunction. And with this, we have to follow the algorithm that I'll show you at the end. We need to cardio protect the patient because the patient can develop a drop of EF later. 

THE MAYO CLINIC PREDICTION MODEL

This is a major risk prediction model that we published some years ago using the medication related risk and the patient-related risk factors. And depending on the medication that I let you read on your own pace, you get a risk, either a score of four, mainly with anthracycline, score of two or of one. And related to the risk factors, you get one point for each. When you get more than six points, the patient is at very high risk of developing cardiotoxicity, five to six high, three to four intermediate, one to two low, and zero, obviously, very low. 

So, you can use this Mayo Risk Prediction Model to decide, if you don't have a reliable lab to send for a global longitudinal strain and just for EF, you can probably cardioprotect the patients early with this. But the thing here is that your number necessary to treat is 100d percent. 

And actually, the Spanish did this study. They said, “Let's don't do any longitudinal strain. Just put everybody on lisinopril or carvedilol.” Well, they showed that it was good in 120 patients that they followed for a year, but again, you had to follow, you have to do it in 100 patients, 100% of the patients. 

With the tailored approach using longitudinal strain, you're probably going to use it in 15% of patients only, so you can save all that medication for other patients. 

CONCLUDING SUMMARY

So, in conclusion, evaluate the patient early before starting treatment, don't forget about the risk factors, previous history of chemotherapy or radiotherapy if this is their second cancer or not. Work together integrative team with your cardiologist and echocardiographers, your cardio-oncology team. Remember that cancer patients and cardiovascular disease share the same risk factors, so we have to protect them as well. And echocardiography, there definitely is a one-stop shop that can provide all the information needed, like basic imaging and advanced imaging, if possible.