How should we deal with cardiotoxicity caused by immunotherapy?

Editor：Cheng Zhan

Immune checkpoint inhibitor therapy is hailed as the breaker of the cancer treatment dilemma,but the toxicity caused by immunotherapy cannot be ignored, especially some fatal adverse reactions, such as immune myocarditis caused by immunotherapy.This journal specially invited Dr. Bettina Heidecker from the Benjamin Franklin Campus of the Charité School of Medicine to conduct in-depth discussions on related issues.

International Circulation: In recent years, Onco-cardiology has become a new interdisciplinary subject. According to the results of corresponding studies, please talk about the prevalence of cardiovascular disease in patients with common malignancies?

Bettina Heidecker：It's actually an important topic. Cardiovascular disease is very common in patients with cancer and any types of malignancies. And cardiovascular disease contributes a relevant part to mortality in patients with cancer. We see that about 13% of all cancer patients have at least one cardiovascular risk factor—and 5 % have cardiovascular disease. We see that the risk for mortality is increased, in particular, with heart failure where the hazard ratio is about 1.8, and with prior myocardial infarction, it's 1.5. And then there are other risk factors like atrial fibrillation.

 Hyperlipidemia is less of a risk factor, but the first few that I mentioned are very relevant. And because of that, actually, cardiology becomes a relevant part in oncology and there is actually a change in thinking about how we should treat cardiovascular disease, even in patients with advanced cancer. While we were less aggressive in the past, because it's so frequently a cause for mortality that the trend is to become more aggressive with treatment of those patients—even with ICD. So the threshold for ICD is getting lower, and also, the one for mechanical circulatory support.

 International Circulation: How do you think about the potential mechanisms for the high prevalence of cardiovascular disease in cancer patients?

Bettina Heidecker:So one important very much talked about topic is checkpoint inhibitors in those with myocarditis, so there we understand the mechanism already very well. The checkpoint inhibitors cause a double inhibition of the immune system so the immune system becomes very aggressive and also attacks cell tissue. So the patients get myocarditis . But then there are other consequences of cancer itself.

 So there’s a lot of research on how cancer itself can cause damage to the heart. We observe this in the clinic all of the time. I had a case, a patient who actually had renal cell carcinoma, and he had an ejection fraction of 15%. And initially, surgeons held off surgery and we all decided it would cause more risk than potential benefit to surgery. We were very concerned that the patient would die during surgery. On the patient's wishes, and also, because there were not really better options, ultimately, the risk was taken to do the surgery. And actually, after surgery the patient finally improved with his ejection fraction to 45%—so doubled after removing the tumor. So there's definitely evidence—not just from this one case—that the tumor itself can cause damage to the heart. And there's a lot of research in that area.

 And then, of course, side effects of treatments. We know radiation can cause coronary artery disease, pulmonary fibrosis as a consequence, pulmonary hypertension, right heart failure. We can get constrictive pericarditis from radiation; cachexia due to the cancer can cause heart failure; the cytokines of the tumor probably do something to the heart that's harmful; and of course the drugs—like Adriamycin—that are known to have direct cardio toxicity. And—sorry, let me add—often we see arrhythmias in those patients, and I think the mechanism is remodeling through radiation and toxins from chemotherapy.

 International Circulation: Immunotherapy has become an important mean of tumor therapy, but at the same time,we should pay great attention to immune-related toxicity,especially cardiotoxicity which is the most difficult. Would you please share us how to better monitor and manage adverse immune reactions?

Bettina Heidecker：We did publish in 2017, when checkpoint inhibitor induced myocarditis started to become a relevant topic in the literature. We did publish in an editorial for Oncotarget,together with my colleague Karina Bruestle, who is now at New York Columbia University,an algorithm on how we suggest patients with checkpoint inhibitor induced treatment, checkpoint inhibitor therapy should be followed.

 We recommend, at baseline, an EKG and echocardiogram—ideally with strain analysis because this is more sensitive in detecting dysfunction than just getting the ejection fraction and troponins—and then repeating this every 2 to 3 weeks. And then if you see signs that the troponins go up, then the patient needs to be evaluated for myocarditis. And one way would be an MRI. If you ever have a suspicion for checkpoint inhibitor induced myocarditis, you should do a biopsy.

 There's actually a case report from UCLA that was just published, and you see heart failure—which I also presented in my talk at ESMO—where it showed that the biopsy was more sensitive than the MRI, and the findings of myocarditis were only showing up late in the course after the biopsy was already positive. And to manage the adverse immune reactions—already in 2017—we suggested, in the algorithm based on the current case reporting case series, to use steroids. That’s still the main therapy and that's in agreement with the guidelines of the American Society of Oncology and, also, of the American Heart Association.

International Circulation: In your opinion, what should we do for the primary prevention of cardiovascular disease in cancer patients?

Bettina Heidecker：If a patient undergoes therapy that could be cardiotoxic, they should definitely see a cardiologist beforehand. That’s also now a clear recommendation in the new guidelines of the European Society of Cardiology. They should get a screening with echocardiogram, and again, ideally, with strain analysis. And if there are any signs of cardiomyopathy—even if the ejection fraction is not decreased yet—preventatively, I would recommend giving beta blockers and ACE inhibitors, at least at a low dose if the patient will have cardiotoxic chemotherapy. And then follow up every three months and then work with the oncologist together to see if chemotherapy will have to be reduced if the ejection fraction goes down or strain shows worsening.